TY - JOUR A1 - Zirafi, Onofrio A1 - Kim, Kyeong-Ae A1 - Ständker, Ludger A1 - Mohr, Katharina B. A1 - Sauter, Daniel A1 - Heigele, Anke A1 - Kluge, Silvia F. A1 - Wiercinska, Eliza A1 - Chudziak, Doreen A1 - Richter, Rudolf A1 - Möpps, Barbara A1 - Gierschik, Peter A1 - Vas, Virag A1 - Geiger, Hartmut A1 - Lamla, Markus A1 - Weil, Tanja A1 - Burster, Timo A1 - Zgraja, Andreas A1 - Daubeuf, Francois A1 - Frossard, Nelly A1 - Hachet-Haas, Muriel A1 - Heunisch, Fabian A1 - Reichetzeder, Christoph A1 - Galzi, Jean-Luc A1 - Perez-Castells, Javier A1 - Canales-Mayordomo, Angeles A1 - Jimenez-Barbero, Jesus A1 - Gimenez-Gallego, Guillermo A1 - Schneider, Marion A1 - Shorter, James A1 - Telenti, Amalio A1 - Hocher, Berthold A1 - Forssmann, Wolf-Georg A1 - Bonig, Halvard A1 - Kirchhoff, Frank A1 - Münch, Jan T1 - Discovery and Characterization of an Endogenous CXCR4 Antagonist JF - Cell reports N2 - CXCL12-CXCR4 signaling controls multiple physiological processes and its dysregulation is associated with cancers and inflammatory diseases. To discover as-yet-unknown endogenous ligands of CXCR4, we screened a blood-derived peptide library for inhibitors of CXCR4-tropic HIV-1 strains. This approach identified a 16 amino acid fragment of serum albumin as an effective and highly specific CXCR4 antagonist. The endogenous peptide, termed EPI-X4, is evolutionarily conserved and generated from the highly abundant albumin precursor by pH-regulated proteases. EPI-X4 forms an unusual lasso-like structure and antagonizes CXCL12-induced tumor cell migration, mobilizes stem cells, and suppresses inflammatory responses in mice. Furthermore, the peptide is abundant in the urine of patients with inflammatory kidney diseases and may serve as a biomarker. Our results identify EPI-X4 as a key regulator of CXCR4 signaling and introduce proteolysis of an abundant precursor protein as an alternative concept for chemokine receptor regulation. Y1 - 2015 U6 - https://doi.org/10.1016/j.celrep.2015.03.061 SN - 2211-1247 VL - 11 IS - 5 SP - 737 EP - 747 PB - Cell Press CY - Cambridge ER - TY - JOUR A1 - Zebger-Gong, Hong A1 - Mueller, Dominik A1 - Diercke, Michaela A1 - Haffner, Dieter A1 - Hocher, Berthold A1 - Verberckmoes, Steven A1 - Schmidt, Sven A1 - D'Haese, Patrick C. A1 - Querfeld, Uwe T1 - 1,25-Dihydroxyvitamin D-3-induced aortic calcifications in experimental uremia: up-regulation of osteoblast markers, calcium-transporting proteins and osterix JF - Journal of hypertension N2 - Background and objective Whether treatment with vitamin D receptor activators contributes to cardiovascular disease in patients with chronic kidney disease is a matter of debate. We studied mechanisms involved in vitamin D-related vascular calcifications in vivo and in vitro. Methods Aortic calcifications were induced in subtotally nephrectomized (SNX) rats by treatment with a high dose (0.25 mu g/kg per day) of 1,25-dihydroxyvitamin D-3 (calcitriol) given for 6 weeks. Likewise, primary rat vascular smooth muscle cells (VSMCs) were incubated with calcitriol at concentrations ranging from 10(-11) to 10(-7) mol/l. Immunohistochemistry revealed that the aortic expression of osteopontin, osteocalcin and bone sialoprotein was significantly increased in calcitriol-treated SNX rats compared to untreated SNX controls. In addition, aortic expression of the transient receptor potential vanilloid calcium channel 6 (TRPV6) and calbindin D9k was significantly up-regulated by treatment with calcitriol. Furthermore, calcitriol significantly increased expression of the osteogenic transcription factor osterix. In-vitro studies showed similar results, confirming that these effects could be attributed to treatment with calcitriol. Conclusions High-dose calcitriol treatment induces an osteoblastic phenotype in VSMC both in SNX rats and in vitro, associated with up-regulation of proteins regulating mineralization and calcium transport, and of the osteogenic transcription factor osterix. KW - calbindin D9k KW - calcitriol KW - calcium transport KW - osteoblast KW - osterix KW - TRPV5 KW - TRPV6 KW - vascular calcification Y1 - 2011 U6 - https://doi.org/10.1097/HJH.0b013e328340aa30 SN - 0263-6352 VL - 29 IS - 2 SP - 339 EP - 348 PB - Lippincott Williams & Wilkins CY - Philadelphia ER - TY - JOUR A1 - Yang, Xiaoping A1 - Darko, Kwame Oteng A1 - Huang, Yanjun A1 - He, Caimei A1 - Yang, Huansheng A1 - He, Shanping A1 - Li, Jianzhong A1 - Li, Jian A1 - Hocher, Berthold A1 - Yin, Yulong T1 - Resistant starch regulates gut microbiota BT - structure, biochemistry and cell signalling JF - Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry and pharmacology N2 - Starch is one of the most popular nutritional sources for both human and animals. Due to the variation of its nutritional traits and biochemical specificities, starch has been classified into rapidly digestible, slowly digestible and resistant starch. Resistant starch has its own unique chemical structure, and various forms of resistant starch are commercially available. It has been found being a multiple-functional regulator for treating metabolic dysfunction. Different functions of resistant starch such as modulation of the gut microbiota, gut peptides, circulating growth factors, circulating inflammatory mediators have been characterized by animal studies and clinical trials. In this mini-review, recent remarkable progress in resistant starch on gut microbiota, particularly the effect of structure, biochemistry and cell signaling on nutrition has been summarized, with highlights on its regulatory effect on gut microbiota. KW - Resistant starch KW - Gut microbiota KW - Nutrition Y1 - 2017 U6 - https://doi.org/10.1159/000477386 SN - 1015-8987 SN - 1421-9778 VL - 42 IS - 1 SP - 306 EP - 318 PB - Karger CY - Basel ER - TY - JOUR A1 - Yang, Fang A1 - Lai, Xinlong A1 - Deng, Li A1 - Liu, Xiaoxiao A1 - Li, Jian A1 - Zeng, Shuixiu A1 - Zhang, Cheng A1 - Hocher, Carl-Friedrich A1 - Hocher, Berthold T1 - Association of endothelin-1 gene polymorphisms with the clinical phenotype in primary nephrotic syndrome of children JF - Life sciences : molecular, cellular and functional basis of therapy N2 - Aims:This study aims to investigate the relationship between plasma endothelin-1 (ET-1) concentrations, ET-1 gene polymorphisms in loci rs5370, rs1630736, 3A/4A and clinical features of primary nephrotic syndrome (NS) in children. Materials and methods: Thirty-six children with primary NS were selected as case group, and 94 healthy children were selected as control group. All subjects were genotyped for three single nucleotide polymorphisms (SNPs) (rs5370, rs10478694 [3A4A) and rs 1630736) in the ET-1 gene by gene sequencing. The plasma ET-1 concentrations were measured using a radio-immunoassay. Key findings: Plasma ET-1 concentrations were higher in NS patients (P = 0.007) as compared to healthy children. The allele frequencies between control and NS patients were significantly different only with respect to the rs10478694 SNP of the ET-1 gene. The allele frequencies between control and NS patients for the rs5370 SNP showed a trend towards difference (P = 0.057). Plasma cholesterol in NS patients is associated with both: the Cl genotype in locus rs5370 and the 3A4A genotype in locus rs10478694 (P < 0.05 in both cases). Significance: The ET systems might play a disease modifying role in pediatric NS. Plasma cholesterol, a hallmark of NS. seems to be associated with genetic variations within the human ET-1 gene. (C) 2014 Elsevier Inc. All rights reserved. KW - Endothelin-1 KW - Gene polymorphism KW - Childhood nephrotic syndrome KW - Cholesterol Y1 - 2014 U6 - https://doi.org/10.1016/j.lfs.2014.04.010 SN - 0024-3205 SN - 1879-0631 VL - 118 IS - 2 SP - 446 EP - 450 PB - Elsevier CY - Oxford ER - TY - JOUR A1 - Xu, Mei A1 - Lu, Yong-Ping A1 - Hasan, Ahmed A. A1 - Hocher, Berthold T1 - Plasma ET-1 concentrations are elevated in patients with hypertension meta-analysis of clinical studies JF - Kidney & blood pressure research : official organ of the Gesellschaft für Nephrologie ; official organ of the Deutsche Liga zur Bekämpfung des Hohen Blutdruckes e.V., Deutsche Hypertonie-Gesellschaft N2 - Background/Aims: A recent study revealed that global overexpression of ET-1 causes a slight reduction in systemic blood pressure. Moreover, heterozygous ET-1 knockout mice are hypertensive. The role of ET-1 in human hypertension was so far not addressed by a strict meta-analysis of published human clinical studies. Methods: We included studies published between January 1, 1990 and February 28, 2017. We included case control studies analyzing untreated essential hypertension or hypertensive patients where antihypertensive medication was discontinued for at least two weeks. Based on the principle of Cochrane systematic reviews, case control studies (CCSs) in PubMed (Medline) and Google Scholar designed to identify the role of endothelin-1 (ET-1) in the pathophysiological of hypertension were screened. Review Manager Version 5.0 (Rev-Man 5.0) was applied for statistical analysis. Mean difference and 95% confidence interval (CI) were shown in inverse variance (IV) fixed-effects model or IV random-effects models. Results: Eleven studies fulfilling our in-and exclusion criteria were eligible for this meta-analysis. These studies included 450 hypertensive patients and 328 controls. Our meta-analysis revealed that ET-1 plasma concentrations were higher in hypertensive patients as compared to the control patients [mean difference between groups 1.57 pg/mL, 95%Ci [0.47 similar to 2.68, P = 0.005]. These finding were driven by patients having systolic blood pressure higher than 160 mmHg and diastolic blood pressure higher than 100 mmHg. Conclusions: This meta-analysis showed that hypertensive patients do have elevated plasma ET-1 concentrations. This finding is driven by those patients with high systolic/diastolic blood pressure. Given that the ET-1 gene did not appear in any of the whole genome association studies searching for hypertension associated gene loci, it is very likely that the elevated plasma ET-1 concentrations in hypertensive patients are secondary to hypertension and may reflect endothelial cell damage. KW - Hypertension KW - ET-1 KW - Meta-analysis Y1 - 2017 U6 - https://doi.org/10.1159/000477572 SN - 1420-4096 SN - 1423-0143 VL - 42 IS - 2 SP - 304 EP - 313 PB - Karger CY - Basel ER - TY - JOUR A1 - Xiong, Yingquan A1 - Delic, Denis A1 - Zeng, Shufei A1 - Chen, Xin A1 - Chu, Chang A1 - Hasan, Ahmed A. A1 - Krämer, Bernhard K. A1 - Klein, Thomas A1 - Yin, Lianghong A1 - Hocher, Berthold T1 - Regulation of SARS CoV-2 host factors in the kidney and heart in rats with 5/6 nephrectomy-effects of salt, ARB, DPP4 inhibitor and SGLT2 blocker JF - BMC nephrology N2 - Background Host factors such as angiotensin-converting enzyme 2 (ACE2) and the transmembrane protease, serine-subtype-2 (TMPRSS2) are important factors for SARS-CoV-2 infection. Clinical and pre-clinical studies demonstrated that RAAS-blocking agents can be safely used during a SARS-CoV-2 infection but it is unknown if DPP-4 inhibitors or SGLT2-blockers may promote COVID-19 by increasing the host viral entry enzymes ACE2 and TMPRSS2. Methods We investigated telmisartan, linagliptin and empagliflozin induced effects on renal and cardiac expression of ACE2, TMPRSS2 and key enzymes involved in RAAS (REN, AGTR2, AGT) under high-salt conditions in a non-diabetic experimental 5/6 nephrectomy (5/6 Nx) model. In the present study, the gene expression of Ace2, Tmprss2, Ren, Agtr2 and Agt was assessed with qRT-PCR and the protein expression of ACE2 and TMPRSS2 with immunohistochemistry in the following experimental groups: Sham + normal diet (ND) + placebo (PBO); 5/6Nx + ND + PBO; 5/6Nx + high salt-diet (HSD) + PBO; 5/6Nx + HSD + telmisartan; 5/6Nx + HSD + linagliptin; 5/6Nx + HSD + empagliflozin. Results In the kidney, the expression of Ace2 was not altered on mRNA level under disease and treatment conditions. The renal TMPRSS2 levels (mRNA and protein) were not affected, whereas the cardiac level was significantly increased in 5/6Nx rats. Intriguingly, the elevated TMPRSS2 protein expression in the heart was significantly normalized after treatment with telmisartan, linagliptin and empagliflozin. Conclusions Our study indicated that there is no upregulation regarding host factors potentially promoting SARS-CoV-2 virus entry into host cells when the SGLT2-blocker empagliflozin, telmisartan and the DPP4-inhibitor blocker linagliptin are used. The results obtained in a preclinical, experimental non-diabetic kidney failure model need confirmation in ongoing interventional clinical trials. KW - SARS CoV-2 host factors KW - 5/6 nephrectomy KW - High-salt diet KW - ARB KW - DPP4 inhibitor KW - SGLT2 blocker Y1 - 2022 U6 - https://doi.org/10.1186/s12882-022-02747-1 SN - 1471-2369 VL - 23 IS - 1 PB - Springer Nature CY - London ER - TY - JOUR A1 - Wengenmayer, Christina A1 - Krikov, Maxim A1 - Mueller, Susanne A1 - Lucht, Kristin A1 - Villringer, Arno A1 - Hocher, Berthold A1 - Unger, Thomas A1 - Thoene-Reineke, Christa T1 - Novel therapy approach in primary stroke prevention simultaneous inhibition of endothelin converting enzyme and neutral endopeptidase in spontaneously hypertensive, stroke-prone rats improves survival JF - Neurological research : a journal of progress in neurosurgery and neurosciences N2 - Objectives: Stroke, frequently a consequence of hypertension, is one of the leading causes of death and neurological disabilities worldwide. In the ischemic brain, levels of endothelin-1, one of the most potent vasoconstrictors, are raised. Anti-inflammatory and neuroprotective effects of endothelin antagonists after stroke have been described in literature. Based on these findings, we investigated the protective effect of the endothelin converting enzyme/neutral endopeptidase blocker, SLV 338, in salt-loaded, stroke-prone, spontaneously hypertensive rats. Methods: Male, 8-week-old spontaneously hypertensive stroke-prone rats were put on a high salt diet and treated with either 30 mg/kg or 100 mg/kg SLV 338 or vehicle for 27 weeks. Blood pressure, neurological outcome, body weight, and mortality were investigated throughout treatment. In weeks 1 and 9, animals were housed in metabolic cages for collection of urinary and blood samples and assessment of salt water and food intake. In weeks 22 and 27, additional blood samples were taken. At the end of the study, all brains were analyzed using magnetic resonance imaging. Results: SLV 338 was well tolerated in all animals. Neurological outcome and infarct size were similar in all groups. Albuminuria was considerably delayed and the incidence of stroke significantly lowered in treated animals. In spontaneously hypertensive stroke-prone rats, treatment with SLV 338 significantly (P=0.01) improved survival in comparison to the vehicle treated group in a blood pressure-independent manner. Discussion: Our data in spontaneously hypertensive stroke-prone rats demonstrate that combined endothelin converting enzyme/neutral endopeptidase inhibition could offer a new therapeutic approach for primary stroke prevention and improvement of mortality. The mechanism seems to be blood pressure-independent. KW - Endothelin KW - Hypertension KW - Natriuretic peptides KW - Stroke Y1 - 2011 U6 - https://doi.org/10.1179/016164111X12881719352534 SN - 0161-6412 VL - 33 IS - 2 SP - 201 EP - 207 PB - Routledge, Taylor & Francis Group CY - Leeds ER - TY - JOUR A1 - Warrington, Nicole A1 - Beaumont, Robin A1 - Horikoshi, Momoko A1 - Day, Felix R. A1 - Helgeland, Øyvind A1 - Laurin, Charles A1 - Bacelis, Jonas A1 - Peng, Shouneng A1 - Hao, Ke A1 - Feenstra, Bjarke A1 - Wood, Andrew R. A1 - Mahajan, Anubha A1 - Tyrrell, Jessica A1 - Robertson, Neil R. A1 - Rayner, N. William A1 - Qiao, Zhen A1 - Moen, Gunn-Helen A1 - Vaudel, Marc A1 - Marsit, Carmen A1 - Chen, Jia A1 - Nodzenski, Michael A1 - Schnurr, Theresia M. A1 - Zafarmand, Mohammad Hadi A1 - Bradfield, Jonathan P. A1 - Grarup, Niels A1 - Kooijman, Marjolein N. A1 - Li-Gao, Ruifang A1 - Geller, Frank A1 - Ahluwalia, Tarunveer Singh A1 - Paternoster, Lavinia A1 - Rueedi, Rico A1 - Huikari, Ville A1 - Hottenga, Jouke-Jan A1 - Lyytikäinen, Leo-Pekka A1 - Cavadino, Alana A1 - Metrustry, Sarah A1 - Cousminer, Diana L. A1 - Wu, Ying A1 - Thiering, Elisabeth Paula A1 - Wang, Carol A. A1 - Have, Christian Theil A1 - Vilor-Tejedor, Natalia A1 - Joshi, Peter K. A1 - Painter, Jodie N. A1 - Ntalla, Ioanna A1 - Myhre, Ronny A1 - Pitkänen, Niina A1 - van Leeuwen, Elisabeth M. A1 - Joro, Raimo A1 - Lagou, Vasiliki A1 - Richmond, Rebecca C. A1 - Espinosa, Ana A1 - Barton, Sheila J. A1 - Inskip, Hazel M. A1 - Holloway, John W. A1 - Santa-Marina, Loreto A1 - Estivill, Xavier A1 - Ang, Wei A1 - Marsh, Julie A. A1 - Reichetzeder, Christoph A1 - Marullo, Letizia A1 - Hocher, Berthold A1 - Lunetta, Kathryn L. A1 - Murabito, Joanne M. A1 - Relton, Caroline L. A1 - Kogevinas, Manolis A1 - Chatzi, Leda A1 - Allard, Catherine A1 - Bouchard, Luigi A1 - Hivert, Marie-France A1 - Zhang, Ge A1 - Muglia, Louis J. A1 - Heikkinen, Jani A1 - Morgen, Camilla S. A1 - van Kampen, Antoine H. C. A1 - van Schaik, Barbera D. C. A1 - Mentch, Frank D. A1 - Langenberg, Claudia A1 - Scott, Robert A. A1 - Zhao, Jing Hua A1 - Hemani, Gibran A1 - Ring, Susan M. A1 - Bennett, Amanda J. A1 - Gaulton, Kyle J. A1 - Fernandez-Tajes, Juan A1 - van Zuydam, Natalie R. A1 - Medina-Gomez, Carolina A1 - de Haan, Hugoline G. A1 - Rosendaal, Frits R. A1 - Kutalik, Zoltán A1 - Marques-Vidal, Pedro A1 - Das, Shikta A1 - Willemsen, Gonneke A1 - Mbarek, Hamdi A1 - Müller-Nurasyid, Martina A1 - Standl, Marie A1 - Appel, Emil V. R. A1 - Fonvig, Cilius Esmann A1 - Trier, Caecilie A1 - van Beijsterveldt, Catharina E. M. A1 - Murcia, Mario A1 - Bustamante, Mariona A1 - Bonàs-Guarch, Sílvia A1 - Hougaard, David M. A1 - Mercader, Josep M. A1 - Linneberg, Allan A1 - Schraut, Katharina E. A1 - Lind, Penelope A. A1 - Medland, Sarah Elizabeth A1 - Shields, Beverley M. A1 - Knight, Bridget A. A1 - Chai, Jin-Fang A1 - Panoutsopoulou, Kalliope A1 - Bartels, Meike A1 - Sánchez, Friman A1 - Stokholm, Jakob A1 - Torrents, David A1 - Vinding, Rebecca K. A1 - Willems, Sara M. A1 - Atalay, Mustafa A1 - Chawes, Bo L. A1 - Kovacs, Peter A1 - Prokopenko, Inga A1 - Tuke, Marcus A. A1 - Yaghootkar, Hanieh A1 - Ruth, Katherine S. A1 - Jones, Samuel E. A1 - Loh, Po-Ru A1 - Murray, Anna A1 - Weedon, Michael N. A1 - Tönjes, Anke A1 - Stumvoll, Michael A1 - Michaelsen, Kim Fleischer A1 - Eloranta, Aino-Maija A1 - Lakka, Timo A. A1 - van Duijn, Cornelia M. A1 - Kiess, Wieland A1 - Koerner, Antje A1 - Niinikoski, Harri A1 - Pahkala, Katja A1 - Raitakari, Olli T. A1 - Jacobsson, Bo A1 - Zeggini, Eleftheria A1 - Dedoussis, George V. A1 - Teo, Yik-Ying A1 - Saw, Seang-Mei A1 - Montgomery, Grant W. A1 - Campbell, Harry A1 - Wilson, James F. A1 - Vrijkotte, Tanja G. M. A1 - Vrijheid, Martine A1 - de Geus, Eco J. C. N. A1 - Hayes, M. Geoffrey A1 - Kadarmideen, Haja N. A1 - Holm, Jens-Christian A1 - Beilin, Lawrence J. A1 - Pennell, Craig E. A1 - Heinrich, Joachim A1 - Adair, Linda S. A1 - Borja, Judith B. A1 - Mohlke, Karen L. A1 - Eriksson, Johan G. A1 - Widen, Elisabeth E. A1 - Hattersley, Andrew T. A1 - Spector, Tim D. A1 - Kaehoenen, Mika A1 - Viikari, Jorma S. A1 - Lehtimaeki, Terho A1 - Boomsma, Dorret I. A1 - Sebert, Sylvain A1 - Vollenweider, Peter A1 - Sorensen, Thorkild I. A. A1 - Bisgaard, Hans A1 - Bonnelykke, Klaus A1 - Murray, Jeffrey C. A1 - Melbye, Mads A1 - Nohr, Ellen A. A1 - Mook-Kanamori, Dennis O. A1 - Rivadeneira, Fernando A1 - Hofman, Albert A1 - Felix, Janine F. A1 - Jaddoe, Vincent W. V. A1 - Hansen, Torben A1 - Pisinger, Charlotta A1 - Vaag, Allan A. A1 - Pedersen, Oluf A1 - Uitterlinden, Andre G. A1 - Jarvelin, Marjo-Riitta A1 - Power, Christine A1 - Hypponen, Elina A1 - Scholtens, Denise M. A1 - Lowe, William L. A1 - Smith, George Davey A1 - Timpson, Nicholas J. A1 - Morris, Andrew P. A1 - Wareham, Nicholas J. A1 - Hakonarson, Hakon A1 - Grant, Struan F. A. A1 - Frayling, Timothy M. A1 - Lawlor, Debbie A. A1 - Njolstad, Pal R. A1 - Johansson, Stefan A1 - Ong, Ken K. A1 - McCarthy, Mark I. A1 - Perry, John R. B. A1 - Evans, David M. A1 - Freathy, Rachel M. T1 - Maternal and fetal genetic effects on birth weight and their relevance to cardio-metabolic risk factors JF - Nature genetics N2 - Birth weight variation is influenced by fetal and maternal genetic and non-genetic factors, and has been reproducibly associated with future cardio-metabolic health outcomes. In expanded genome-wide association analyses of own birth weight (n = 321,223) and offspring birth weight (n = 230,069 mothers), we identified 190 independent association signals (129 of which are novel). We used structural equation modeling to decompose the contributions of direct fetal and indirect maternal genetic effects, then applied Mendelian randomization to illuminate causal pathways. For example, both indirect maternal and direct fetal genetic effects drive the observational relationship between lower birth weight and higher later blood pressure: maternal blood pressure-raising alleles reduce offspring birth weight, but only direct fetal effects of these alleles, once inherited, increase later offspring blood pressure. Using maternal birth weight-lowering genotypes to proxy for an adverse intrauterine environment provided no evidence that it causally raises offspring blood pressure, indicating that the inverse birth weight-blood pressure association is attributable to genetic effects, and not to intrauterine programming. Y1 - 2019 SN - 1061-4036 SN - 1546-1718 VL - 51 IS - 5 SP - 804 EP - + PB - Nature Publ. Group CY - New York ER - TY - GEN A1 - Wang, Guang A1 - Li, Pei-zhi A1 - Zhang, Shi-yao A1 - Zhong, Shan A1 - Chu, Chang A1 - Zeng, Shufei A1 - Yan, Yu A1 - Cheng, Xin A1 - Chuai, Manli A1 - Hocher, Berthold A1 - Yang, Xuesong T1 - Lipopolysaccharides (LPS) Induced Angiogenesis During Chicken Embryogenesis is Abolished by Combined ETA/ETB Receptor Blockade T2 - Cellular Physiology and Biochemistry N2 - Background/Aims: Angiogenesis plays a key role during embryonic development. The vascular endothelin (ET) system is involved in the regulation of angiogenesis. Lipopolysaccharides (LPS) could induce angiogenesis. The effects of ET blockers on baseline and LPS-stimulated angiogenesis during embryonic development remain unknown so far. Methods: The blood vessel density (BVD) of chorioallantoic membranes (CAMs), which were treated with saline (control), LPS, and/or BQ123 and the ETB blocker BQ788, were quantified and analyzed using an IPP 6.0 image analysis program. Moreover, the expressions of ET-1, ET-2, ET3, ET receptor A (ETRA), ET receptor B (ETRB) and VEGFR2 mRNA during embryogenesis were analyzed by semi-quantitative RT-PCR. Results: All components of the ET system are detectable during chicken embryogenesis. LPS increased angiogenesis substantially. This process was completely blocked by the treatment of a combination of the ETA receptor blockers-BQ123 and the ETB receptor blocker BQ788. This effect was accompanied by a decrease in ETRA, ETRB, and VEGFR2 gene expression. However, the baseline angiogenesis was not affected by combined ETA/ETB receptor blockade. Conclusion: During chicken embryogenesis, the LPS-stimulated angiogenesis, but not baseline angiogenesis, is sensitive to combined ETA/ETB receptor blockade. (C) 2018 The Author(s) Published by S. Karger AG, Basel T3 - Zweitveröffentlichungen der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe - 615 KW - Lipopolysaccharides (LPS) KW - Angiogenesis KW - Chicken chorioallantoic membrane (CAM) KW - Endothelin (ET) Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:kobv:517-opus4-424552 SN - 1866-8372 IS - 615 ER - TY - JOUR A1 - Wang, Guang A1 - Li, Pei-zhi A1 - Zhang, Shi-yao A1 - Zhong, Shan A1 - Chu, Chang A1 - Zeng, Shufei A1 - Yan, Yu A1 - Cheng, Xin A1 - Chuai, Manli A1 - Hocher, Berthold A1 - Yang, Xuesong T1 - Lipopolysaccharides (LPS) Induced Angiogenesis During Chicken Embryogenesis is Abolished by Combined ETA/ETB Receptor Blockade JF - Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry and pharmacology N2 - Background/Aims: Angiogenesis plays a key role during embryonic development. The vascular endothelin (ET) system is involved in the regulation of angiogenesis. Lipopolysaccharides (LPS) could induce angiogenesis. The effects of ET blockers on baseline and LPS-stimulated angiogenesis during embryonic development remain unknown so far. Methods: The blood vessel density (BVD) of chorioallantoic membranes (CAMs), which were treated with saline (control), LPS, and/or BQ123 and the ETB blocker BQ788, were quantified and analyzed using an IPP 6.0 image analysis program. Moreover, the expressions of ET-1, ET-2, ET3, ET receptor A (ETRA), ET receptor B (ETRB) and VEGFR2 mRNA during embryogenesis were analyzed by semi-quantitative RT-PCR. Results: All components of the ET system are detectable during chicken embryogenesis. LPS increased angiogenesis substantially. This process was completely blocked by the treatment of a combination of the ETA receptor blockers-BQ123 and the ETB receptor blocker BQ788. This effect was accompanied by a decrease in ETRA, ETRB, and VEGFR2 gene expression. However, the baseline angiogenesis was not affected by combined ETA/ETB receptor blockade. Conclusion: During chicken embryogenesis, the LPS-stimulated angiogenesis, but not baseline angiogenesis, is sensitive to combined ETA/ETB receptor blockade. KW - Lipopolysaccharides (LPS) KW - Angiogenesis KW - Chicken chorioallantoic membrane (CAM) KW - Endothelin (ET) Y1 - 2018 U6 - https://doi.org/10.1159/000492547 SN - 1015-8987 SN - 1421-9778 VL - 48 IS - 5 SP - 2084 EP - 2090 PB - Karger CY - Basel ER - TY - JOUR A1 - von Websky, Karoline A1 - Reichetzeder, Christoph A1 - Hocher, Berthold T1 - Physiology and pathophysiology of incretins in the kidney JF - Current opinion in nephrology and hypertension : reviews of all advances, evaluations of key references, comprehensive listing of papers N2 - Purpose of reviewIncretin-based therapy with glucagon-like peptide-1 receptor (GLP-1R) agonists and dipeptidyl peptidase-4 (DPP-4) inhibitors is considered a promising therapeutic option for type 2 diabetes mellitus. Cumulative evidence, mainly from preclinical animal studies, reveals that incretin-based therapies also may elicit beneficial effects on kidney function. This review gives an overview of the physiology, pathophysiology, and pharmacology of the renal incretin system.Recent findingsActivation of GLP-1R in the kidney leads to diuretic and natriuretic effects, possibly through direct actions on renal tubular cells and sodium transporters. Moreover, there is evidence that incretin-based therapy reduces albuminuria, glomerulosclerosis, oxidative stress, and fibrosis in the kidney, partially through GLP-1R-independent pathways. Molecular mechanisms by which incretins exert their renal effects are understood incompletely, thus further studies are needed.SummaryThe GLP-1R and DPP-4 are expressed in the kidney in various species. The kidney plays an important role in the excretion of incretin metabolites and most GLP-1R agonists and DPP-4 inhibitors, thus special attention is required when applying incretin-based therapy in renal impairment. Preclinical observations suggest direct renoprotective effects of incretin-based therapies in the setting of hypertension and other disorders of sodium retention, as well as in diabetic and nondiabetic nephropathy. Clinical studies are needed in order to confirm translational relevance from preclinical findings for treatment options of renal diseases. KW - DDP-4 inhibition KW - diabetes KW - diabetic nephropathy KW - GLP-1 receptor KW - hypertension KW - incretins KW - kidney KW - renal impairment Y1 - 2014 U6 - https://doi.org/10.1097/01.mnh.0000437542.77175.a0 SN - 1062-4821 SN - 1473-6543 VL - 23 IS - 1 SP - 54 EP - 60 PB - Lippincott Williams & Wilkins CY - Philadelphia ER - TY - JOUR A1 - von Websky, Karoline A1 - Hasan, Ahmed Abdallah Abdalrahman Mohamed A1 - Reichetzeder, Christoph A1 - Tsuprykov, Oleg A1 - Hocher, Berthold T1 - Impact of vitamin D on pregnancy-related disorders and on offspring outcome JF - The Journal of Steroid Biochemistry and Molecular Biology N2 - Observational studies from all over the world continue to find high prevalence rates of vitamin D insufficiency and deficiency in many populations, including pregnant women. Beyond its classical function as a regulator of calcium and phosphate metabolism, vitamin D elicits numerous effects in the human body. Current evidence highlights a vital role of vitamin D in mammalian gestation. During pregnancy, adaptations in maternal vitamin D metabolism lead to a physiologic increase of vitamin D levels, mainly because of an increased renal production, although other potential sources like the placenta are being discussed. A sufficient supply of mother and child with calcium and vitamin D during pregnancy ensures a healthy bone development of the fetus, whereas lack of either of these nutrients can lead to the development of rickets in the child. Moreover, vitamin D insufficiency during pregnancy has consistently been associated with adverse maternal and neonatal pregnancy outcomes. In multitudinous studies, low maternal vitamin D status was associated with a higher risk for pre-eclampsia, gestational diabetes mellitus and other gestational diseases. Likewise, several negative consequences for the fetus have been reported, including fetal growth restriction, increased risk of preterm birth and a changed susceptibility for later-life diseases. However, study results are diverging and causality has not been proven so far. Meta-analyses on the relationship between maternal vitamin D status and pregnancy outcomes revealed a wide heterogeneity of studied populations and the applied methodology in vitamin D assessment. Until today, clinical guidelines for supplementation cannot be based on high-quality evidence and it is not clear if the required intake for pregnant women differs from non-pregnant women. Long-term safety data of vitamin D supplementation in pregnant women has not been established and overdosing of vitamin D might have unfavorable effects, especially in mothers and newborns with mutations of genes involved in vitamin D metabolism. Reliable data from large observational and interventional randomized control trials are urgently needed as a basis for any detailed and safe recommendations for supplementation in the general population and, most importantly, in pregnant women. This is of utmost importance, as ensuring a sufficient vitamin D-supply of mother and child implies a great potential for the prevention of birth complications and development of diseases. KW - Vitamin D deficiency KW - Free vitamin D KW - Vitamin D binding protein KW - Epigenetics KW - DNA methylation KW - Single nucleotide polymorphism KW - Preeclampsia KW - Gestational diabetes mellitus KW - Small for gestational age KW - Long term health Y1 - 2018 U6 - https://doi.org/10.1016/j.jsbmb.2017.11.008 SN - 0960-0760 VL - 180 SP - 51 EP - 64 PB - Elsevier CY - Oxford ER - TY - JOUR A1 - Vignon-Zellweger, Nicolas A1 - Relle, Katharina A1 - Rahnenfuehrer, Jan A1 - Schwab, Karima A1 - Hocher, Berthold A1 - Theuring, Franz T1 - Endothelin-1 overexpression and endothelial nitric oxide synthase knock-out induce different pathological responses in the heart of male and female mice JF - Life sciences : molecular, cellular and functional basis of therapy N2 - Aims: The nitric oxide and endothelin systems are key components of a local paracrine hormone network in the heart. We previously reported that diastolic dysfunction observed in mice lacking the endothelial nitric oxide synthase (eNOS-/-) can be prevented by a genetic overexpression of ET-1. Sexual dimorphisms have been reported in both ET-1 and NO systems. Particularly, eNOS-/- mice present sex related phenotypic differences. Main methods: We used the ET-1 transgenic (ET+/+), eNOS-/-, and crossbred ET+/+ eNOS-/- mice, and wild type controls. We measured cardiac function by heart catheterization. Cardiac ventricles were collected for histological and molecular profiling. Key findings: We report here that (i) the level of ET-1 expression in eNOS-/- mice was elevated in males but not in females. (ii) Left ventricular end-diastolic blood pressure was higher in male eNOS-/- mice than in females. (ii) eNOS-/- males but not females developed cardiomyocyte hypertrophy. (iv) Perivascular fibrosis of intra-cardiac arteries developed in female ET+/+ and eNOS-/- mice but not in males. Additionally, (v) the cardiac expression of metalloprotease-9 was higher in eNOS-/- males compared to females. Finally, (vi) cardiac proteome analysis revealed that the protein abundance of the oxidative stress related enzyme superoxide dismutase presented with sexual dimorphism in eNOS-/- and ET+/+ mice. Significance: These results indicate that the cardiac phenotypes of ET-1 transgenic mice and eNOS knockout mice are sex specific. Since both systems are key players in the pathogenesis of cardiovascular diseases, our findings might be important in the context of gender differences in patients with such diseases. (C) 2013 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/3.0/). KW - Endothelin-1 KW - Nitric oxide KW - Cardiac function KW - Sexual dimorphism Y1 - 2014 U6 - https://doi.org/10.1016/j.lfs.2013.12.003 SN - 0024-3205 SN - 1879-0631 VL - 118 IS - 2 SP - 219 EP - 225 PB - Elsevier CY - Oxford ER - TY - JOUR A1 - Vignon-Zellweger, Nicolas A1 - Relle, Katharina A1 - Kienlen, Elodie A1 - Alter, Markus L. A1 - Seider, Patrick A1 - Sharkovska, Juliya A1 - Heiden, Susi A1 - Kalk, Philipp A1 - Schwab, Karima A1 - Albrecht-Kuepper, Barbara A1 - Theuring, Franz A1 - Stasch, Johannes-Peter A1 - Hocher, Berthold T1 - Endothelin-1 overexpression restores diastolic function in eNOS knockout mice JF - Journal of hypertension N2 - Background The cardiac nitric oxide and endothelin-1 (ET-1) systems are closely linked and play a critical role in cardiac physiology. The balance between both systems is often disturbed in cardiovascular diseases. To define the cardiac effect of excessive ET-1 in a status of nitric oxide deficiency, we compared left ventricular function and morphology in wild-type mice, ET-1 transgenic (ET+/+) mice, endothelial nitric oxide synthase knockout (eNOS(-/-)) mice, and ET(+/+)eNOS(-/-) mice. Methods and results eNOS(-/-) and ET(+/+)eNOS(-/-) mice developed high blood pressure compared with wild-type and ET+/+ mice. Left ventricular catheterization showed that eNOS(-/-) mice, but not ET(+/+)eNOS(-/-), developed diastolic dysfunction characterized by increased end-diastolic pressure and relaxation constant tau. To elucidate the causal molecular mechanisms driving the rescue of diastolic function in ET(+/+)eNOS(-/-) mice, the cardiac proteome was analyzed. Two-dimensional gel electrophoresis coupled to mass spectrometry offers an appropriate hypothesis-free approach. ET-1 overexpression on an eNOS(-/-) background led to an elevated abundance and change in posttranslational state of antioxidant enzymes (e. g., peroxiredoxin-6, glutathione S-transferase mu 2, and heat shock protein beta 7). In contrast to ET(+/+)eNOS(-/-) mice, eNOS(-/-) mice showed an elevated abundance of proteins responsible for sarcomere disassembly (e. g., cofilin-1 and cofilin-2). In ET(+/+)eNOS(-/-) mice, glycolysis was favored at the expense of fatty acid oxidation. Conclusion eNOS(-/-) mice developed diastolic dysfunction; this was rescued by ET-1 transgenic overexpression. This study furthermore suggests that cardiac ET-1 overexpression in case of eNOS deficiency causes specifically the regulation of proteins playing a role in oxidative stress, myocytes contractility, and energy metabolism. KW - cardiovascular diseases KW - endothelin KW - nitric oxide Y1 - 2011 U6 - https://doi.org/10.1097/HJH.0b013e3283450770 SN - 0263-6352 SN - 1473-5598 VL - 29 IS - 5 SP - 961 EP - 970 PB - Lippincott Williams & Wilkins CY - Philadelphia ER - TY - JOUR A1 - Vignon-Zellweger, Nicolas A1 - Rahnenführer, Jan A1 - Theuring, Franz A1 - Hocher, Berthold T1 - Analysis of cardiac and renal endothelin receptors by in situ hybridization in mice JF - Clinical laboratory : the peer reviewed journal for clinical laboratories and laboratories related to blood transfusion N2 - Background: Endothelin-1 (ET-1) is a multifunctional peptide, which is implicated in the renal and cardiac physicology as well as in many pathologies of these systems. ET-1's actions take place after the activation of two receptors: ETA and ETB. The expression of these receptors may be modulated during the pathologic process. The analysis of the distribution and level of expression of the receptors in animal models is therefore crucial. Methods: We developed a protocol for non-radioactive in situ hybridization for the mRNA of the two endothelin receptors on paraffin-embedded tissue using digoxigenin-labeled RNA probes. Results: In heart and kidney, the staining was reliable and specific. In a mouse model for endothelin/nitric oxide imbalance, cardiac ETB expression was reduced. The distribution of the receptors was in accordance with the actual knowledge. Differences in cell specific expression are discussed. Conclusions: We developed a protocol for the in situ hybridization of the endothelin receptors in mice. Given that the endothelin system is implicated in the development of many diseases, we believe that this protocol may be useful for a number of future preclinical studies. KW - Endothelin-1 KW - endothelin receptors KW - in situ hybridization KW - mouse Y1 - 2012 U6 - https://doi.org/10.7754/Clin.Lab.2012.120216 SN - 1433-6510 VL - 58 IS - 9-10 SP - 939 EP - 949 PB - Clin Lab Publ., Verl. Klinisches Labor CY - Heidelberg ER - TY - JOUR A1 - Vickers, Steven P. A1 - Cheetham, Sharon C. A1 - Birmingham, Gareth D. A1 - Rowley, Helen L. A1 - Headland, Katie R. A1 - Dickinson, Keith A1 - Grempler, Rolf A1 - Hocher, Berthold A1 - Mark, Michael A1 - Klein, Thomas T1 - Effects of the DPP-4 Inhibitor, Linagliptin, in Diet-Induced obese rats a comparison in Naive and Exenatide-Treated Animals JF - Clinical laboratory : the peer reviewed journal for clinical laboratories and laboratories related to blood transfusion N2 - Background: To assess the chronic effect of the DPP-4 inhibitor, linagliptin, alone, in combination with exenatide, and during exenatide withdrawal, in diet-induced obese (DIO) rats. Methods: Female Wistar rats were exposed to a cafeteria diet to induce obesity. Animals were then dosed with vehicle or linagliptin (3 mg/kg PO) orally once-daily for a 28 day period. In a subsequent study, rats received exenatide (either 3 or 30 mu g/kg/day) or vehicle by osmotic mini-pump for 28 days. In addition, groups of animals were dosed orally with linagliptin either alone or in combination with a 3 mu g/kg/day exenatide dose for the study duration. In a final study, rats were administered exenatide (30 mu g/kg/day) or vehicle by osmotic mini-pump for eleven days. Subsequently, exenatide-treated animals were transferred to vehicle or continued exenatide infusion for a further ten days. Animals transferred from exenatide to vehicle were also dosed orally with either vehicle or linagliptin. In all studies, body weight, food and water intake were recorded daily and relevant plasma parameters and carcass composition were determined. Results: In contrast to exenatide, linagliptin did not significantly reduce body weight or carcass fat in DIO rats versus controls. Linagliptin augmented the effect of exenatide to reduce body fat when given in combination but did not affect the body weight response. In rats withdrawn from exenatide, weight regain was observed such that body weight was not significantly different to controls. Linagliptin reduced weight regain after withdrawal of exenatide such that a significant difference from controls was evident. Conclusions: These data demonstrate that linagliptin does not significantly alter body weight in either untreated or exenatide-treated DIO rats, although it delays weight gain after exenatide withdrawal. This finding may suggest the utility of DPP-4 inhibitors in reducing body weight during periods of weight gain. KW - Dipeptidyl peptidase 4 inhibitor KW - Linagliptin KW - obesity KW - weight loss Y1 - 2012 U6 - https://doi.org/10.7754/Clin.Lab.2011.110919 SN - 1433-6510 VL - 58 IS - 7-8 SP - 787 EP - 799 PB - Clin Lab Publ., Verl. Klinisches Labor CY - Heidelberg ER - TY - JOUR A1 - van der Valk, Ralf J. P. A1 - Kreiner-Moller, Eskil A1 - Kooijman, Marjolein N. A1 - Guxens, Monica A1 - Stergiakouli, Evangelia A1 - Saaf, Annika A1 - Bradfield, Jonathan P. A1 - Geller, Frank A1 - Hayes, M. Geoffrey A1 - Cousminer, Diana L. A1 - Koerner, Antje A1 - Thiering, Elisabeth A1 - Curtin, John A. A1 - Myhre, Ronny A1 - Huikari, Ville A1 - Joro, Raimo A1 - Kerkhof, Marjan A1 - Warrington, Nicole M. A1 - Pitkanen, Niina A1 - Ntalla, Ioanna A1 - Horikoshi, Momoko A1 - Veijola, Riitta A1 - Freathy, Rachel M. A1 - Teo, Yik-Ying A1 - Barton, Sheila J. A1 - Evans, David M. A1 - Kemp, John P. A1 - St Pourcain, Beate A1 - Ring, Susan M. A1 - Smith, George Davey A1 - Bergstrom, Anna A1 - Kull, Inger A1 - Hakonarson, Hakon A1 - Mentch, Frank D. A1 - Bisgaard, Hans A1 - Chawes, Bo Lund Krogsgaard A1 - Stokholm, Jakob A1 - Waage, Johannes A1 - Eriksen, Patrick A1 - Sevelsted, Astrid A1 - Melbye, Mads A1 - van Duijn, Cornelia M. A1 - Medina-Gomez, Carolina A1 - Hofman, Albert A1 - de Jongste, Johan C. A1 - Taal, H. Rob A1 - Uitterlinden, Andre G. A1 - Armstrong, Loren L. A1 - Eriksson, Johan A1 - Palotie, Aarno A1 - Bustamante, Mariona A1 - Estivill, Xavier A1 - Gonzalez, Juan R. A1 - Llop, Sabrina A1 - Kiess, Wieland A1 - Mahajan, Anubha A1 - Flexeder, Claudia A1 - Tiesler, Carla M. T. A1 - Murray, Clare S. A1 - Simpson, Angela A1 - Magnus, Per A1 - Sengpiel, Verena A1 - Hartikainen, Anna-Liisa A1 - Keinanen-Kiukaanniemi, Sirkka A1 - Lewin, Alexandra A1 - Alves, Alexessander Da Silva Couto A1 - Blakemore, Alexandra I. F. A1 - Buxton, Jessica L. A1 - Kaakinen, Marika A1 - Rodriguez, Alina A1 - Sebert, Sylvain A1 - Vaarasmaki, Marja A1 - Lakka, Timo A1 - Lindi, Virpi A1 - Gehring, Ulrike A1 - Postma, Dirkje S. A1 - Ang, Wei A1 - Newnham, John P. A1 - Lyytikainen, Leo-Pekka A1 - Pahkala, Katja A1 - Raitakari, Olli T. A1 - Panoutsopoulou, Kalliope A1 - Zeggini, Eleftheria A1 - Boomsma, Dorret I. A1 - Groen-Blokhuis, Maria A1 - Ilonen, Jorma A1 - Franke, Lude A1 - Hirschhorn, Joel N. A1 - Pers, Tune H. A1 - Liang, Liming A1 - Huang, Jinyan A1 - Hocher, Berthold A1 - Knip, Mikael A1 - Saw, Seang-Mei A1 - Holloway, John W. A1 - Melen, Erik A1 - Grant, Struan F. A. A1 - Feenstra, Bjarke A1 - Lowe, William L. A1 - Widen, Elisabeth A1 - Sergeyev, Elena A1 - Grallert, Harald A1 - Custovic, Adnan A1 - Jacobsson, Bo A1 - Jarvelin, Marjo-Riitta A1 - Atalay, Mustafa A1 - Koppelman, Gerard H. A1 - Pennell, Craig E. A1 - Niinikoski, Harri A1 - Dedoussis, George V. A1 - Mccarthy, Mark I. A1 - Frayling, Timothy M. A1 - Sunyer, Jordi A1 - Timpson, Nicholas J. A1 - Rivadeneira, Fernando A1 - Bonnelykke, Klaus A1 - Jaddoe, Vincent W. V. T1 - A novel common variant in DCST2 is associated with length in early life and height in adulthood JF - Human molecular genetics N2 - Common genetic variants have been identified for adult height, but not much is known about the genetics of skeletal growth in early life. To identify common genetic variants that influence fetal skeletal growth, we meta-analyzed 22 genome-wide association studies (Stage 1; N = 28 459). We identified seven independent top single nucleotide polymorphisms (SNPs) (P < 1 x 10(-6)) for birth length, of which three were novel and four were in or near loci known to be associated with adult height (LCORL, PTCH1, GPR126 and HMGA2). The three novel SNPs were followed-up in nine replication studies (Stage 2; N = 11 995), with rs905938 in DC-STAMP domain containing 2 (DCST2) genome-wide significantly associated with birth length in a joint analysis (Stages 1 + 2; beta = 0.046, SE = 0.008, P = 2.46 x 10(-8), explained variance = 0.05%). Rs905938 was also associated with infant length (N = 28 228; P = 5.54 x 10(-4)) and adult height (N = 127 513; P = 1.45 x 10(-5)). DCST2 is a DC-STAMP-like protein family member and DC-STAMP is an osteoclast cell-fusion regulator. Polygenic scores based on 180 SNPs previously associated with human adult stature explained 0.13% of variance in birth length. The same SNPs explained 2.95% of the variance of infant length. Of the 180 known adult height loci, 11 were genome-wide significantly associated with infant length (SF3B4, LCORL, SPAG17, C6orf173, PTCH1, GDF5, ZNFX1, HHIP, ACAN, HLA locus and HMGA2). This study highlights that common variation in DCST2 influences variation in early growth and adult height. Y1 - 2015 U6 - https://doi.org/10.1093/hmg/ddu510 SN - 0964-6906 SN - 1460-2083 VL - 24 IS - 4 SP - 1155 EP - 1168 PB - Oxford Univ. Press CY - Oxford ER - TY - JOUR A1 - Tsuprykov, Oleg A1 - Chen, Xin A1 - Hocher, Carl-Friedrich A1 - Skoblo, Roman A1 - Yin, Lianghong A1 - Hocher, Berthold T1 - Why should we measure free 25(OH) vitamin D? JF - The Journal of Steroid Biochemistry and Molecular Biology N2 - Vitamin D, either in its D-2 or D-3 form, is essential for normal human development during intrauterine life, kidney function and bone health. Vitamin D deficiency has also been linked to cancer development and some auto immune diseases. Given this huge impact of vitamin Don human health, it is important for daily clinical practice and clinical research to have reliable tools to judge on the vitamin D status. The major circulating form of vitamin D is 25-hydroxyvitamin D (25(OH)D), although it is not the most active metabolite, the concentrations of total 25-hydroxyvitamin D in the serum are currently routinely used in clinical practice to assess vitamin D status. In the circulation, vitamin D - like other steroid hormones - is bound tightly to a special carrier - vitamin D-binding protein (DBP). Smaller amounts are bound to blood proteins - albumin and lipoproteins. Only very tiny amounts of the total vitamin D are free and potentially biologically active. Currently used vitamin D assays do not distinguish between the three forms of vitamin D - DBP-bound vitamin D, albumin-bound vitamin D and free, biologically active vitamin D. Diseases or conditions that affect the synthesis of DBP or albumin thus have a huge impact on the amount of circulating total vitamin D. DBP and albumin are synthesized in the liver, hence all patients with an impairment of liver function have alterations in their total vitamin D blood concentrations, while free vitamin D levels remain mostly constant. Sex steroids, in particular estrogens, stimulate the synthesis of DBP. This explains why total vitamin D concentrations are higher during pregnancy as compared to nonpregnant women, while the concentrations of free vitamin D remain similar in both groups of women. The vitamin D-DBP as well as vitamin D-albumin complexes are filtered through the glomeruli and re-uptaken by megalin in the proximal tubule. Therefore, all acute and chronic kidney diseases that are characterized by a tubular damage, are associated with a loss of vitamin D-DBP complexes in the urine. Finally, the gene encoding DBP protein is highly polymorphic in different human racial groups. In the current review, we will discuss how liver function, estrogens, kidney function and the genetic background might influence total circulating vitamin D levels and will discuss what vitamin D metabolite is more appropriate to measure under these conditions: free vitamin D or total vitamin D. KW - 1,25(OH)(2) vitamin D KW - Bioavailable vitamin D KW - Calculated free 25(OH) vitamin D KW - Free 25(OH) vitamin D KW - Free vitamin D KW - Directly measured free vitamin D KW - Genetic polymorphism KW - Total 25(OH) vitamin D KW - Vitamin D-binding protein Y1 - 2107 U6 - https://doi.org/10.1016/j.jsbmb.2017.11.014 SN - 0960-0760 VL - 180 SP - 87 EP - 104 PB - Elsevier CY - Oxford ER - TY - JOUR A1 - Tsuprykov, Oleg A1 - Chaykovska, Lyubov A1 - Kretschmer, Axel A1 - Stasch, Johannes-Peter A1 - Pfab, Thiemo A1 - Krause-Relle, Katharina A1 - Reichetzeder, Christoph A1 - Kalk, Philipp A1 - Adamski, Jerzy A1 - Hocher, Berthold T1 - Endothelin-1 overexpression improves renal function in eNOS knockout mice JF - Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry and pharmacology N2 - Background/Aims: To investigate the renal phenotype under conditions of an activated renal ET-1 system in the status of nitric oxide deficiency, we compared kidney function and morphology in wild-type, ET-1 transgenic (ET+/+), endothelial nitric oxide synthase knockout (eNOS-/-) and ET+/+eNOS-/- mice. Methods: We assessed blood pressure, parameters of renal morphology, plasma cystatin C, urinary protein excretion, expression of genes associated with glomerular filtration barrier and tissue remodeling, and plasma metabolites using metabolomics. Results: eNOS-/- and ET+/+eNOS-/- mice developed hypertension. Osteopontin, albumin and protein excretion were increased in eNOS-/- and restored in ET+/+eNOS-/- animals. All genetically modified mice developed renal interstitial fibrosis and glomerulosclerosis. Genes involved in tissue remodeling (serpinel, TIMP1, Collal, CCL2) were up-regulated in eNOS-/-, but not in ET+/+eNOS-/- mice. Plasma levels of free carnitine and acylcarnitines, amino acids, diacyl phosphatidylcholines, lysophosphatidylcholines and hexoses were descreased in eNOS-/- and were in the normal range in ET+/+eNOS-/- mice. Conclusion: eNOS-/- mice developed renal dysfunction, which was partially rescued by ET-1 overexpression in eNOS-/- mice. The metabolomics results suggest that ET-1 overexpression on top of eNOS knockout is associated with a functional recovery of mitochondria (rescue effect in 13-oxidation of fatty acids) and an increase in antioxidative properties (normalization of monounsaturated fatty acids levels). (C) 2015 The Author(s) Published by S. Karger AG, Basel KW - Chronic kidney disease KW - Endothelial nitric oxide synthase KW - Endothelin KW - Mice KW - Nitric oxide Y1 - 2015 U6 - https://doi.org/10.1159/000438516 SN - 1015-8987 SN - 1421-9778 VL - 37 IS - 4 SP - 1474 EP - 1490 PB - Karger CY - Basel ER - TY - CHAP A1 - Tsuprykov, Oleg A1 - Buse, Claudia A1 - Skoblo, Roman A1 - Hocher, Berthold T1 - Free 25 (OH) vitamin D, but not total 25 (OH) vitamin D, is strongly correlated with gestational age and calcium in normal human pregnancy T2 - Journal of bone and mineral research Y1 - 2017 SN - 0884-0431 SN - 1523-4681 VL - 32 SP - S323 EP - S323 PB - Wiley CY - Hoboken ER - TY - JOUR A1 - Tsuprykov, Oleg A1 - Buse, Claudia A1 - Skoblo, Roman A1 - Haq, Afrozul A1 - Hocher, Berthold T1 - Reference intervals for measured and calculated free 25-hydroxyvitamin D in normal pregnancy JF - The Journal of Steroid Biochemistry and Molecular Biology N2 - The determination of free 25-hydroxyvitamin D (25(OH)D) as compared to the analysis of total 25-hydroxyvitamin D might reflect better the vitamin D status during pregnancy, since vitamin D-binding protein (DBP) concentrations increase throughout pregnancy and the vast majority of 25(OH)D is tightly bound to DBP thus strongly influencing total 25(OH)D. The concentration of the biologically active free 25(OH)D - on the other hand - is much less dependent on the DBP concentrations. The study was conducted in May-June 2016 in 368 Caucasian pregnant healthy women - residents of Northeastern Germany. Free 25(OH)D was either measured directly by commercial ELISA kit or assessed by calculation via total 25(OH)D, DBP, and albumin serum concentrations. Regardless of the detection method, free 25(OH)D lowers in the 3rd trimester comparing to the 1st trimester (by 12% and 21%, p < 0.05 and p < 0.001, for measured and calculated free 25(OH)D, respectively), whereas total 25(OH)D was not decreased in late pregnancy. DBP rises with gestational age. Total 25(OH)D was not correlated with serum calcium (p = 0.251), whereas free 25(OH)D was significantly (p = 0.007 for measured free 25(OH)D and p < 0.001 for calculated free 25(OH)D) positively correlated with calcium. All 25(OH) D isoforms were significantly negatively correlated with bone-specific alkaline phosphatase (BSAP), however the correlation strength was the lowest with total 25(OH)D (rho = -0.108, p = 0.038), whereas both measured and calculated free 25(OH)D revealed better associations with BSAP (rho = -0.203 and rho = -0.211 for measured and calculated free 25(OH)D, respectively, p < 0.001 for both). We established pregnancy trimester specific reference intervals for free measured and calculated 25(OH)D and DBP. Both measured and calculated free 25(OH)D showed better correlations with parameters of the endocrine vitamin D system (calcium and BSAP). Both ways of measuring free 25(OH)D in pregnant women are suitable as novel laboratory parameter for vitamin D status monitoring during human pregnancy and might replace in the future the routine total 25(OH)D assessment. KW - Measured free 25-hydroxyvitamin D KW - Calculated free 25-hydroxyvitamin D KW - Vitamin D-binding protein KW - Pregnancy KW - Reference intervals Y1 - 2018 U6 - https://doi.org/10.1016/j.jsbmb.2018.03.005 SN - 0960-0760 VL - 181 SP - 80 EP - 87 PB - Elsevier CY - Oxford ER - TY - JOUR A1 - Tsuprykov, Oleg A1 - Ando, Ryotaro A1 - Reichetzeder, Christoph A1 - von Websky, Karoline A1 - Antonenko, Viktoriia A1 - Sharkovska, Yuliya A1 - Chaykovska, Lyubov A1 - Rahnenfuehrer, Jan A1 - Hasan, Ahmed Abdallah Abdalrahman Mohamed A1 - Tammen, Harald A1 - Alter, Markus L. A1 - Klein, Thomas A1 - Ueda, Seiji A1 - Yamagishi, Sho-ichi A1 - Okuda, Seiya A1 - Hocher, Berthold T1 - The dipeptidyl peptidase inhibitor linagliptin and the angiotensin II receptor blocker telmisartan show renal benefit by different pathways in rats with 5/6 nephrectomy JF - Kidney international : official journal of the International Society of Nephrology N2 - Dipeptidyl peptidase (DPP)-4 inhibitors delay chronic kidney disease (CKD) progression in experimental diabetic nephropathy in a glucose-independent manner. Here we compared the effects of the DPP-4 inhibitor linagliptin versus telmisartan in preventing CKD progression in non-diabetic rats with 5/6 nephrectomy. Animals were allocated to 1 of 4 groups: sham operated plus placebo; 5/6 nephrectomy plus placebo; 5/6 nephrectomy plus linagliptin; and 5/6 nephrectomy plus telmisartan. Interstitial fibrosis was significantly decreased by 48% with linagliptin but a non-significant 24% with telmisartan versus placebo. The urine albumin-to-creatinine ratio was significantly decreased by 66% with linagliptin and 92% with telmisartan versus placebo. Blood pressure was significantly lowered by telmisartan, but it was not affected by linagliptin. As shown by mass spectrometry, the number of altered peptide signals for linagliptin in plasma was 552 and 320 in the kidney. For telmisartan, there were 108 peptide changes in plasma and 363 in the kidney versus placebo. Linagliptin up-regulated peptides derived from collagen type I, apolipoprotein C1, and heterogeneous nuclear ribonucleoproteins A2/B1, a potential downstream target of atrial natriuretic peptide, whereas telmisartan up-regulated angiotensin II. A second study was conducted to confirm these findings in 5/6 nephrectomy wild-type and genetically deficient DPP-4 rats treated with linagliptin or placebo. Linagliptin therapy in wild-type rats was as effective as DPP-4 genetic deficiency in terms of albuminuria reduction. Thus, linagliptin showed comparable efficacy to telmisartan in preventing CKD progression in non-diabetic rats with 5/6 nephrectomy. However, the underlying pathways seem to be different. Copyright (C) 2016, International Society of Nephrology. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). KW - albuminuria KW - angiotensin receptor blockers KW - chronic kidney disease KW - DPP-4 inhibition KW - proteinuria KW - proteomic analysis Y1 - 2016 U6 - https://doi.org/10.1016/j.kint.2016.01.016 SN - 0085-2538 SN - 1523-1755 VL - 89 SP - 1049 EP - 1061 PB - Nature Publ. Group CY - New York ER - TY - JOUR A1 - Tian, Mei A1 - Reichetzeder, Christoph A1 - Li, Jian A1 - Hocher, Berthold T1 - Low birth weight, a risk factor for diseases in later life, is a surrogate of insulin resistance at birth JF - Journal of hypertension N2 - Low birth weight (LBW) is associated with diseases in adulthood. The birthweight attributed risk is independent of confounding such as gestational age, sex of the newborn but also social factors. The birthweight attributed risk for diseases in later life holds for the whole spectrum of birthweight. This raises the question what pathophysiological principle is actually behind the association. In this review, we provide evidence that LBW is a surrogate of insulin resistance. Insulin resistance has been identified as a key factor leading to type 2 diabetes, cardiovascular disease as well as kidney diseases. We first provide evidence linking LBW to insulin resistance during intrauterine life. This might be caused by both genetic (genetic variations of genes controlling glucose homeostasis) and/or environmental factors (due to alterations of macronutrition and micronutrition of the mother during pregnancy, but also effects of paternal nutrition prior to conception) leading via epigenetic modifications to early life insulin resistance and alterations of intrauterine growth, as insulin is a growth factor in early life. LBW is rather a surrogate of insulin resistance in early life - either due to inborn genetic or environmental reasons - rather than a player on its own. KW - epigenetics KW - fetal programing KW - genetics KW - insulin resistance KW - low birth weight Y1 - 2019 U6 - https://doi.org/10.1097/HJH.0000000000002156 SN - 0263-6352 SN - 1473-5598 VL - 37 IS - 11 SP - 2123 EP - 2134 PB - Kluwer CY - Philadelphia ER - TY - JOUR A1 - Tepel, Martin A1 - Armbruster, Franz Paul A1 - Groen, Hans Juergen A1 - Scholze, Alexandra A1 - Reichetzeder, Christoph A1 - Roth, Heinz Jürgen A1 - Hocher, Berthold T1 - Nonoxidized, biologically active parathyroid hormone determines mortality in hemodialysis patients JF - The journal of clinical endocrinology & metabolism N2 - Background: It was shown that nonoxidized PTH (n-oxPTH) is bioactive, whereas the oxidation of PTH results in a loss of biological activity. Methods: In this study we analyzed the association of n-oxPTH on mortality in hemodialysis patients using a recently developed assay system. Results: Hemodialysis patients (224 men, 116 women) had a median age of 66 years. One hundred seventy patients (50%) died during the follow-up period of 5 years. Median n-oxPTH levels were higher in survivors (7.2 ng/L) compared with deceased patients (5.0 ng/L; P = .002). Survival analysis showed an increased survival in the highest n-oxPTH tertile compared with the lowest n-oxPTH tertile (chi(2), 14.3; P = 0008). Median survival was 1702 days in the highest n-oxPTH tertile, whereas it was only 453 days in the lowest n-oxPTH tertile. Multivariable-adjusted Cox regression showed that higher age increased odds for death, whereas higher n-oxPTH reduced the odds for death. Another model analyzing a subgroup of patients with intact PTH (iPTH) concentrations at baseline above the upper normal range of the iPTH assay (70 ng/L) revealed that mortality in this subgroup was associated with oxidized PTH but not with n-oxPTH levels. Conclusions: The predictive power of n-oxPTH and iPTH on the mortality of hemodialysis patients differs substantially. Measurements of n-oxPTH may reflect the hormone status more precisely. The iPTH-associated mortality is most likely describing oxidative stress-related mortality. Y1 - 2013 U6 - https://doi.org/10.1210/jc.2013-2139 SN - 0021-972X SN - 1945-7197 VL - 98 IS - 12 SP - 4744 EP - 4751 PB - Endocrine Society CY - Chevy Chase ER - TY - JOUR A1 - Tao, Ting A1 - Su, Qiongli A1 - Xu, Simeng A1 - Deng, Jun A1 - Zhou, Sichun A1 - Zhuang, Yu A1 - Huang, Yanjun A1 - He, Caimei A1 - He, Shanping A1 - Peng, Mei A1 - Hocher, Berthold A1 - Yang, Xiaoping T1 - Down-regulation of PKM2 decreases FASN expression in bladder cancer cells through AKT/mTOR/SREBP-1c axis JF - Journal of cellular physiology N2 - Fatty acid synthase (FASN) catalyzing the terminal steps in the de novo biogenesis of fatty acids is correlated with low survival and high disease recurrence in patients with bladder cancer. Pyruvate kinase M2 (PKM2) regulates the final step of glycolysis levels and provides a growth advantage to tumors. However, it is unclear whether the change of PKM2 has an effect on FASN and what is the mechanisms underlying. Here we describe a novel function of PKM2 in control of lipid metabolism by mediating transcriptional activation of FASN, showing the reduced expression of sterol regulatory element binding protein 1c (SREBP-1c). We first discovered that PKM2 physically interacts with the SREBP-1c using biochemical approaches, and downregulation of PKM2 reduced the expression of SREBP-1c by inactivating the AKT/mTOR signaling pathway, which in turn directly suppressed the transcription of major lipogenic genes FASN to reduce tumor growths. Furthermore, either PKM2 inhibitor-Shikonin or FASN inhibitor-TVB-3166 alone induced a strong antiproliferative and anticolony forming effect in bladder cancer cell line. The combination of both inhibitors exhibits a super synergistic effect on blocking the bladder cancer cells growth. It provides a new target and scientific basis for the treatment of bladder cancer. KW - bladder cancer cells KW - FASN KW - p-AKT KW - PKM2 KW - p-mTOR KW - SREBP-1c Y1 - 2018 U6 - https://doi.org/10.1002/jcp.27129 SN - 0021-9541 SN - 1097-4652 VL - 234 IS - 3 SP - 3088 EP - 3104 PB - Wiley CY - Hoboken ER - TY - GEN A1 - Tammen, Harald A1 - Koemhoff, Martin A1 - Mark, Michael A1 - Hocher, Berthold A1 - Delic, Denis A1 - Hess, Rüdiger A1 - von Eynatten, Maximilian A1 - Klein, Thomas T1 - Linagliptin treatment is associated with improved cobalamin (vitamin B-12) storage in mice and potentially in humans T2 - Diabetologia : journal of the European Association for the Study of Diabetes (EASD) Y1 - 2018 SN - 0012-186X SN - 1432-0428 VL - 61 SP - S252 EP - S253 PB - Springer CY - New York ER - TY - JOUR A1 - Taal, H. Rob A1 - St Pourcain, Beate A1 - Thiering, Elisabeth A1 - Das, Shikta A1 - Mook-Kanamori, Dennis O. A1 - Warrington, Nicole M. A1 - Kaakinen, Marika A1 - Kreiner-Moller, Eskil A1 - Bradfield, Jonathan P. A1 - Freathy, Rachel M. A1 - Geller, Frank A1 - Guxens, Monica A1 - Cousminer, Diana L. A1 - Kerkhof, Marjan A1 - Timpson, Nicholas J. A1 - Ikram, M. Arfan A1 - Beilin, Lawrence J. A1 - Bonnelykke, Klaus A1 - Buxton, Jessica L. A1 - Charoen, Pimphen A1 - Chawes, Bo Lund Krogsgaard A1 - Eriksson, Johan A1 - Evans, David M. A1 - Hofman, Albert A1 - Kemp, John P. A1 - Kim, Cecilia E. A1 - Klopp, Norman A1 - Lahti, Jari A1 - Lye, Stephen J. A1 - McMahon, George A1 - Mentch, Frank D. A1 - Mueller-Nurasyid, Martina A1 - O'Reilly, Paul F. A1 - Prokopenko, Inga A1 - Rivadeneira, Fernando A1 - Steegers, Eric A. P. A1 - Sunyer, Jordi A1 - Tiesler, Carla A1 - Yaghootkar, Hanieh A1 - Breteler, Monique M. B. A1 - Debette, Stephanie A1 - Fornage, Myriam A1 - Gudnason, Vilmundur A1 - Launer, Lenore J. A1 - van der Lugt, Aad A1 - Mosley, Thomas H. A1 - Seshadri, Sudha A1 - Smith, Albert V. A1 - Vernooij, Meike W. A1 - Blakemore, Alexandra I. F. A1 - Chiavacci, Rosetta M. A1 - Feenstra, Bjarke A1 - Fernandez-Banet, Julio A1 - Grant, Struan F. A. A1 - Hartikainen, Anna-Liisa A1 - van der Heijden, Albert J. A1 - Iniguez, Carmen A1 - Lathrop, Mark A1 - McArdle, Wendy L. A1 - Molgaard, Anne A1 - Newnham, John P. A1 - Palmer, Lyle J. A1 - Palotie, Aarno A1 - Pouta, Annneli A1 - Ring, Susan M. A1 - Sovio, Ulla A1 - Standl, Marie A1 - Uitterlinden, Andre G. A1 - Wichmann, H-Erich A1 - Vissing, Nadja Hawwa A1 - DeCarli, Charles A1 - van Duijn, Cornelia M. A1 - McCarthy, Mark I. A1 - Koppelman, Gerard H. A1 - Estivill, Xavier A1 - Hattersley, Andrew T. A1 - Melbye, Mads A1 - Bisgaard, Hans A1 - Pennell, Craig E. A1 - Widen, Elisabeth A1 - Hakonarson, Hakon A1 - Smith, George Davey A1 - Heinrich, Joachim A1 - Jarvelin, Marjo-Riitta A1 - Jaddoe, Vincent W. V. A1 - Adair, Linda S. A1 - Ang, Wei A1 - Atalay, Mustafa A1 - van Beijsterveldt, Toos A1 - Bergen, Nienke A1 - Benke, Kelly A1 - Berry, Diane J. A1 - Bradfield, Jonathan P. A1 - Charoen, Pimphen A1 - Coin, Lachlan A1 - Cousminer, Diana L. A1 - Das, Shikta A1 - Davis, Oliver S. P. A1 - Elliott, Paul A1 - Evans, David M. A1 - Feenstra, Bjarke A1 - Flexeder, Claudia A1 - Frayling, Tim A1 - Freathy, Rachel M. A1 - Gaillard, Romy A1 - Geller, Frank A1 - Groen-Blokhuis, Maria A1 - Goh, Liang-Kee A1 - Guxens, Monica A1 - Haworth, Claire M. A. A1 - Hadley, Dexter A1 - Hebebrand, Johannes A1 - Hinney, Anke A1 - Hirschhorn, Joel N. A1 - Holloway, John W. A1 - Holst, Claus A1 - Hottenga, Jouke Jan A1 - Horikoshi, Momoko A1 - Huikari, Ville A1 - Hypponen, Elina A1 - Iniguez, Carmen A1 - Kaakinen, Marika A1 - Kilpelainen, Tuomas O. A1 - Kirin, Mirna A1 - Kowgier, Matthew A1 - Lakka, Hanna-Maaria A1 - Lange, Leslie A. A1 - Lawlor, Debbie A. A1 - Lehtimaki, Terho A1 - Lewin, Alex A1 - Lindgren, Cecilia A1 - Lindi, Virpi A1 - Maggi, Reedik A1 - Marsh, Julie A1 - Middeldorp, Christel A1 - Millwood, Iona A1 - Mook-Kanamori, Dennis O. A1 - Murray, Jeffrey C. A1 - Nivard, Michel A1 - Nohr, Ellen Aagaard A1 - Ntalla, Ioanna A1 - Oken, Emily A1 - O'Reilly, Paul F. A1 - Palmer, Lyle J. A1 - Panoutsopoulou, Kalliope A1 - Pararajasingham, Jennifer A1 - Prokopenko, Inga A1 - Rodriguez, Alina A1 - Salem, Rany M. A1 - Sebert, Sylvain A1 - Siitonen, Niina A1 - Sovio, Ulla A1 - St Pourcain, Beate A1 - Strachan, David P. A1 - Sunyer, Jordi A1 - Taal, H. Rob A1 - Teo, Yik-Ying A1 - Thiering, Elisabeth A1 - Tiesler, Carla A1 - Uitterlinden, Andre G. A1 - Valcarcel, Beatriz A1 - Warrington, Nicole M. A1 - White, Scott A1 - Willemsen, Gonneke A1 - Yaghootkar, Hanieh A1 - Zeggini, Eleftheria A1 - Boomsma, Dorret I. A1 - Cooper, Cyrus A1 - Estivill, Xavier A1 - Gillman, Matthew A1 - Grant, Struan F. A. A1 - Hakonarson, Hakon A1 - Hattersley, Andrew T. A1 - Heinrich, Joachim A1 - Hocher, Berthold A1 - Jaddoe, Vincent W. V. A1 - Jarvelin, Marjo-Riitta A1 - Lakka, Timo A. A1 - McCarthy, Mark I. A1 - Melbye, Mads A1 - Mohlke, Karen L. A1 - Dedoussis, George V. A1 - Ong, Ken K. A1 - Pearson, Ewan R. A1 - Pennell, Craig E. A1 - Price, Thomas S. A1 - Power, Chris A1 - Raitakari, Olli T. A1 - Saw, Seang-Mei A1 - Scherag, Andre A1 - Simell, Olli A1 - Sorensen, Thorkild I. A. A1 - Timpson, Nicholas J. A1 - Widen, Elisabeth A1 - Wilson, James F. A1 - Ang, Wei A1 - van Beijsterveldt, Toos A1 - Bergen, Nienke A1 - Benke, Kelly A1 - Berry, Diane J. A1 - Bradfield, Jonathan P. A1 - Charoen, Pimphen A1 - Coin, Lachlan A1 - Cousminer, Diana L. A1 - Das, Shikta A1 - Elliott, Paul A1 - Evans, David M. A1 - Frayling, Tim A1 - Freathy, Rachel M. A1 - Gaillard, Romy A1 - Groen-Blokhuis, Maria A1 - Guxens, Monica A1 - Hadley, Dexter A1 - Hottenga, Jouke Jan A1 - Huikari, Ville A1 - Hypponen, Elina A1 - Kaakinen, Marika A1 - Kowgier, Matthew A1 - Lawlor, Debbie A. A1 - Lewin, Alex A1 - Lindgren, Cecilia A1 - Marsh, Julie A1 - Middeldorp, Christel A1 - Millwood, Iona A1 - Mook-Kanamori, Dennis O. A1 - Nivard, Michel A1 - O'Reilly, Paul F. A1 - Palmer, Lyle J. A1 - Prokopenko, Inga A1 - Rodriguez, Alina A1 - Sebert, Sylvain A1 - Sovio, Ulla A1 - St Pourcain, Beate A1 - Standl, Marie A1 - Strachan, David P. A1 - Sunyer, Jordi A1 - Taal, H. Rob A1 - Thiering, Elisabeth A1 - Tiesler, Carla A1 - Uitterlinden, Andre G. A1 - Valcarcel, Beatriz A1 - Warrington, Nicole M. A1 - White, Scott A1 - Willemsen, Gonneke A1 - Yaghootkar, Hanieh A1 - Boomsma, Dorret I. A1 - Estivill, Xavier A1 - Grant, Struan F. A. A1 - Hakonarson, Hakon A1 - Hattersley, Andrew T. A1 - Heinrich, Joachim A1 - Jaddoe, Vincent W. V. A1 - Jarvelin, Marjo-Riitta A1 - McCarthy, Mark I. A1 - Pennell, Craig E. A1 - Power, Chris A1 - Timpson, Nicholas J. A1 - Widen, Elisabeth A1 - Ikram, M. Arfan A1 - Fornage, Myriam A1 - Smith, Albert V. A1 - Seshadri, Sudha A1 - Schmidt, Reinhold A1 - Debette, Stephanie A1 - Vrooman, Henri A. A1 - Sigurdsson, Sigurdur A1 - Ropele, Stefan A1 - Coker, Laura H. A1 - Longstreth, W. T. A1 - Niessen, Wiro J. A1 - DeStefano, Anita L. A1 - Beiser, Alexa A1 - Zijdenbos, Alex P. A1 - Struchalin, Maksim A1 - Jack, Clifford R. A1 - Nalls, Mike A. A1 - Au, Rhoda A1 - Hofman, Albert A1 - Gudnason, Haukur A1 - van der Lugt, Aad A1 - Harris, Tamara B. A1 - Meeks, William M. A1 - Vernooij, Meike W. A1 - van Buchem, Mark A. A1 - Catellier, Diane A1 - Gudnason, Vilmundur A1 - Windham, B. Gwen A1 - Wolf, Philip A. A1 - van Duijn, Cornelia M. A1 - Mosley, Thomas H. A1 - Schmidt, Helena A1 - Launer, Lenore J. A1 - Breteler, Monique M. B. A1 - DeCarli, Charles T1 - Common variants at 12q15 and 12q24 are associated with infant head circumference JF - Nature genetics N2 - To identify genetic variants associated with head circumference in infancy, we performed a meta-analysis of seven genome-wide association studies (GWAS) (N = 10,768 individuals of European ancestry enrolled in pregnancy and/or birth cohorts) and followed up three lead signals in six replication studies (combined N = 19,089). rs7980687 on chromosome 12q24 (P = 8.1 x 10(-9)) and rs1042725 on chromosome 12q15 (P = 2.8 x 10(-10)) were robustly associated with head circumference in infancy. Although these loci have previously been associated with adult height(1), their effects on infant head circumference were largely independent of height (P = 3.8 x 10(-7) for rs7980687 and P = 1.3 x 10(-7) for rs1042725 after adjustment for infant height). A third signal, rs11655470 on chromosome 17q21, showed suggestive evidence of association with head circumference (P = 3.9 x 10(-6)). SNPs correlated to the 17q21 signal have shown genome-wide association with adult intracranial volume(2), Parkinson's disease and other neurodegenerative diseases(3-5), indicating that a common genetic variant in this region might link early brain growth with neurological disease in later life. Y1 - 2012 U6 - https://doi.org/10.1038/ng.2238 SN - 1061-4036 VL - 44 IS - 5 SP - 532 EP - + PB - Nature Publ. Group CY - New York ER - TY - JOUR A1 - Sun, Sheng-Yun A1 - Huang, Jin A1 - Meng, Min-Jie A1 - Lu, Jia-Hai A1 - Hocher, Berthold A1 - Liu, Kang-Li A1 - Yang, Qin-He A1 - Zhu, Xiao-Feng T1 - Improvement of lipid profile and reduction of body weight by Shan He Jian Fei Granules in high fat diet-induced obese rats JF - Clinical laboratory : the peer reviewed journal for clinical laboratories and laboratories related to blood transfusion N2 - Background: The goal was to study lipid profiles (TG, TC, LDL, HDL), effects on serum leptin, and fat tissue adiponectin, and resistin as well as body weight effects of Shan He Jian Fei Granules (SHJFG) in rats on a high fat diet. Methods: Rats were randomly divided into five groups: normal control group fed with normal fat diet, rats on high fat diet receiving low dosage, middle dosage, high dosage of Shan He Jian Fei Granules (SHJFG) as well as a high fat diet group receiving placebo. Rats were treated for 8 weeks. Body weight and naso-anal length of each rat were recorded and Lee's index was calculated. Serum TG, TC, LDL, HDL and leptin concentrations were analyzed. The gene expressions of adiponectin and resistin in adipose tissues were tested by RT-PCR. Results: Compared to the high-fat diet group, body weights, Lee's indexes, weight of fat tissues and serum TG, TC, LDL and leptin of SHJFG groups significantly decreased (p<0.05), whereas mRNA expressions of adiponectin and resistin of SHJFG groups significantly increased (p<0.05). Conclusions: SHJFG could significantly lower body weight and serum TG, TC, and LDL of obese rats. The effects of SHJFG in lowering leptin synthesis and raising mRNA expression of adiponectin and resistin in fat tissues may act as part of the mechanisms in lowering body weight of obese rats. Further studies are needed to demonstrate whether SHJFG may also reduce overall cardiovascular morbidity and mortality like other lipid lowering drugs. KW - obesity KW - high-fat diet KW - Shan He Jian Fei Granules (SHJFG) KW - lipid KW - adiponectin KW - resistin KW - leptin Y1 - 2012 SN - 1433-6510 VL - 58 IS - 1-2 SP - 81 EP - 87 PB - Clin Lab Publ., Verl. Klinisches Labor CY - Heidelberg ER - TY - JOUR A1 - Stasch, Johannes-Peter A1 - Schlossmann, Jens A1 - Hocher, Berthold T1 - Renal effects of soluble guanylate cyclase stimulators and activators: A review of the preclinical evidence JF - Current opinion in pharmacology N2 - Direct stimulation of soluble guanylate cyclase (sGC) is emerging as a potential new approach for the treatment of renal disorders. sGC catalyzes the formation of cyclic guanosine monophosphate (cGMP), deficiency of which is implicated in the pathogenesis of chronic kidney disease (CKD). Therefore, new classes of drugs sGC stimulators and activators are being investigated in preclinical models under conditions where nitric oxide is deficient. In preclinical models with different etiologies of CKD, the sGC stimulators BAY 41-2272, BAY 41-8543, BAY 60-4552, riociguat and vericiguat and the sGC activators cinaciguat, ataciguat, BI 703704 and GSK2181236A have shown consistently renoprotective effects. Clinical trials are required to confirm these findings in humans, and to ascertain whether these agents could provide a future alternative to guideline-recommended treatments. Y1 - 2015 U6 - https://doi.org/10.1016/j.coph.2014.12.014 SN - 1471-4892 SN - 1471-4973 VL - 21 SP - 95 EP - 104 PB - Elsevier CY - Oxford ER - TY - JOUR A1 - Sharkovska, Yuliya A1 - Reichetzeder, Christoph A1 - Alter, Markus L. A1 - Tsuprykov, Oleg A1 - Bachmann, Sebastian A1 - Secher, Thomas A1 - Klein, Thomas A1 - Hocher, Berthold T1 - Blood pressure and glucose independent renoprotective effects of dipeptidyl peptidase-4 inhibition in a mouse model of type-2 diabetic nephropathy JF - Journal of hypertension N2 - Background: Despite the beneficial effects of type 4 dipeptidyl peptidase (DPP-4) inhibitors on glucose levels, its effects on diabetic nephropathy remain unclear. Method: This study examined the long-term renoprotective effects of DPP-4 inhibitor linagliptin in db/db mice, a model of type 2 diabetes. Results were compared with the known beneficial effects of renin-angiotensin system blockade by enalapril. Ten-week-old male diabetic db/db mice were treated for 3 months with either vehicle (n = 10), 3 mg linagliptin/kg per day (n = 8), or 20 mg enalapril/kg per day (n = 10). Heterozygous db/m mice treated with vehicle served as healthy controls (n = 8). Results: Neither linagliptin nor enalapril had significant effects on the parameters of glucose metabolism or blood pressure in diabetic db/db mice. However, linagliptin treatment reduced albuminuria and attenuated kidney injury. In addition, expression of podocyte marker podocalyxin was normalized. We also analysed DPP-4 expression by immunofluorescence in human kidney biopsies and detected upregulation of DPP-4 in the glomeruli of patients with diabetic nephropathy, suggesting that our findings might be of relevance for human kidney disease as well. Conclusion: Treatment with DPP-4 inhibitor linagliptin delays the progression of diabetic nephropathy damage in a glucose-independent and blood-pressure-independent manner. The observed effects may be because of the attenuation of podocyte injury and inhibition of myofibroblast transformation. KW - diabetic nephropathy KW - DPP-4 inhibitors KW - linagliptin Y1 - 2014 U6 - https://doi.org/10.1097/HJH.0000000000000328 SN - 0263-6352 SN - 1473-5598 VL - 32 IS - 11 SP - 2211 EP - 2223 PB - Lippincott Williams & Wilkins CY - Philadelphia ER - TY - JOUR A1 - Sharkovska, Yuliya A1 - Kalk, Philipp A1 - von Websky, Karoline A1 - Relle, Katharina A1 - Pfab, Thiemo A1 - Alter, Markus L. A1 - Fischer, Yvan A1 - Hocher, Berthold T1 - Renoprotective effects of combined endothelin-converting enzyme/neutral endopeptidase inhibitor SLV338 in acute and chronic experimental renal damage JF - Clinical laboratory : the peer reviewed journal for clinical laboratories and laboratories related to blood transfusion N2 - Background: Acute kidney injury (AKI) as well as chronic renal failure are associated with a huge mortality/morbidity. However, so far no drugs have been approved for the treatment of acute kidney failure and only a few for the treatment of chronic kidney disease (CKD). We analysed the effect of SLV 338, a neutral endopeptidase (NEP)/endothelin converting enzyme (ECE)-inhibitor in animal models of acute kidney failure as well as chronic renal failure. Methods: Acute renal failure was induced in male Wistar rats by uninephrectomy and clamping of the remaining kidney for 55 minutes. SLV338 (total dose: 4.9 mg/kg) or vehicle was continuously infused for 2 hours (starting 20 minutes prior to clamping). Sham operated animals served as controls. Plasma creatinine was measured at baseline and day 2 and 8 after renal ischemia-reperfusion. Hypertensive renal damage was induced in male Sprague Dawley rats by nitric oxide deficiency using L-NAME (50 mg/kg per day, added to drinking water for 4 weeks). One group was treated over the same time period with SLV338 (30 mg/kg per day, mixed with food). Systolic blood pressure was monitored weekly. At study end, urine and blood samples were collected and kidneys were harvested. Results: Acute renal ischemia-reperfusion caused a 5-fold plasma creatinine elevation (day 2), which was significantly attenuated by more than 50 % in animals treated with SLV338 (p < 0.05). Renal failure was accompanied by a 67 % mortality in vehicle-treated rats, but only 20 % after SLV338 treatment (p = 0.03 compared to sham controls). Chronic L-NAME administration caused hypertension, urinary albumin excretion, glomerulosclerosis, renal arterial remodelling, and renal interstitial fibrosis. Treatment with SLV338 did not significantly affect blood pressure, but abolished renal tissue damage (interstitial fibrosis, glomerulosclerosis, renal arterial remodelling (p < 0.05 versus L-NAME group in each case). Conclusions: The dual ECE/NEP inhibitor SLV338 preserves kidney function and reduces mortality in severe acute ischemic renal failure. Moreover, combined ECE/NEP inhibition prevents hypertensive renal tissue damage in a blood pressure independent manner in L-NAME-treated rats. KW - Renal failure KW - endothelin-converting enzyme KW - neutral endopeptidase Y1 - 2011 SN - 1433-6510 VL - 57 IS - 7-8 SP - 507 EP - 515 PB - Clin Lab Publ., Verl. Klinisches Labor CY - Heidelberg ER - TY - JOUR A1 - Sharkovska, Yuliya A1 - Kalk, Philipp A1 - Lawrenz, Bettina A1 - Godes, Michael A1 - Hoffmann, Linda Sarah A1 - Wellkisch, Kathrin A1 - Geschka, Sandra A1 - Relle, Katharina A1 - Hocher, Berthold A1 - Stasch, Johannes-Peter T1 - Nitric oxide-independent stimulation of soluble guanylate cyclase reduces organ damage in experimental low- renin and high-renin models N2 - Objectives The nitric oxide-soluble guanylate cyclase (sGC)-cGMP signal transduction pathway is impaired in different cardiovascular diseases, including pulmonary hypertension, heart failure and arterial hypertension. Riociguat is a novel stimulator of soluble guanylate cyclase (sGC). However, little is known about the effects of sGC stimulators in experimental models of hypertension. We thus investigated the cardio-renal protective effects of riociguat in low- renin and high-renin rat models of hypertension. Methods The vasorelaxant effect of riociguat was tested in vitro on isolated saphenous artery rings of normal and nitrate tolerant rabbits. The cardiovascular in-vivo effects of sGC stimulation were evaluated in hypertensive renin-transgenic rats treated with the nitric oxide-synthase inhibitor N- nitro-L-arginine methyl ester (L-NAME) (high-renin model) and in rats with 5/6 nephrectomy (low-renin model). Results In both animal models, riociguat treatment improved survival and normalized blood pressure. Moreover, in the L-NAME study part, riociguat reduced cardiac target organ damage as indicated by lower plasma ANP, lower relative left ventricular weight and lower cardiac interstitial fibrosis, and reduced renal target organ damage as indicated by lower plasma creatinine and urea, less glomerulosclerosis and less renal interstitial fibrosis. In the 5/6 nephrectomy study part, riociguat reduced cardiac target organ damage as indicated by lower plasma ANP, lower relative left ventricular weight, lower myocyte diameter and lower arterial media/lumen ratio, and reduced renal target organ damage as indicated by improved creatinine clearance and less renal interstitial fibrosis. Conclusion We demonstrate for the first time that the novel sGC stimulator riociguat shows in two independent models of hypertension a potent protection against cardiac and renal target organ damage. J Hypertens 28: 1666-1675 (c) 2010 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins. Y1 - 2010 UR - http://journals.lww.com/jhypertension/pages/default.aspx U6 - https://doi.org/10.1097/Hjh.0b013e32833b558c SN - 0263-6352 ER - TY - CHAP A1 - Sharkovska, Y. A1 - Pohl, K. K. A1 - Hocher, Berthold A1 - Dschietzig, T. T1 - Cardiac expression of relaxin and its receptor RXFP1 in rats with renovascular hypertension T2 - EUROPEAN HEART JOURNAL Y1 - 2013 SN - 0195-668X SN - 1522-9645 VL - 34 IS - 10 SP - 1056 EP - 1056 PB - OXFORD UNIV PRESS CY - OXFORD ER - TY - CHAP A1 - Sharkovska, Y. A1 - Alter, Markus L. A1 - Reichetzeder, Christoph A1 - Tsuprykov, Oleg A1 - Klein, T. A1 - Hocher, Berthold T1 - DPP-4 inhibition with linagliptin delays the progression of diabetic nephropathy in db/db mice T2 - Diabetologia : journal of the European Association for the Study of Diabetes (EASD) Y1 - 2012 SN - 0012-186X SN - 1432-0428 VL - 55 IS - 5 SP - S20 EP - S20 PB - Springer CY - New York ER - TY - CHAP A1 - Scholze, Alexandra A1 - Petersen, Lise A1 - Hocher, Berthold A1 - Rasmussen, Lars M. A1 - Tepel, Martin T1 - Role of fibroblast growth factor-23 and soluble alpha klotho in chronic kidney disease T2 - Nephrology, dialysis, transplantation Y1 - 2014 SN - 0931-0509 SN - 1460-2385 VL - 29 SP - 120 EP - 121 PB - Oxford Univ. Press CY - Oxford ER - TY - JOUR A1 - Scholze, Alexandra A1 - Liu, Ying A1 - Pedersen, Lise A1 - Xia, Shengqiang A1 - Roth, Heinz J. A1 - Hocher, Berthold A1 - Rasmussen, Lars Melholt A1 - Tepel, Martin T1 - Soluble alpha-Klotho and its relation to kidney function and fibroblast growth factor-23 JF - The journal of clinical endocrinology & metabolism N2 - Context: Relations between fibroblast growth factor-23 (FGF-23), soluble alpha-klotho (s-alpha-klotho), and kidney function in chronic kidney disease (CKD) are still unclear. Especially the role of s-alpha-klotho requires further study. Objectives: Our objectives were to analyze the relation of s-alpha-klotho to estimated glomerular filtration rate (eGFR), FGF-23, and other parameters of calcium-phosphate metabolism and to investigate the response of s-alpha-klotho to cholecalciferol. Patients, Design, and Setting: Twenty-four CKD (stage 1-5) patients participated in this 8-week randomized controlled trial (vitamin D and chronic renal insufficiency). Interventions: Interventions included 40 000 IU cholecalciferol or placebo weekly. Main Outcome Measure: S-alpha-klotho was determined by ELISA with antihuman klotho antibodies 67G3 and 91F1. Results: For all patients, s-alpha-klotho concentrations did not differ between CKD stages. When patients were subdivided based on FGF-23 concentrations, a positive association of s-alpha-klotho with eGFR became apparent in patients with lower than median FGF-23 concentrations but not in those above median value. Patients with s-alpha-klotho below 204 pg/mL showed higher age, lower phosphate clearance, and lower bone-specific alkaline phosphatase compared with patients with higher s-alpha-klotho. Treatment with cholecalciferol significantly increased 1,25-dihydroxyvitamin D. The increase of FGF-23 had only borderline significance. There was no significant effect of high-dose cholecalciferol administration for 8 weeks on plasma s-alpha-klotho. Conclusions: CKD patients with s-alpha-klotho below 204 pg/mL had higher age, lower phosphate clearance, and lower bone-specific alkaline phosphatase. An association of s-alpha-klotho with eGFR was observed only in the presence of close to normal, but not high, FGF-23 concentrations. Cholecalciferol treatment did not change s-alpha-klotho concentrations. Y1 - 2014 U6 - https://doi.org/10.1210/jc.2013-4171 SN - 0021-972X SN - 1945-7197 VL - 99 IS - 5 SP - E855 EP - E861 PB - Endocrine Society CY - Washington ER - TY - JOUR A1 - Schmerbach, K. A1 - Kalk, Philipp. A1 - Wengenmayer, Christina A1 - Lucht, K. A1 - Unger, T. A1 - Hocher, Berthold A1 - Thoene-Reineke, C. T1 - Renal outcome in equipotent Antihypertensive Treatment with Telmisartan, Ramipril and in combination in SHR-SP Rats JF - Clinical laboratory : the peer reviewed journal for clinical laboratories and laboratories related to blood transfusion N2 - Background: The ONTARGET trial revealed an association of ACEI/ARB combination treatment (telmisartan and ramipril) with adverse renal outcome versus respective monotherapy; preclinical evidence regarding renal outcome in ACEI/ARB combination treatment is scarce. Methods: Spontaneously hypertensive stroke prone rats (SHR-SP) rats on a salt-rich diet were randomly allocated to 4 groups: SHR (untreated, n = 24), SHR + telmisartan (SHR-T, 2.39 +/- 0.69 mg/kg bw; n = 27), SHR + ramipril (SHR-R, 6.28 +/- 3.48 mg/kg bw; n = 27) and combination treatment (SHR-TR, 0.51 +/- 0.14 mg/kg bw; same dose for telmisartan and ramipril; n = 26). Study duration was 12 weeks, blood pressure was assessed weekly and doses were adjusted to maintain equal blood pressure. Finally, blood and urine samples were obtained and kidneys were harvested for histological studies. Results: Blood pressure in untreated rats rose to a maximum of 239 mmHg, whereas in all treatment groups it remained stable betvveen 140 and 150 mmHg. Mortality was 50% in the untreated group, whereas all treatment groups survived completely. Renal function - as indicated by plasma urea and cystatin c - was significantly worse in SHR-TR animals compared to all other groups. With plasma creatinine a similar trend was observed. All treatment options significantly decreased albuminuria. Renal glomerulosclerosis was decreased by monotherapy, whereas combination therapy failed to have a significant effect. Interstitial fibrosis was decreased to a similar extent by all treatment options. Conclusions: ACEI/ARB combination treatment failed to render significant additional benefits on renal outcome in hypertensive rats when compared to monotherapy. Instead our data indicate that dual RAAS blockade might have an adverse effect on kidney function and histology when compared to monotherapy in salt-loaded SHR-SP. KW - Renal failure KW - angiotensin receptor blockers KW - ACE inhibitors KW - telmisartan KW - ramipril Y1 - 2012 U6 - https://doi.org/10.7754/Clin.Lab.2011.110622 SN - 1433-6510 VL - 58 IS - 7-8 SP - 625 EP - 633 PB - Clin Lab Publ., Verl. Klinisches Labor CY - Heidelberg ER - TY - JOUR A1 - Schildroth, Janice A1 - Rettig-Zimmermann, Juliane A1 - Kalk, Philipp A1 - Steege, Andreas A1 - Faehling, Michael A1 - Sendeski, Mauricio A1 - Paliege, Alexander A1 - Lai, En Yin A1 - Bachmann, Sebastian A1 - Persson, Pontus B. A1 - Hocher, Berthold A1 - Patzak, Andreas T1 - Endothelin type A and B receptors in the control of afferent and efferent arterioles in mice JF - Nephrology, dialysis, transplantation N2 - Background. Endothelin 1 contributes to renal blood flow control and pathogenesis of kidney diseases. The differential effects, however, of endothelin 1 (ET-1) on afferent (AA) and efferent arterioles (EA) remain to be established. Methods. We investigated endothelin type A and B receptor (ETA-R, ETB-R) functions in the control of AA and EA. Arterioles of ETB-R deficient, rescued mice [ETB (-/-)] and wild types [ETB(+/+)] were microperfused. Results. ET-1 constricted AA stronger than EA in ETB (-/-) and ETB(+/+) mice. Results in AA: ET-1 induced similar constrictions in ETB(-/-) and ETB(+/+) mice. BQ-123 (ETA-R antagonist) inhibited this response in both groups. ALA-ET-1 and IRL1620 (ETB-R agonists) had no effect on arteriolar diameter. L-NAME did neither affect basal diameters nor ET-1 responses. Results in EA: ET-1 constricted EA stronger in ETB(+/+) compared to ETB(-/-). BQ-123 inhibited the constriction completely only in ETB(-/-). ALA-ET-1 and IRL1620 constricted only arterioles of ETB(+/+) mice. L-NAME decreased basal diameter in ETB(+/+), but not in ETB(-/-) mice and increased the ET-1 response similarly in both groups. The L-NAME actions indicate a contribution of ETB-R in basal nitric oxide (NO) release in EA and suggest dilatory action of ETA-R in EA. Conclusions. ETA-R mediates vasoconstriction in AA and contributes to vasoconstriction in EA in this mouse model. ETB-R has no effect in AA but mediates basal NO release and constriction in EA. The stronger effect of ET-1 on AA supports observations of decreased glomerular filtration rate to ET-1 and indicates a potential contribution of ET-1 to the pathogenesis of kidney diseases. KW - endothelin KW - ETB receptor-deficient mouse KW - glomerular arterioles KW - renal haemodynamics Y1 - 2011 U6 - https://doi.org/10.1093/ndt/gfq534 SN - 0931-0509 VL - 26 IS - 3 SP - 779 EP - 789 PB - Oxford Univ. Press CY - Oxford ER - TY - GEN A1 - Schernthaner, G. A1 - Groop, P. A1 - Cooper, M. A1 - Perkovic, V A1 - Hocher, Berthold A1 - Kanasaki, K. A1 - Sharma, K. A1 - Stanton, R. A1 - Toto, R. A1 - Cescutti, Jessica A1 - Gordat, M. A1 - Meinicke, T. A1 - Koitka-Weber, A. A1 - Woerle, H. A1 - Eynatten, M. T1 - EFFECTS OF LINAGLIPTIN ON GLYCAEMIC CONTROL AND ALBUMINURIA IN TYPE 2 DIABETES - THE MARLINA-T2D (TM) TRIAL T2 - Nephrology Y1 - 2016 U6 - https://doi.org/10.1111/nep.12887 SN - 1320-5358 SN - 1440-1797 VL - 21 SP - 60 EP - 60 PB - Wiley-Blackwell CY - Hoboken ER - TY - JOUR A1 - Satwiko, Muhammad Gahan A1 - Ikeda, Koji A1 - Nakayama, Kazuhiko A1 - Yagi, Keiko A1 - Hocher, Berthold A1 - Hirata, Ken-Ichi A1 - Emoto, Noriaki T1 - Targeted activation of endothelin-1 exacerbates hypoxia-induced pulmonary hypertension JF - Biochemical and biophysical research communications N2 - Pulmonary arterial hypertension (PAH) is a fatal disease that eventually results in right heart failure and death. Current pharmacologic therapies for PAH are limited, and there are no drugs that could completely cure PAH. Enhanced activity of endothelin system has been implicated in PAH severity and endothelin receptor antagonists have been used clinically to treat PAH. However, there is limited experimental evidence on the direct role of enhanced endothelin system activity in PAL-I. Here, we investigated the correlation between endothelin-1 (ET-1) and PAH using ET-1 transgenic (ETTG) mice. Exposure to chronic hypoxia increased right ventricular pressure and pulmonary arterial wall thickness in ETTG mice compared to those in wild type mice. Of note, ETTG mice exhibited modest but significant increase in right ventricular pressure and vessel wall thickness relative to wild type mice even under normoxic conditions. To induce severe PAH, we administered SU5416, a vascular endothelial growth factor receptor inhibitor, combined with exposure to chronic hypoxia. Treatment with SU5416 modestly aggravated hypoxia-induced pulmonary hypertension, right ventricular hypertrophy, and pulmonary arterial vessel wall thickening in ETTG mice in association with increased interleukin-6 expression in blood vessels. However, there was no sign of obliterative endothelial cell proliferation and plexiform lesion formation in the lungs. These results demonstrated that enhanced endothelin system activity could be a causative factor in the development of PAH and provided rationale for the inhibition of endothelin system to treat PAH. (C) 2015 Elsevier Inc. All rights reserved. KW - Pulmonary arterial hypertension KW - Endothelin KW - Hypoxia KW - SU5416 Y1 - 2015 U6 - https://doi.org/10.1016/j.bbrc.2015.08.002 SN - 0006-291X SN - 1090-2104 VL - 465 IS - 3 SP - 356 EP - 362 PB - Elsevier CY - San Diego ER - TY - JOUR A1 - Rokutan, Hirofumi A1 - Suckow, Christian A1 - von Hähling, Stephan A1 - Strassburg, Sabine A1 - Bockmeyer, Barbara A1 - Döhner, Wolfram A1 - Waller, Christiane A1 - Bauersachs, Johann A1 - von Websky, Karoline A1 - Hocher, Berthold A1 - Anker, Stefan D. A1 - Springer, Jochen T1 - Furosemide induces mortality in a rat model of chronic heart failure JF - International journal of cardiology N2 - Objectives: In an experimental heart failure model, we tested the hypothesis that furosemide causes excess mortality. Background: Post-hoc analysis of large clinical heart failure trails revealed that furosemide treatment might be associated with worsening of morbidity and even mortality in heart failure patients. Methods and results: Myocardial infarction was induced in 7 +/- 1 week old male Wistar rats by ligation of the left coronary artery. In study 1, animals were randomly assigned to treatment with furosemide (10 mg/kg/d via drinking water, n = 33) or placebo (n = 33) starting 18 days after surgery. In study 2, animals received furosemide from day 18 and were then randomized to ongoing treatment with either furosemide only (n = 38) or furosemide plus ACE-inhibitor Ramipril (1 mg/kg/d, n = 38) starting on day 42. In study 1 survival rate in the furosemide group was lower than in the placebo group (hazard ratio {HR} 3.39, 95% confidence interval {CI} 1.14 to 10.09, p = 0.028). The furosemide group had a lower body weight (-6%, p = 0.028) at the end of the study and a higher sclerosis index of the glomeruli (+9%, p=0.026) than the placebo group. Wet lung weight, infarct size, and cardiac function were similar between the groups. In study 2, the furosemide group had a higher mortality rate than the furosemide + ramipril group (HR 4.55, 95% CI 2.0 to 10.0, p = 0.0003). Conclusion: In our rat model of heart failure furosemide, provided at a standard dose, was associated with increased mortality. This increased mortality could be prevented by additional administration of an ACE-inhibitor. KW - Angiotensin converting enzyme inhibitor KW - Furosemide KW - Heart failure KW - Loop diuretics KW - Mortality Y1 - 2012 U6 - https://doi.org/10.1016/j.ijcard.2011.03.005 SN - 0167-5273 VL - 160 IS - 1 SP - 20 EP - 25 PB - Elsevier CY - Clare ER - TY - JOUR A1 - Reichetzeder, Christoph A1 - von Websky, Karoline A1 - Tsuprykov, Oleg A1 - Samarin, Azadeh Mohagheghi A1 - Falke, Luise Gabriele A1 - Putra, Sulistyo Emantoko Dwi A1 - Hasan, Ahmed Abdallah Abdalrahman Mohamed A1 - Antonenko, Viktoriia A1 - Curato, Caterina A1 - Rippmann, Joerg A1 - Klein, Thomas A1 - Hocher, Berthold T1 - Head-to-head comparison of structurally unrelated dipeptidyl peptidase 4 inhibitors in the setting of renal ischemia reperfusion injury JF - British journal of pharmacology : journal of The British Pharmacological Society N2 - BACKGROUND AND PURPOSE Results regarding protective effects of dipeptidyl peptidase 4 (DPP4) inhibitors in renal ischaemia-reperfusion injury (IRI) are conflicting. Here we have compared structurally unrelated DPP4 inhibitors in a model of renal IRI. EXPERIMENTAL APPROACH IRI was induced in uninephrectomizedmale rats by renal artery clamping for 30 min. The shamgroup was uninephrectomized but not subjected to IRI. DPP4 inhibitors or vehicle were given p. o. once daily on three consecutive days prior to IRI: linagliptin (1.5 mg.kg(-1).day(-1)), vildagliptin (8mg.kg(-1).day(-1)) and sitagliptin (30 mg.kg(-1).day(-1)). An additional group received sitagliptin until study end (before IRI: 30 mg.kg(-1).day(-1); after IRI: 15mg.kg(-1).day(-1)). KEY RESULTS Plasma-active glucagon-like peptide type 1 (GLP(-1)) increased threefold to fourfold in all DPP4 inhibitor groups 24 h after IRI. Plasma cystatin C, a marker of GFR, peaked 48 h after IRI. Compared with the placebo group, DPP4 inhibition did not reduce increased plasma cystatin C levels. DPP4 inhibitors ameliorated histopathologically assessed tubular damage with varying degrees of drug-specific efficacies. Renal osteopontin expression was uniformly reduced by all DPP4 inhibitors. IRI-related increased renal cytokine expression was not decreased by DPP4 inhibition. Renal DPP4 activity at study end was significantly inhibited in the linagliptin group, but only numerically reduced in the prolonged/dose-adjusted sitagliptin group. Active GLP(-1) plasma levels at study end were increased only in the prolonged/dose-adjusted sitagliptin treatment group. CONCLUSIONS AND IMPLICATIONS In rats with renal IRI, DPP4 inhibition did not alter plasma cystatin C, a marker of glomerular function, but may protect against tubular damage. Y1 - 2017 U6 - https://doi.org/10.1111/bph.13822 SN - 0007-1188 SN - 1476-5381 VL - 174 SP - 2273 EP - 2286 PB - Wiley CY - Hoboken ER - TY - CHAP A1 - Reichetzeder, Christoph A1 - von Websky, Karoline A1 - Tsuprykov, Oleg A1 - Antonenko, V. A1 - Samarin, Azin Mohagheghi A1 - Hocher, Berthold T1 - Effects of DPP-4 inhibition on glomerular and tubular function in a rat model of ischaemia-reperfusion injury T2 - Diabetologia : journal of the European Association for the Study of Diabetes (EASD) Y1 - 2015 SN - 0012-186X SN - 1432-0428 VL - 58 SP - S34 EP - S35 PB - Springer CY - New York ER - TY - JOUR A1 - Reichetzeder, Christoph A1 - Tsuprykov, Oleg A1 - Hocher, Berthold T1 - Endothelin receptor antagonists in clinical research - Lessons learned from preclinical and clinical kidney studies JF - Life sciences : molecular, cellular and functional basis of therapy N2 - Endothelin receptor antagonists (ETRAs) are approved for the treatment of pulmonary hypertension and scleroderma-related digital ulcers. The efforts to approve this class of drugs for renal indications, however, failed so far. Preclinical studies were promising. Transgenic overexpression of ET-1 or ET-2 in rodents causes chronic renal failure. Blocking the ET system was effective in the treatment of renal failure in rodent models. However, various animal studies indicate that blocking the renal tubular ETAR and ETBR causes water and salt retention partially mediated via the epithelial sodium transporter in tubular cells. ETRAs were successfully tested clinically in renal indications in phase 2 trials for the treatment of diabetic nephropathy. They showed efficacy in terms of reducing albumin excretion on top of guideline based background therapy (RAS blockade). However, these promising results could not be translated to successful phase Ill trials so far. The spectrum of serious adverse events was similar to other phase III trials using ETRAs. Potential underlying reasons for these failures and options to solve these issues are discussed. In addition preclinical and clinical studies suggest caution when addressing renal patient populations such as patients with hepatorenal syndrome, patients with any type of cystic kidney disease and patients at risk of contrast media induced nephropathy. The lessons learned in renal indications are also important for other potential promising indications of ETRAs like cancer and heart failure. (C) 2014 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/3.0/). KW - Endothelin receptor antagonists KW - Kidney KW - Side effects KW - Safety KW - Water and salt retention KW - Clinical trials Y1 - 2014 U6 - https://doi.org/10.1016/j.lfs.2014.02.025 SN - 0024-3205 SN - 1879-0631 VL - 118 IS - 2 SP - 141 EP - 148 PB - Elsevier CY - Oxford ER - TY - JOUR A1 - Reichetzeder, Christoph A1 - Putra, Sulistyo Emantoko Dwi A1 - Li, Jian A1 - Hocher, Berthold T1 - Developmental Origins of Disease - Crisis Precipitates Change JF - Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry and pharmacology N2 - The concept of developmental origins of diseases has gained a huge interest in recent years and is a constantly emerging scientific field. First observations hereof originated from epidemiological studies, linking impaired birth outcomes to adult chronic, noncommunicable disease. By now there is a considerable amount of both epidemiological and experimental evidence highlighting the impact of early life events on later life disease susceptibility. Albeit far from being completely understood, more recent studies managed to elucidate underlying mechanisms, with epigenetics having become almost synonymous with developmental programming. The aim of this review was to give a comprehensive overview of various aspects and mechanisms of developmental origins of diseases. Starting from initial research foci mainly centered on a nutritionally impaired intrauterine environment, more recent findings such as postnatal nutrition, preterm birth, paternal programming and putative interventional approaches are summarized. The review outlines general underlying mechanisms and particularly discusses mechanistic explanations for sexual dimorphism in developmental programming. Furthermore, novel hypotheses are presented emphasizing a non-mendelian impact of parental genes on the offspring's phenotype. KW - Nutrition KW - Thrifty phenotype KW - Developmental programming KW - Paternal, maternal, sex differences KW - Epigenetics Y1 - 2016 U6 - https://doi.org/10.1159/000447801 SN - 1015-8987 SN - 1421-9778 VL - 39 SP - 919 EP - 938 PB - Karger CY - Basel ER - TY - JOUR A1 - Reichetzeder, Christoph A1 - Putra, S. E. Dwi A1 - Pfab, T. A1 - Slowinski, T. A1 - Neuber, Corinna A1 - Kleuser, Burkhard A1 - Hocher, Berthold T1 - Increased global placental DNA methylation levels are associated with gestational diabetes JF - Clinical epigenetics N2 - Background: Gestational diabetes mellitus (GDM) is associated with adverse pregnancy outcomes. It is known that GDM is associated with an altered placental function and changes in placental gene regulation. More recent studies demonstrated an involvement of epigenetic mechanisms. So far, the focus regarding placental epigenetic changes in GDM was set on gene-specific DNA methylation analyses. Studies that robustly investigated placental global DNA methylation are lacking. However, several studies showed that tissue-specific alterations in global DNA methylation are independently associated with type 2 diabetes. Thus, the aim of this study was to characterize global placental DNA methylation by robustly measuring placental DNA 5-methylcytosine (5mC) content and to examine whether differences in placental global DNA methylation are associated with GDM. Methods: Global DNA methylation was quantified by the current gold standard method, LC-MS/MS. In total, 1030 placental samples were analyzed in this single-center birth cohort study. Results: Mothers with GDM displayed a significantly increased global placental DNA methylation (3.22 +/- 0.63 vs. 3.00 +/- 0.46 %; p = 0.013; +/- SD). Bivariate logistic regression showed a highly significant positive correlation between global placental DNA methylation and the presence of GDM (p = 0.0009). Quintile stratification according to placental DNA 5mC levels revealed that the frequency of GDM was evenly distributed in quintiles 1-4 (2.9-5.3 %), whereas the frequency in the fifth quintile was significantly higher (10.7 %; p = 0.003). Bivariate logistic models adjusted for maternal age, BMI, ethnicity, recurrent miscarriages, and familiar diabetes predisposition clearly demonstrated an independent association between global placental DNA hypermethylation and GDM. Furthermore, an ANCOVA model considering known predictors of DNA methylation substantiated an independent association between GDM and placental DNA methylation. Conclusions: This is the first study that employed a robust quantitative assessment of placental global DNA methylation in over a thousand placental samples. The study provides large scale evidence that placental global DNA hypermethylation is associated with GDM, independent of established risk factors. KW - Placenta KW - Gestational diabetes KW - Insulin resistance KW - LC-MS/MS KW - Global DNA methylation KW - Epigenetics KW - Hypermethylation Y1 - 2016 U6 - https://doi.org/10.1186/s13148-016-0247-9 SN - 1868-7083 VL - 8 PB - BioMed Central CY - London ER - TY - CHAP A1 - Reichetzeder, Christoph A1 - Pasch, A. A1 - von Websky, Karoline A1 - Tsuprykov, Oleg A1 - Klein, T. A1 - Hocher, Berthold T1 - The DPP-4 inhibitor linagliptin increases plasma fetuin-A concentrations in a rat model of uraemic calcification T2 - Diabetologia : journal of the European Association for the Study of Diabetes (EASD) Y1 - 2014 SN - 0012-186X SN - 1432-0428 VL - 57 SP - S522 EP - S522 PB - Springer CY - New York ER - TY - GEN A1 - Reichetzeder, Christoph A1 - Hocher, Berthold T1 - DPP4 inhibition prevents AKI T2 - Oncotarget KW - acute kidney injury KW - DPP-4 inhibitors KW - ischemia reperfusion injury KW - gliptins KW - Dipeptidyl peptidase IV Y1 - 2017 U6 - https://doi.org/10.18632/oncotarget.20212 SN - 1949-2553 VL - 8 SP - 64655 EP - 64656 PB - Impact Journals LLC CY - Orchard Park ER - TY - JOUR A1 - Reichetzeder, Christoph A1 - Heunisch, Fabian A1 - von Einem, Gina-Franziska A1 - Tsuprykov, Oleg A1 - Kellner, Karl-Heinz A1 - Dschietzig, Thomas A1 - Kretschmer, Axel A1 - Hocher, Berthold T1 - Pre-interventional kynurenine predicts medium-term outcome after contrast media exposure due to coronary angiography JF - Kidney & blood pressure research : official organ of the Gesellschaft für Nephrologie ; official organ of the Deutsche Liga zur Bekämpfung des Hohen Blutdruckes e.V., Deutsche Hypertonie-Gesellschaft N2 - Background/Aims: Contrast induced acute kidney injury (CI-AKI) remains a serious complication of contrast media enhanced procedures like coronary angiography. There is still a lack of established biomarkers that help to identify patients at high risk for short and long-term complications. The aim of the current study was to evaluate plasma kynurenine as a predictive biomarker for CI-AKI and long-term complications, measured by the combined endpoint "major adverse kidney events" (MAKE) up to 120 days after CM application. Methods: In this prospective cohort study 245 patients undergoing coronary angiography were analyzed. Blood samples were obtained at baseline, 24h and 48h after contrast media (CM) application to diagnose CI-AKI. Patients were followed for 120 days for adverse clinical events including death, the need for dialysis, and a doubling of plasma creatinine. Occurrence of any of these events was summarized in the combined endpoint MAKE. Results: Preinterventional plasma kynurenine was not associated with CI-AKI. Patients who later developed MAKE displayed significantly increased preinterventional plasma kynurenine levels (p<0.0001). ROC analysis revealed that preinterventional kynurenine is highly predictive for MAKE (AUC=0.838; p<0.0001). The optimal cutoff was found at >= 3.5 mu mol/L. Using this cutoff, the Kaplan-Meier estimator demonstrated that concentrations of plasma kynurenine >= 3.5 mu mol/L were significantly associated with a higher prevalence of MAKE until follow up (p<0.0001). This association remained significant in multivariate Cox regression models adjusted for relevant factors of long-term renal outcome. Conclusion: Preinterventional plasma kynurenine might serve as a highly predictive biomarker for MAKE up to 120 days after coronary angiography. KW - Contrast induced acute kidney injury KW - Coronary angiography KW - Major adverse kidney event KW - Kynurenine KW - Preinterventional biomarker Y1 - 2017 U6 - https://doi.org/10.1159/000477222 SN - 1420-4096 SN - 1423-0143 VL - 42 IS - 2 SP - 244 EP - 256 PB - Karger CY - Basel ER - TY - JOUR A1 - Reichetzeder, Christoph A1 - Chen, Hong A1 - Foeller, Michael A1 - Slowinski, Torsten A1 - Li, Jian A1 - Chen, You-Peng A1 - Lang, Florian A1 - Hocher, Berthold T1 - Maternal vitamin D deficiency and fetal programming - lessons learned from humans and mice JF - Kidney & blood pressure research : official organ of the Gesellschaft für Nephrologie N2 - Background/Aims: Cardiovascular disease partially originates from poor environmental and nutritional conditions in early life. Lack of micronutrients like 25 hydroxy vitamin D-3 (25OHD) during pregnancy may be an important treatable causal factor. The present study explored the effect of maternal 25OHD deficiency on the offspring. Methods: We performed a prospective observational study analyzing the association of maternal 25OHD deficiency during pregnancy with birth outcomes considering confounding. To show that vitamin D deficiency may be causally involved in the observed associations, mice were set on either 25OHD sufficient or insufficient diets before and during pregnancy. Growth, glucose tolerance and mortality was analyzed in the F1 generation. Results: The clinical study showed that severe 25OHD deficiency was associated with low birth weight and low gestational age. ANCOVA models indicated that established confounding factors such as offspring sex, smoking during pregnancy and maternal BMI did not influence the impact of 25OHD on birth weight. However, there was a significant interaction between 25OHD and gestational age. Maternal 25OHD deficiency was also independently associated with low APGAR scores 5 minutes postpartum. The offspring of 25OHD deficient mice grew slower after birth, had an impaired glucose tolerance shortly after birth and an increased mortality during follow-up. Conclusions: Our study demonstrates an association between maternal 25OHD and offspring birth weight. The effect of 25OHD on birth weight seems to be mediated by vitamin D controlling gestational age. Results from an animal experiment suggest that gestational 25OHD insufficiency is causally linked to adverse pregnancy outcomes. Since birth weight and prematurity are associated with an adverse cardiovascular outcome in later life, this study emphasizes the need for novel monitoring and treatment guidelines of vitamin D deficiency during pregnancy. KW - Vitamin D KW - Birth weight KW - Preterm delivery KW - Fetal programming KW - Glucose tolerance KW - Cardiovascular diseases Y1 - 2014 U6 - https://doi.org/10.1159/000355809 SN - 1420-4096 SN - 1423-0143 VL - 39 IS - 4 SP - 315 EP - 329 PB - Karger CY - Basel ER - TY - JOUR A1 - Putra, Sulistyo Emantoko Dwi A1 - Tsuprykov, Oleg A1 - Von Websky, Karoline A1 - Ritter, Teresa A1 - Reichetzeder, Christoph A1 - Hocher, Berthold T1 - Dealing with large sample sizes: comparison of a new one spot dot blot method to western blot JF - Clinical laboratory : the peer reviewed journal for clinical laboratories and laboratories related to blood transfusion N2 - Background: Western blot is the gold standard method to determine individual protein expression levels. However, western blot is technically difficult to perform in large sample sizes because it is a time consuming and labor intensive process. Dot blot is often used instead when dealing with large sample sizes, but the main disadvantage of the existing dot blot techniques, is the absence of signal normalization to a housekeeping protein. Methods: In this study we established a one dot two development signals (ODTDS) dot blot method employing two different signal development systems. The first signal from the protein of interest was detected by horseradish peroxidase (HRP). The second signal, detecting the housekeeping protein, was obtained by using alkaline phosphatase (AP). Results: Inter-assay results variations within ODTDS dot blot and western blot and intra-assay variations between both methods were low (1.04 - 5.71%) as assessed by coefficient of variation. Conclusions: ODTDS dot blot technique can be used instead of western blot when dealing with large sample sizes without a reduction in results accuracy. KW - one dot two development signals (ODTDS) dot blot KW - western blot KW - protein quantification KW - large sample size studies KW - comparison Y1 - 2014 U6 - https://doi.org/10.7754/Clin.Lab.2014.140317 SN - 1433-6510 VL - 60 IS - 11 SP - 1871 EP - 1877 PB - Clin Lab Publ., Verl. Klinisches Labor CY - Heidelberg ER - TY - JOUR A1 - Putra, Sulistyo Emantoko Dwi A1 - Neuber, Corinna A1 - Reichetzeder, Christoph A1 - Hocher, Berthold A1 - Kleuser, Burkhard T1 - Analysis of genomic DNA methylation levels in human placenta using liquid Chromatography-Electrospray ionization tandem mass spectrometry JF - Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry and pharmacology N2 - Background: DNA-methylation is a common epigenetic tool which plays a crucial role in gene regulation and is essential for cell differentiation and embryonic development. The placenta is an important organ where gene activity can be regulated by epigenetic DNA modifications, including DNA methylation. This is of interest as, the placenta is the interface between the fetus and its environment, the mother. Exposure to environmental toxins and nutrition during pregnancy may alter DNA methylation of the placenta and subsequently placental function and as a result the phenotype of the offspring. The aim of this study was to develop a reliable method to quantify DNA methylation in large clinical studies. This will be a tool to analyze the degree of DNA methylation in the human placenta in relationship to clinical readouts. Methods: Liquid chromatography-electrospray ionization/multi-stage mass spectrometry (LC-ESI/MS/MS) technique was used for the quantification of the 5dmC/dG ratio in placentas from 248 healthy pregnancies. We were able to demonstrate that this method is a reliable and stable way to determine global placental DNA methylation in large clinical trials. Results/Conclusion: The degree of placental DNA methylation seen in our pilot study varies substantially from 2% to 5%. The clinical implications of this variation need to be demonstrated in adequately powered large studies. KW - Pregnancy KW - Placenta KW - Methylation KW - Global KW - LC-MS/MS KW - Fetal programming KW - Clinical Y1 - 2014 U6 - https://doi.org/10.1159/000358666 SN - 1015-8987 SN - 1421-9778 VL - 33 IS - 4 SP - 945 EP - 952 PB - Karger CY - Basel ER - TY - JOUR A1 - Putra, Sulistyo E. Dwi A1 - Reichetzeder, Christoph A1 - Meixner, Martin A1 - Liere, Karsten A1 - Slowinski, Torsten A1 - Hocher, Berthold T1 - DNA methylation of the glucocorticoid receptor gene promoter in the placenta is associated with blood pressure regulation in human pregnancy JF - Journal of hypertension N2 - Background: Blood pressure (BP) regulation during pregnancy is influenced by hormones of placental origin. It was shown that the glucocorticoid system is altered in hypertensive pregnancy disorders such as preeclampsia. Epigenetic mechanism might influence the activity of genes involved in placental hormone/hormone receptor synthesis/action during pregnancy. Method: In the current study, we analyzed the association of 50-C-phosphate-G-30 (CpG) site methylation of different glucocorticoid receptor gene (NR3C1) promoter regions with BP during pregnancy. The study was performed as a nested case-control study (n = 80) out of 1045 mother/ child pairs from the Berlin Birth Cohort. Placental DNA was extracted and bisulfite converted. Nested PCR products from six NR3C1 proximal promoter regions [glucocorticoid receptor gene promotor region B (GR-1B), C (GR-1C), D (GR-1D), E (GR-1E), F (GR-1F), and H (GR-1H)] were analyzed by next generation sequencing. Results: NR3C1 promoter regions GR-1D and GR-1E had a much higher degree of DNA methylation as compared to GR-1B, GR-1F or GR-1H when analyzing the entire study population. Comparison of placental NR3C1 CpG site methylation among hypotensive, normotensive and hypertensive mothers revealed several differently methylated CpG sites in the GR-1F promoter region only. Both hypertension and hypotension were associated with increased DNA methylation of GR-1F CpG sites. These associations were independent of confounding factors, such as family history of hypertension, smoking status before pregnancy and prepregnancy BMI. Assessment of placental glucocorticoid receptor expression by western blot showed that observed DNA methylation differences were not associated with altered levels of placental glucocorticoid receptor expression. However, correlation matrices of all NR3C1 proximal promoter regions demonstrated different correlation patterns of intraregional and interregional DNA methylation in the three BP groups, putatively indicating altered transcriptional control of glucocorticoid receptor isoforms. Conclusion: Our study provides evidence of an independent association between placental NR3C1 proximal promoter methylation and maternal BP. Furthermore, we observed different patterns of NR3C1 promoter methylation in normotensive, hypertensive and hypotensive pregnancy. KW - DNA methylation KW - epigenetics KW - glucocorticoid receptor KW - hypertension KW - hypotension KW - NR3C1 gene KW - placenta KW - pregnancy Y1 - 2017 U6 - https://doi.org/10.1097/HJH.0000000000001450 SN - 0263-6352 SN - 1473-5598 VL - 35 SP - 2276 EP - 2286 PB - Lippincott Williams & Wilkins CY - Philadelphia ER - TY - CHAP A1 - Pfab, T. A1 - Sharkovska, Yukiya A1 - Alter, Markus L. A1 - von Websky, Karoline A1 - Mark, M. A1 - Klein, T. A1 - Hocher, Berthold T1 - Effect of linagliptin on infarction size and cardiac function in rats after myocardial ischaemia reperfusion T2 - Diabetologia : journal of the European Association for the Study of Diabetes (EASD) Y1 - 2011 SN - 0012-186X VL - 54 SP - S329 EP - S329 PB - Springer CY - New York ER - TY - JOUR A1 - Peng, Tao A1 - Zhu, Ganghua A1 - Dong, Yunpeng A1 - Zeng, Junjie A1 - Li, Wei A1 - Guo, Weiwei A1 - Chen, Yong A1 - Duan, Maoli A1 - Hocher, Berthold A1 - Xie, Dinghua T1 - BMP4: a possible key factor in differentiation of auditory neuron-like cells from bone-derived mesenchymal stromal cells JF - Clinical laboratory : the peer reviewed journal for clinical laboratories and laboratories related to blood transfusion N2 - Background: Previous studies have shown that BMP4 may play an important part in the development of auditory neurons (ANs), which are degenerated in sensorineural hearing loss. However, whether BMP4 can promote sensory fate specification from mesenchymal stromal cells (MSCs) is unknown so far. Methods: MSCs isolated from Sprague-Dawley (SD) rats were confirmed by expression of MSC markers using flow cytometry and adipogenesis/osteogenesis using differentiation assays. MSCs treated with a complex of neurotrophic factors (BMP4 group and non-BMP4 group) were induced into auditory neuron-like cells, then the differences between the two groups were analyzed in morphological observation, cell growth curve, qRT-PCR, and immunofluorescence. Results: Flow cytometric analysis showed that the isolated cells expressed typical MSC surface markers. After adipogenic and osteogenic induction, the cells were stained by oil red O and Alizarin Red. The neuronal induced cells were in the growth plateau and had special forms of neurons. In the presence of BMP4, the inner ear genes NF-M, Neurog1, GluR4, NeuroD, Calretinin, NeuN, Tau, and GATA3 were up-regulated in MSCs. Conclusions: MSCs have the capacity to differentiate into auditory neuron-like cells in vitro. As an effective inducer, BMP4 may play a key role in transdifferentiation. KW - differentiation KW - auditory neurons KW - BMP4 Y1 - 2015 U6 - https://doi.org/10.7754/Clin.Lab.2015.150217 SN - 1433-6510 VL - 61 IS - 9 SP - 1171 EP - 1178 PB - Clin Lab Publ., Verl. Klinisches Labor CY - Heidelberg ER - TY - JOUR A1 - Ott, Ina M. A1 - Alter, Markus L. A1 - von Websky, Karoline A1 - Kretschmer, Axel A1 - Tsuprykov, Oleg A1 - Sharkovska, Yuliya A1 - Krause-Relle, Katharina A1 - Raila, Jens A1 - Henze, Andrea A1 - Stasch, Johannes-Peter A1 - Hocher, Berthold T1 - Effects of Stimulation of Soluble Guanylate Cyclase on Diabetic Nephropathy in Diabetic eNOS Knockout Mice on Top of Angiotensin II Receptor Blockade JF - PLOS ONE N2 - The prevalence of diabetes mellitus and its complications, such as diabetic nephropathy (DN), is rising worldwide and prevention and treatment are therefore becoming increasingly important. Therapy of DN is particularly important for patients who do not adequately respond to angiotensin receptor blocker (ARB) treatment. Novel approaches include the stimulation of soluble guanylate cyclase (sGC) as it is reported to have beneficial effects on cardiac and renal damage. We aimed to investigate the effects of the sGC stimulator riociguat and ARB telmisartan on kidney function and structure in a hypertensive model of diabetic nephropathy. Seventy-six diabetic male eNOS knockout C57BL/6J mice were randomly divided after having received streptozotocin: telmisartan (1 mg/kg/d), riociguat (3 mg/kg/d), riociguat+telmisartan (3+1 mg/kg/d), and vehicle. Fourteen mice were used as non-diabetic controls. Treatment duration was 11 weeks. Glucose concentrations were increased and similar in all diabetic groups. Telmisartan insignificantly reduced blood pressure by 5.9 mmHg compared with diabetic controls (111.2 +/- 2.3 mmHg vs. 117.1 +/- 2.2 mmHg; p = 0.071). Treatment with riociguat both alone and in combination with telmisartan led to a significant reduction of blood pressure towards diabetic vehicle (105.2 +/- 2.5 mmHg and 105.0 +/- 3.2 mmHg, respectively, vs. 117.1 +/- 2.2 mmHg). Combined treatment also significantly decreased albuminuria compared with diabetic controls (47.3 +/- 9.6 mu g/24 h vs. 170.8 +/- 34.2 mu g/24 h; p = 0.002) reaching levels similar to those of non-diabetic controls (34.4 +/- 10.6 mu g/24 h), whereas the reduction by single treatment with either telmisartan (97.8 +/- 26.4 mu g/24 h) or riociguat (97.1 +/- 15.7 mu g/24 h) was not statistically significant. The combination treatment led to a significant (p < 0.01) decrease of tissue immunoreactivity of malondialdehyde, as consequence of reduced oxidative stress. In conclusion, stimulation of sGC significantly reduced urinary albumin excretion in diabetic eNOS knockout mice treated already with ARB. Thus, this new drug class on top of standard ARBs administration may offer a new therapeutic approach for patients resistant to ARB treatment. Y1 - 2012 U6 - https://doi.org/10.1371/journal.pone.0042623 SN - 1932-6203 VL - 7 IS - 8 PB - PUBLIC LIBRARY SCIENCE CY - SAN FRANCISCO ER - TY - JOUR A1 - Ong, Albert C. M. A1 - von Websky, Karoline A1 - Hocher, Berthold T1 - Endothelin and Tubulointerstitial Renal Disease JF - Seminars in nephrology N2 - All components of the endothelin (ET) system are present in renal tubular cells. In this review, we summarize current knowledge about ET and the most common tubular diseases: acute kidney injury (AKI) and polycystic kidney disease. AKI originally was called acute tubular necrosis, pointing to the most prominent morphologic findings. Similarly, cysts in polycystic kidney disease, and especially in autosomal-dominant polycystic kidney disease, are of tubular origin. Preclinical studies have indicated that the ET system and particularly ETA receptors are involved in the pathogenesis of ischemia-reperfusion injury, although these findings have not been translated to clinical studies. The ET system also has been implicated in radiocontrast-dye-induced AKI, however, ET-receptor blockade in a large human study was not successful. The ET system is activated in sepsis models of AKI; the effectiveness of ET blocking agents in preclinical studies is variable depending on the model and the ET-receptor antagonist used. Numerous studies have shown that the ET system plays an important role in the complex pathophysiology associated with cyst formation and disease progression in polycystic kidney disease. However, results from selective targeting of ET-receptor subtypes in animal models of polycystic kidney disease have proved disappointing and do not support clinical trials. These studies have shown that a critical balance between ETA and ETB receptor action is necessary to maintain structure and function in the cystic kidney. In summary, ETs have been implicated in the pathogenesis of several renal tubulointerstitial diseases, however, experimental animal findings have not yet led to use of ET blockers in human beings. (C) 2015 Elsevier Inc. All rights reserved. KW - Endothelin KW - acute kidney injury KW - polycystic kidney disease KW - ADPKD KW - ET-1 KW - ETA KW - ETB Y1 - 2015 U6 - https://doi.org/10.1016/j.semnephrol.2015.03.004 SN - 0270-9295 SN - 1558-4488 VL - 35 IS - 2 SP - 197 EP - 207 PB - Elsevier CY - Philadelphia ER - TY - JOUR A1 - Nair, Anil V. A1 - Hocher, Berthold A1 - Verkaart, Sjoerd A1 - van Zeeland, Femke A1 - Pfab, Thiemo A1 - Slowinski, Torsten A1 - Chen, You-Peng A1 - Schlingmann, Karl Peter A1 - Schaller, Andre A1 - Gallati, Sabina A1 - Bindels, Rene J. A1 - Konrad, Martin A1 - Hönderop, Joost G. T1 - Loss of insulin-induced activation of TRPM6 magnesium channels results in impaired glucose tolerance during pregnancy JF - Proceedings of the National Academy of Sciences of the United States of America N2 - Hypomagnesemia affects insulin resistance and is a risk factor for diabetes mellitus type 2 (DM2) and gestational diabetes mellitus (GDM). Two single nucleotide polymorphisms (SNPs) in the epithelial magnesium channel TRPM6 ((VI)-I-1393, (KE)-E-1584) were predicted to confer susceptibility for DM2. Here, we show using patch clamp analysis and total internal reflection fluorescence microscopy, that insulin stimulates TRPM6 activity via a phosphoinositide 3-kinase and Rac1-mediated elevation of cell surface expression of TRPM6. Interestingly, insulin failed to activate the genetic variants TRPM6 ((VI)-I-1393) and TRPM6((KE)-E-1584), which is likely due to the inability of the insulin signaling pathway to phosphorylate TRPM6(T-1391) and TRPM6(S-1583). Moreover, by measuring total glycosylated hemoglobin (TGH) in 997 pregnant women as a measure of glucose control, we demonstrate that TRPM6((VI)-I-1393) and TRPM6((KE)-E-1584) are associated with higher TGH and confer a higher likelihood of developing GDM. The impaired response of TRPM6((VI)-I-1393) and TRPM6((KE)-E-1584) to insulin represents a unique molecular pathway leading to GDM where the defect is located in TRPM6. KW - kidney KW - distal convoluted tubule KW - transient receptor potential KW - vesicular trafficking Y1 - 2012 U6 - https://doi.org/10.1073/pnas.1113811109 SN - 0027-8424 VL - 109 IS - 28 SP - 11324 EP - 11329 PB - National Acad. of Sciences CY - Washington ER - TY - JOUR A1 - Middeldorp, Christel M. A1 - Mahajan, Anubha A1 - Horikoshi, Momoko A1 - Robertson, Neil R. A1 - Beaumont, Robin N. A1 - Bradfield, Jonathan P. A1 - Bustamante, Mariona A1 - Cousminer, Diana L. A1 - Day, Felix R. A1 - De Silva, N. Maneka A1 - Guxens, Monica A1 - Mook-Kanamori, Dennis O. A1 - St Pourcain, Beate A1 - Warrington, Nicole M. A1 - Adair, Linda S. A1 - Ahlqvist, Emma A1 - Ahluwalia, Tarunveer Singh A1 - Almgren, Peter A1 - Ang, Wei A1 - Atalay, Mustafa A1 - Auvinen, Juha A1 - Bartels, Meike A1 - Beckmann, Jacques S. A1 - Bilbao, Jose Ramon A1 - Bond, Tom A1 - Borja, Judith B. A1 - Cavadino, Alana A1 - Charoen, Pimphen A1 - Chen, Zhanghua A1 - Coin, Lachlan A1 - Cooper, Cyrus A1 - Curtin, John A. A1 - Custovic, Adnan A1 - Das, Shikta A1 - Davies, Gareth E. A1 - Dedoussis, George V. A1 - Duijts, Liesbeth A1 - Eastwood, Peter R. A1 - Eliasen, Anders U. A1 - Elliott, Paul A1 - Eriksson, Johan G. A1 - Estivill, Xavier A1 - Fadista, Joao A1 - Fedko, Iryna O. A1 - Frayling, Timothy M. A1 - Gaillard, Romy A1 - Gauderman, W. James A1 - Geller, Frank A1 - Gilliland, Frank A1 - Gilsanz, Vincente A1 - Granell, Raquel A1 - Grarup, Niels A1 - Groop, Leif A1 - Hadley, Dexter A1 - Hakonarson, Hakon A1 - Hansen, Torben A1 - Hartman, Catharina A. A1 - Hattersley, Andrew T. A1 - Hayes, M. Geoffrey A1 - Hebebrand, Johannes A1 - Heinrich, Joachim A1 - Helgeland, Oyvind A1 - Henders, Anjali K. A1 - Henderson, John A1 - Henriksen, Tine B. A1 - Hirschhorn, Joel N. A1 - Hivert, Marie-France A1 - Hocher, Berthold A1 - Holloway, John W. A1 - Holt, Patrick A1 - Hottenga, Jouke-Jan A1 - Hypponen, Elina A1 - Iniguez, Carmen A1 - Johansson, Stefan A1 - Jugessur, Astanand A1 - Kahonen, Mika A1 - Kalkwarf, Heidi J. A1 - Kaprio, Jaakko A1 - Karhunen, Ville A1 - Kemp, John P. A1 - Kerkhof, Marjan A1 - Koppelman, Gerard H. A1 - Korner, Antje A1 - Kotecha, Sailesh A1 - Kreiner-Moller, Eskil A1 - Kulohoma, Benard A1 - Kumar, Ashish A1 - Kutalik, Zoltan A1 - Lahti, Jari A1 - Lappe, Joan M. A1 - Larsson, Henrik A1 - Lehtimaki, Terho A1 - Lewin, Alexandra M. A1 - Li, Jin A1 - Lichtenstein, Paul A1 - Lindgren, Cecilia M. A1 - Lindi, Virpi A1 - Linneberg, Allan A1 - Liu, Xueping A1 - Liu, Jun A1 - Lowe, William L. A1 - Lundstrom, Sebastian A1 - Lyytikainen, Leo-Pekka A1 - Ma, Ronald C. W. A1 - Mace, Aurelien A1 - Magi, Reedik A1 - Magnus, Per A1 - Mamun, Abdullah A. A1 - Mannikko, Minna A1 - Martin, Nicholas G. A1 - Mbarek, Hamdi A1 - McCarthy, Nina S. A1 - Medland, Sarah E. A1 - Melbye, Mads A1 - Melen, Erik A1 - Mohlke, Karen L. A1 - Monnereau, Claire A1 - Morgen, Camilla S. A1 - Morris, Andrew P. A1 - Murray, Jeffrey C. A1 - Myhre, Ronny A1 - Najman, Jackob M. A1 - Nivard, Michel G. A1 - Nohr, Ellen A. A1 - Nolte, Ilja M. A1 - Ntalla, Ioanna A1 - Oberfield, Sharon E. A1 - Oken, Emily A1 - Oldehinkel, Albertine J. A1 - Pahkala, Katja A1 - Palviainen, Teemu A1 - Panoutsopoulou, Kalliope A1 - Pedersen, Oluf A1 - Pennell, Craig E. A1 - Pershagen, Goran A1 - Pitkanen, Niina A1 - Plomin, Robert A1 - Power, Christine A1 - Prasad, Rashmi B. A1 - Prokopenko, Inga A1 - Pulkkinen, Lea A1 - Raikkonen, Katri A1 - Raitakari, Olli T. A1 - Reynolds, Rebecca M. A1 - Richmond, Rebecca C. A1 - Rivadeneira, Fernando A1 - Rodriguez, Alina A1 - Rose, Richard J. A1 - Salem, Rany A1 - Santa-Marina, Loreto A1 - Saw, Seang-Mei A1 - Schnurr, Theresia M. A1 - Scott, James G. A1 - Selzam, Saskia A1 - Shepherd, John A. A1 - Simpson, Angela A1 - Skotte, Line A1 - Sleiman, Patrick M. A. A1 - Snieder, Harold A1 - Sorensen, Thorkild I. A. A1 - Standl, Marie A1 - Steegers, Eric A. P. A1 - Strachan, David P. A1 - Straker, Leon A1 - Strandberg, Timo A1 - Taylor, Michelle A1 - Teo, Yik-Ying A1 - Thiering, Elisabeth A1 - Torrent, Maties A1 - Tyrrell, Jessica A1 - Uitterlinden, Andre G. A1 - van Beijsterveldt, Toos A1 - van der Most, Peter J. A1 - van Duijn, Cornelia M. A1 - Viikari, Jorma A1 - Vilor-Tejedor, Natalia A1 - Vogelezang, Suzanne A1 - Vonk, Judith M. A1 - Vrijkotte, Tanja G. M. A1 - Vuoksimaa, Eero A1 - Wang, Carol A. A1 - Watkins, William J. A1 - Wichmann, H-Erich A1 - Willemsen, Gonneke A1 - Williams, Gail M. A1 - Wilson, James F. A1 - Wray, Naomi R. A1 - Xu, Shujing A1 - Xu, Cheng-Jian A1 - Yaghootkar, Hanieh A1 - Yi, Lu A1 - Zafarmand, Mohammad Hadi A1 - Zeggini, Eleftheria A1 - Zemel, Babette S. A1 - Hinney, Anke A1 - Lakka, Timo A. A1 - Whitehouse, Andrew J. O. A1 - Sunyer, Jordi A1 - Widen, Elisabeth E. A1 - Feenstra, Bjarke A1 - Sebert, Sylvain A1 - Jacobsson, Bo A1 - Njolstad, Pal R. A1 - Stoltenberg, Camilla A1 - Smith, George Davey A1 - Lawlor, Debbie A. A1 - Paternoster, Lavinia A1 - Timpson, Nicholas J. A1 - Ong, Ken K. A1 - Bisgaard, Hans A1 - Bonnelykke, Klaus A1 - Jaddoe, Vincent W. V. A1 - Tiemeier, Henning A1 - Jarvelin, Marjo-Riitta A1 - Evans, David M. A1 - Perry, John R. B. A1 - Grant, Struan F. A. A1 - Boomsma, Dorret I. A1 - Freathy, Rachel M. A1 - McCarthy, Mark I. A1 - Felix, Janine F. T1 - The Early Growth Genetics (EGG) and EArly Genetics and Lifecourse Epidemiology (EAGLE) consortia BT - design, results and future prospects JF - European journal of epidemiology N2 - The impact of many unfavorable childhood traits or diseases, such as low birth weight and mental disorders, is not limited to childhood and adolescence, as they are also associated with poor outcomes in adulthood, such as cardiovascular disease. Insight into the genetic etiology of childhood and adolescent traits and disorders may therefore provide new perspectives, not only on how to improve wellbeing during childhood, but also how to prevent later adverse outcomes. To achieve the sample sizes required for genetic research, the Early Growth Genetics (EGG) and EArly Genetics and Lifecourse Epidemiology (EAGLE) consortia were established. The majority of the participating cohorts are longitudinal population-based samples, but other cohorts with data on early childhood phenotypes are also involved. Cohorts often have a broad focus and collect(ed) data on various somatic and psychiatric traits as well as environmental factors. Genetic variants have been successfully identified for multiple traits, for example, birth weight, atopic dermatitis, childhood BMI, allergic sensitization, and pubertal growth. Furthermore, the results have shown that genetic factors also partly underlie the association with adult traits. As sample sizes are still increasing, it is expected that future analyses will identify additional variants. This, in combination with the development of innovative statistical methods, will provide detailed insight on the mechanisms underlying the transition from childhood to adult disorders. Both consortia welcome new collaborations. Policies and contact details are available from the corresponding authors of this manuscript and/or the consortium websites. KW - Genetics KW - Consortium KW - Childhood traits and disorders KW - Longitudinal Y1 - 2019 U6 - https://doi.org/10.1007/s10654-019-00502-9 SN - 0393-2990 SN - 1573-7284 VL - 34 IS - 3 SP - 279 EP - 300 PB - Springer CY - Dordrecht ER - TY - JOUR A1 - Luo, Ting A1 - Chen, Xiaoyi A1 - Zeng, Shufei A1 - Guan, Baozhang A1 - Hu, Bo A1 - Meng, Yu A1 - Liu, Fanna A1 - Wong, Taksui A1 - Lu, Yongpin A1 - Yun, Chen A1 - Hocher, Berthold A1 - Yin, Lianghong T1 - Bioinformatic identification of key genes and analysis of prognostic values in clear cell renal cell carcinoma JF - Oncology Letters N2 - The present study aimed to identify new key genes as potential biomarkers for the diagnosis, prognosis or targeted therapy of clear cell renal cell carcinoma (ccRCC). Three expression profiles (GSE36895, GSE46699 and GSE71963) were collected from Gene Expression Omnibus. GEO2R was used to identify differentially expressed genes (DEGs) in ccRCC tissues and normal samples. The Database for Annotation, Visualization and Integrated Discovery was utilized for functional and pathway enrichment analysis. STRING v10.5 and Molecular Complex Detection were used for protein-protein interaction (PPI) network construction and module analysis, respectively. Regulation network analyses were performed with the WebGestal tool. UALCAN web-portal was used for expression validation and survival analysis of hub genes in ccRCC patients from The Cancer Genome Atlas (TCGA). A total of 65 up- and 164 downregulated genes were identified as DEGs. DEGs were enriched with functional terms and pathways compactly related to ccRCC pathogenesis. Seventeen hub genes and one significant module were filtered out and selected from the PPI network. The differential expression of hub genes was verified in TCGA patients. Kaplan-Meier plot showed that high mRNA expression of enolase 2 (ENO2) was associated with short overall survival in ccRCC patients (P=0.023). High mRNA expression of cyclin D1 (CCND1) (P<0.001), fms related tyrosine kinase 1 (FLT1) (P=0.004), plasminogen (PLG) (P<0.001) and von Willebrand factor (VWF) (P=0.008) appeared to serve as favorable factors in survival. These findings indicate that the DEGs may be key genes in ccRCC pathogenesis and five genes, including ENO2, CCND1, PLT1, PLG and VWF, may serve as potential prognostic biomarkers in ccRCC. KW - clear cell renal cell carcinoma KW - bioinformatics KW - differentially expressed genes KW - biomarkers KW - Kaplan-Meier plot Y1 - 2018 U6 - https://doi.org/10.3892/ol.2018.8842 SN - 1792-1074 SN - 1792-1082 VL - 16 IS - 2 SP - 1747 EP - 1757 PB - Spandidos publ LTD CY - Athens ER - TY - JOUR A1 - Lu, Yong-Ping A1 - Zeng, De-Ying A1 - Chen, You-Peng A1 - Liang, Xu-Jing A1 - Xu, Jie-Ping A1 - Huang, Si-Min A1 - Lai, Zhi-Wei A1 - Wen, Wang-Rong A1 - von Websky, Karoline A1 - Hocher, Berthold T1 - Low birth weight is associated with lower respiratory tract infections in children with hand, foot, and mouth disease JF - Clinical laboratory : the peer reviewed journal for clinical laboratories and laboratories related to blood transfusion N2 - Background: Low birth weight (LBW) might be a risk factor for acquiring lower respiratory tract infections (LRTIs) associated with disease related complications in early childhood. HFMD, a frequent viral infection in southern China, is a leading cause of lower respiratory tract infections in children. We analyzed whether LBW is a risk factor for children with HFMD to develop lower respiratory tract infections. Methods: A total of 298 children with HFMD, admitted to a hospital in Qingyuan city, Guangdong province, were recruited. Demographic data and clinical parameters such as serum glucose level and inflammatory markers including peripheral white blood cell count, serum C-reactive protein, and erythrocyte sedimentation rate were routinely collected on admission. Birth weight data were derived from birth records. Results: Mean birth weight (BW) was 167 g lower in patients with HFMD and LRTIs as compared to patients with solely HFMD (p = 0.022) and the frequency of birth weight below the tenth percentile was significantly higher in patients with HFMD and LRTIs (p = 0.002). Conclusions: The results of the study show that low birth weight is associated with a higher incidence of lower respiratory tract infections in young children with HFMD. KW - hand KW - foot and mouth disease (HFMD) KW - low birth weight (LBW) KW - lower respiratory tract infections (LRTIs) KW - pneumonia KW - children Y1 - 2013 U6 - https://doi.org/10.7754/Clin.Lab.2012.120725 SN - 1433-6510 VL - 59 IS - 9-10 SP - 985 EP - 992 PB - Clin Lab Publ., Verl. Klinisches Labor CY - Heidelberg ER - TY - GEN A1 - Lu, Yong-Ping A1 - Reichetzeder, Christoph A1 - Prehn, Cornelia A1 - Yin, Liang-Hong A1 - Yun, Chen A1 - Zeng, Shufei A1 - Chu, Chang A1 - Adamski, Jerzy A1 - Hocher, Berthold T1 - Cord blood Lysophosphatidylcholine 16:1 is positively associated with birth weight T2 - Postprints der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe N2 - Background/Aims: Impaired birth outcomes, like low birth weight, have consistently been associated with increased disease susceptibility to hypertension in later life. Alterations in the maternal or fetal metabolism might impact on fetal growth and influence birth outcomes. Discerning associations between the maternal and fetal metabolome and surrogate parameters of fetal growth could give new insight into the complex relationship between intrauterine conditions, birth outcomes, and later life disease susceptibility. Methods: Using flow injection tandem mass spectrometry, targeted metabolomics was performed in serum samples obtained from 226 mother/child pairs at delivery. Associations between neonatal birth weight and concentrations of 163 maternal and fetal metabolites were analyzed. Results: After FDR adjustment using the Benjamini-Hochberg procedure lysophosphatidylcholines (LPC) 14:0, 16:1, and 18:1 were strongly positively correlated with birth weight. In a stepwise linear regression model corrected for established confounding factors of birth weight, LPC 16: 1 showed the strongest independent association with birth weight (CI: 93.63 - 168.94; P = 6.94x10(-11)). The association with birth weight was stronger than classical confounding factors such as offspring sex (CI: - 258.81- -61.32; P = 0.002) and maternal smoking during pregnancy (CI: -298.74 - -29.51; P = 0.017). Conclusions: After correction for multiple testing and adjustment for potential confounders, LPC 16:1 showed a very strong and independent association with birth weight. The underlying molecular mechanisms linking fetal LPCs with birth weight need to be addressed in future studies. (c) 2018 The Author(s) Published by S. Karger AG, Basel T3 - Zweitveröffentlichungen der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe - 631 KW - metabolomics KW - Lysophosphatidylcholine KW - birth weight KW - DOHaD KW - hypertension KW - Type 2 Diabetes Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:kobv:517-opus4-424566 SN - 1866-8372 IS - 631 ER - TY - JOUR A1 - Lu, Yong-Ping A1 - Reichetzeder, Christoph A1 - Prehn, Cornelia A1 - Yin, Liang-Hong A1 - Yun, Chen A1 - Zeng, Shufei A1 - Chu, Chang A1 - Adamski, Jerzy A1 - Hocher, Berthold T1 - Cord blood Lysophosphatidylcholine 16:1 is positively associated with birth weight JF - Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry and pharmacology N2 - Background/Aims: Impaired birth outcomes, like low birth weight, have consistently been associated with increased disease susceptibility to hypertension in later life. Alterations in the maternal or fetal metabolism might impact on fetal growth and influence birth outcomes. Discerning associations between the maternal and fetal metabolome and surrogate parameters of fetal growth could give new insight into the complex relationship between intrauterine conditions, birth outcomes, and later life disease susceptibility. Methods: Using flow injection tandem mass spectrometry, targeted metabolomics was performed in serum samples obtained from 226 mother/child pairs at delivery. Associations between neonatal birth weight and concentrations of 163 maternal and fetal metabolites were analyzed. Results: After FDR adjustment using the Benjamini-Hochberg procedure lysophosphatidylcholines (LPC) 14:0, 16:1, and 18:1 were strongly positively correlated with birth weight. In a stepwise linear regression model corrected for established confounding factors of birth weight, LPC 16: 1 showed the strongest independent association with birth weight (CI: 93.63 - 168.94; P = 6.94x10(-11)). The association with birth weight was stronger than classical confounding factors such as offspring sex (CI: - 258.81- -61.32; P = 0.002) and maternal smoking during pregnancy (CI: -298.74 - -29.51; P = 0.017). Conclusions: After correction for multiple testing and adjustment for potential confounders, LPC 16:1 showed a very strong and independent association with birth weight. The underlying molecular mechanisms linking fetal LPCs with birth weight need to be addressed in future studies. (c) 2018 The Author(s) Published by S. Karger AG, Basel KW - Metabolomics KW - Lysophosphatidylcholine KW - Birth Weight KW - DOHaD KW - Hypertension KW - Type 2 Diabetes Y1 - 2018 U6 - https://doi.org/10.1159/000487118 SN - 1015-8987 SN - 1421-9778 VL - 45 IS - 2 SP - 614 EP - 624 PB - Karger CY - Basel ER - TY - JOUR A1 - Lu, Yong-Ping A1 - Reichetzeder, Christoph A1 - Prehn, Cornelia A1 - von Websky, Karoline A1 - Slowinski, Torsten A1 - Chen, You-Peng A1 - Yin, Liang-Hong A1 - Kleuser, Burkhard A1 - Yang, Xue-Song A1 - Adamski, Jerzy A1 - Hocher, Berthold T1 - Fetal serum metabolites are independently associated with Gestational diabetes mellitus JF - Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry and pharmacology N2 - Background/Aims: Gestational diabetes (GDM) might be associated with alterations in the metabolomic profile of affected mothers and their offspring. Until now, there is a paucity of studies that investigated both, the maternal and the fetal serum metabolome in the setting of GDM. Mounting evidence suggests that the fetus is not just passively affected by gestational disease but might play an active role in it. Metabolomic studies performed in maternal blood and fetal cord blood could help to better discern distinct fetal from maternal disease interactions. Methods: At the time of birth, serum samples from mothers and newborns (cord blood samples) were collected and screened for 163 metabolites utilizing tandem mass spectrometry. The cohort consisted of 412 mother/child pairs, including 31 cases of maternal GDM. Results: An initial non-adjusted analysis showed that eight metabolites in the maternal blood and 54 metabolites in the cord blood were associated with GDM. After Benjamini-Hochberg (BH) procedure and adjustment for confounding factors for GDM, fetal phosphatidylcholine acyl-alkyl C 32:1 and proline still showed an independent association with GDM. Conclusions: This study found metabolites in cord blood which were associated with GDM, even after adjustment for established risk factors of GDM. To the best of our knowledge, this is the first study demonstrating an independent association between fetal serum metabolites and maternal GDM. Our findings might suggest a potential effect of the fetal metabolome on maternal GDM. (c) 2018 The Author(s) Published by S. Karger AG, Basel KW - Gestational diabetes KW - Metabolomics KW - Phosphatidylcholine acyl-alkyl C 32:1 KW - Proline Y1 - 2018 U6 - https://doi.org/10.1159/000487119 SN - 1015-8987 SN - 1421-9778 VL - 45 IS - 2 SP - 625 EP - 638 PB - Karger CY - Basel ER - TY - GEN A1 - Lu, Yong-Ping A1 - Reichetzeder, Christoph A1 - Prehn, Cornelia A1 - von Websky, Karoline A1 - Slowinski, Torsten A1 - Chen, You-Peng A1 - Yin, Liang-Hong A1 - Kleuser, Burkhard A1 - Yang, Xue-Song A1 - Adamski, Jerzy A1 - Hocher, Berthold T1 - Fetal serum metabolites are independently associated with Gestational diabetes mellitus T2 - Postprints der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe N2 - Background/Aims: Gestational diabetes (GDM) might be associated with alterations in the metabolomic profile of affected mothers and their offspring. Until now, there is a paucity of studies that investigated both, the maternal and the fetal serum metabolome in the setting of GDM. Mounting evidence suggests that the fetus is not just passively affected by gestational disease but might play an active role in it. Metabolomic studies performed in maternal blood and fetal cord blood could help to better discern distinct fetal from maternal disease interactions. Methods: At the time of birth, serum samples from mothers and newborns (cord blood samples) were collected and screened for 163 metabolites utilizing tandem mass spectrometry. The cohort consisted of 412 mother/child pairs, including 31 cases of maternal GDM. Results: An initial non-adjusted analysis showed that eight metabolites in the maternal blood and 54 metabolites in the cord blood were associated with GDM. After Benjamini-Hochberg (BH) procedure and adjustment for confounding factors for GDM, fetal phosphatidylcholine acyl-alkyl C 32:1 and proline still showed an independent association with GDM. Conclusions: This study found metabolites in cord blood which were associated with GDM, even after adjustment for established risk factors of GDM. To the best of our knowledge, this is the first study demonstrating an independent association between fetal serum metabolites and maternal GDM. Our findings might suggest a potential effect of the fetal metabolome on maternal GDM. (c) 2018 The Author(s) Published by S. Karger AG, Basel T3 - Zweitveröffentlichungen der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe - 637 KW - Gestational diabetes KW - metabolomics KW - phosphatidylcholine acyl-alkyl C 32:1 KW - proline Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:kobv:517-opus4-424585 SN - 1866-8372 IS - 637 ER - TY - JOUR A1 - Lu, Yong-Ping A1 - Lung, Xu-Jing A1 - Xiao, Xiao-Min A1 - Huang, Si-Min A1 - Liu, Zhi-Wei A1 - Li, Jian A1 - Hocher, Berthold A1 - Chen, You-Peng T1 - Telbivudine during the second and third trimester of pregnancy interrupts HBV intrauterine transmission: a systematic review and meta-analysis JF - Clinical laboratory : the peer reviewed journal for clinical laboratories and laboratories related to blood transfusion N2 - Beckground: Evaluate the efficacy and safety of telbivudine during the 2nd and 3rd trimester of pregnancy in intrauterine transmission of hepatitis B virus (HBV). Based on the principle of Cochrane systematic reviews, a database was constructed from Medline, EMBASE, Cochrane Library, the US National Science Digital Library (NSDL), the China Biological Medicine Database (CBM-disc), and contact with Chinese experts in the field from November 2006 to February 2013. Results: Either the Mantel-Haenszel or Inverse Variance fixed-effects model or Mantel-Haenszel or Inverse Variance random-effects model was applied for all analyses indicated by odds ratio (OR) and 95% confidence interval (CI). The meta-analysis based on new onset of HBsAg seropositivity of infants at 6 - 12 months postpartum revealed that the control group had an intrauterine transmission rate of 8.25 - 42.31%. This rate was reduced to 0 - 14.29% in the telbivudine treatment group (OR 0.09, 95% CI 0.04 - 0.22, including seven trials, p < 0.001). The rates of intrauterine transmission based on new onset of HBV DNA seropositivity of infants at 6 - 12 months postpartum were 8.25 - 19.23% in the control group and 0 - 3.57% in the treatment group (OR 0.07, 95% CI 0.02 - 0.22, p < 0.001, including only five trials, since two trials had no data on HBV DNA in infants). With the exception of CK elevations, adverse effect frequencies were similar in both groups. Conclusions: Telbivudine is an effective and safe drug for preventing intrauterine transmission of HBV. KW - telbivudine KW - meta-analysis KW - intrauterine KW - transmission of hepatitis B virus (HBV) KW - clinical studies KW - safety efficacy Y1 - 2014 U6 - https://doi.org/10.7754/Clin.Lab.2013.130408 SN - 1433-6510 VL - 60 IS - 4 SP - 571 EP - 586 PB - Clin Lab Publ., Verl. Klinisches Labor CY - Heidelberg ER - TY - JOUR A1 - Lu, Yong-Ping A1 - Hasan, Ahmed A. A1 - Zeng, Shufei A1 - Hocher, Berthold T1 - Plasma ET-1 concentrations are elevated in pregnant women with hypertension - meta-analysis of clinical studies JF - Kidney & blood pressure research : official organ of the Gesellschaft für Nephrologie ; official organ of the Deutsche Liga zur Bekämpfung des Hohen Blutdruckes e.V., Deutsche Hypertonie-Gesellschaft N2 - Background/Aims: The ET system might be involved in the pathogenesis of hypertensive disorders during pregnancy. The objective is to analyse the impact of ET-1 in hypertensive pregnant women by a strict meta-analysis of published human clinical studies. Methods: Based on the principle of Cochrane systematic reviews, Cohort studies in PubMed (Medline), Google Scholar and China Biological Medicine Database (CBM-disc) designed to identify the role of endothelin-1 (ET-1) in the pathophysiology of gestational hypertension and preeclampsia were screened. Review Manager Version 5.0 (Rev-Man 5.0) was applied for statistical analysis. Mean difference and 95% confidence interval (CI) were shown in inverse variance (IV) fixed-effects model or IV random-effects model. Results: Sixteen published cohort studies including 1739 hypertensive cases and 409 controls were used in the meta-analysis. ET-1 plasma concentrations were higher in hypertensive pregnant women as compared to the controls (mean difference between groups: 19.02 [15.60～22.44], P < 0.00001,). These finding were driven by severity of hypertension and/or degree of proteinuria. Conclusion: Plasma ET-1 concentrations are elevated in hypertensive disorders during human pregnancy. In particular women with preeclampsia (hypertensive pregnant women with proteinuria) have substantially elevated plasma ET-1 concentration as compared to pregnant women with normal blood pressure. KW - Et-1 KW - Pregnancy KW - Hypertension KW - Meta-analysis Y1 - 2017 U6 - https://doi.org/10.1159/000482004 SN - 1420-4096 SN - 1423-0143 VL - 42 IS - 4 SP - 654 EP - 663 PB - Karger CY - Basel ER - TY - JOUR A1 - Lu, Yong Ping A1 - Tsuprykov, Oleg A1 - Vignon-Zellweger, Nicolas A1 - Heiden, Susi A1 - Hocher, Berthold T1 - Global Overexpression of ET-1 Decreases Blood Pressure - A Systematic Review and Meta-Analysis of ET-1 Transgenic Mice JF - Naunyn-Schmiedeberg's archives of pharmacology N2 - Background/Aims: ET-1 has independent effects on blood pressure regulation in vivo, it is involved in tubular water and salt excretion, promotes constriction of smooth muscle cells, modulates sympathetic nerve activity, and activates the liberation of nitric oxide. To determine the net effect of these partially counteracting mechanisms on blood pressure, a systematic meta-analysis was performed. Methods: Based on the principles of Cochrane systematic reviews, we searched in major literature databases - MEDLINE (PubMed), Embase, Google Scholar, and the China Biological Medicine Database (CBM-disc) - for articles relevant to the topic of the blood pressure phenotype of endothelin-1 transgenic (ET-1+/+) mice from January 1, 1988 to March 31, 2016. Review Manager Version 5.0 (Rev-Man 5.0) software was applied for statistical analysis. In total thirteen studies reported blood pressure data. Results: The meta-analysis of blood pressure data showed that homozygous ET-1 transgenic mice (ET-1+/+ mice) had a significantly lower blood pressure as compared to WT mice (mean difference:-2.57 mmHg, 95% CI: -4.98 similar to -0.16, P = 0.04), with minimal heterogeneity (P = 0.86). A subgroup analysis of mice older than 6 months revealed that the blood pressure difference between ET-1+/+ mice and WT mice was even more pronounced (mean difference: -6.19 mmHg, 95% CI: -10.76 similar to -1.62, P = 0.008), with minimal heterogeneity (P = 0.91). Conclusion: This meta-analysis provides robust evidence that global ET-1 overexpression in mice lowers blood pressure in an age-dependent manner. Older ET-1+/+ mice have a somewhat more pronounced reduction of blood pressure. (C) 2016 The Author(s) Published by S. Karger AG, Basel KW - Endothelin-1 transgenic mice KW - Blood pressure KW - Kidney weight KW - Heart weight Y1 - 2016 U6 - https://doi.org/10.1159/000450567 SN - 1420-4096 SN - 1423-0143 VL - 41 SP - 770 EP - 780 PB - Karger CY - Basel ER - TY - JOUR A1 - Liang, Xu-Jing A1 - Huang, Si-Min A1 - Li, Jian-Ping A1 - Zhu, Xian-Nv A1 - Lu, Yong-Ping A1 - Hocher, Berthold A1 - Chen, You-Peng T1 - Hepatic impairment induced by scrub typhus is associated with new onset of renal dysfunction JF - Clinical laboratory : the peer reviewed journal for clinical laboratories and laboratories related to blood transfusion N2 - Background: Scrub typhus is a potentially fatal infectious disease caused by Orientia tsutsugamushi. There is little attention given to hepatic impairment in the adults with scrub typhus. This study investigated the incidence and the prognostic implications of hepatic impairment in patients with scrub typhus. Methods: We retrospectively reviewed a total of 143 adult patients with scrub typhus who were admitted between January 1999 and December 2010 in Guangdong province, China. The patients were divided into three groups, e.g., normal, mild, and moderate to severe groups based on the elevated serum ALT and/or total bilirubin levels. Furthermore, clinical characteristics and prognosis of the patient groups were compared. Results: 109 patients (76.2%) had abnormal liver function. Among the patients with hepatic impairment 45 cases (31.4%), 54 cases (37.8%), and 10 cases (7.0%) had mild, moderate, and severe hepatic damage, respectively. The moderate to severe hepatic impairment group had higher levels of serum creatinine compared with that of normal hepatic function. The incidence of new onset of renal dysfunction - defined as peak serum creatinine >= 176 mu mol/L during hospital stay with no evidence of renal disease prior hospitalization - was 0% in the mild hepatic impairment group, 8.9% in the moderate hepatic impairment group, and 21.9% in the severe hepatic impairment group, (p = 0.005 for trend). Additionally, the patients with hepatic impairment (n = 109) had higher incidences of episodes of thrombocytopenia (45.9% vs. 8.82%, p < 0.001), hypoalbuminemia (50.5% vs. 11.8%, p < 0.001), new onset of renal dysfunction (16.5% vs. 0.0%, p = 0.011), and electrocardiogram abnormality (28.4% vs. 8.82%, p = 0.019) than the patients without hepatic impairment. Conclusions: The degree of hepatic impairment induced by scrub typhus is associated with new onset of renal dysfunction. KW - hepatic impairment KW - renal dysfunction KW - complication KW - outcome KW - scrub typhus Y1 - 2014 U6 - https://doi.org/10.7754/Clin.Lab.2013.121203 SN - 1433-6510 VL - 60 IS - 1 SP - 63 EP - 68 PB - Clin Lab Publ., Verl. Klinisches Labor CY - Heidelberg ER - TY - JOUR A1 - Li, Jian A1 - Wang, Zi-Neng A1 - Schlemm, Ludwig A1 - Pfab, Thiemo A1 - Xiao, Xiao-Min A1 - Chen, You-Peng A1 - Hocher, Berthold T1 - Low birth weight and elevated head-to-abdominal circumference ratio are associated with elevated fetal glycated serum protein concentrations JF - Journal of hypertension N2 - Objective To analyze the association between low birth weight, head-to-abdominal circumference ratio, and insulin resistance in early life. Method and results Glycated serum proteins (GSPs) were quantified at delivery in 612 Chinese mother/child pairs serving as a surrogate of maternal and fetal glycemia. Differential ultrasound examination of the fetal's body (head circumference, biparietal diameter, pectoral diameter, abdominal circumference, and femur length) was done in average 1 week prior to delivery. Multivariable regression analysis considering gestational age at delivery, the child's sex, maternal BMI, maternal age at delivery, maternal body weight, and pregnancyinduced hypertension revealed that fetal GSP was inversely associated with birth weight (R(2) = 0.416; P < 0.001). Fetal GSP was furthermore positively associated with the head-to-abdominal circumference ratio, whereas the maternal GSP was negatively correlated with the offspring's head-to-abdominal circumference ratio (R(2) = 0.285; P = 0.010 and R(2) = 0.261; P = 0.020, respectively). The increased head-to-abdominal circumference ratio in newborns with higher fetal GSP is mainly due to a reduced abdominal circumference rather than reduced growth of the brain. Conclusion The disproportional intrauterine growth is in line with the concept of so-called brain sparing, a mechanism maintaining the intrauterine growth of the brain at the expense of trunk growth. Our data suggest that the low birth weight phenotype, linked to cardiovascular diseases like hypertension in later life, might be a phenotype of disproportional intrauterine growth retardation and early life insulin resistance. KW - disproportional intrauterine growth retardation KW - insulin resistance KW - low birth weight KW - ultrasound Y1 - 2011 U6 - https://doi.org/10.1097/HJH.0b013e328349a2e6 SN - 0263-6352 VL - 29 IS - 9 SP - 1712 EP - 1718 PB - Lippincott Williams & Wilkins CY - Philadelphia ER - TY - JOUR A1 - Li, Jian A1 - Wang, Zi-Neng A1 - Chen, You-Peng A1 - Dong, Yun-Peng A1 - Shuai, Han-Lin A1 - Xiao, Xiao-Min A1 - Reichetzeder, Christoph A1 - Hocher, Berthold T1 - Late gestational maternal serum cortisol is inversely associated with fetal brain growth JF - Neuroscience & biobehavioral reviews : official journal of the International Behavioral Neuroscience Society N2 - To analyze the association between fetal brain growth and late gestational blood serum cortisol in normal pregnancy.Blood total cortisol was quantified at delivery in 432 Chinese mother/child pairs. Key inclusion criteria of the cohort were: no structural anomalies of the newborn, singleton pregnancy, no alcohol abuse, no drug abuse or history of smoking no hypertensive disorders and no impairment of glucose tolerance and no use of steroid medication during pregnancy. Differential ultrasound examination of the fetal body was done in early (gestational day 89.95 +/- 7.31), middle (gestational day 160.17 16.12) and late pregnancy (gestational day 268.89 +/- 12.42). Newborn's cortisol was not correlated with any of the ultrasound measurements during pregnancy nor with birth weight. Multivariable regression analysis, considering timing of the ultrasound examination, the child's sex, maternal BMI, maternal age, maternal body weight at delivery, the timing of cortisol measurement and maternal uterine contraction states, revealed that maternal serum total cortisol was significantly negative correlated with ultrasound parameters describing the fetal brain: late biparietal diameter (R-2 =0.512, p =0.009), late head circumference (R-2 = 0.498, p= 0.001), middle biparietal diameter (R-2= 0.819, p = 0.013), middle cerebellum transverse diameter R-2 = 0.76, p= 0.014) and early biparietal diameter(R-2 = 0.819, p = 0.013). The same analysis revealed that birth weight as well as ultrasound parameters such as abdominal circumference and femur length were not correlated to maternal cortisol levels. In conclusion, our study demonstrates that maternal cortisol secretion within physiological ranges may be inversely correlated to fetal brain growth but not to birth weight. It remains to be demonstrated whether maternal cortisol secretion negatively influencing fetal brain growth translates to adverse neurological outcomes in later life. KW - Brain development KW - Fetal programming KW - Cortisol Maternal cortisol KW - Head circumference KW - Biparietal diameter Y1 - 2012 U6 - https://doi.org/10.1016/j.neubiorev.2011.12.006 SN - 0149-7634 VL - 36 IS - 3 SP - 1085 EP - 1092 PB - Elsevier CY - Oxford ER - TY - JOUR A1 - Li, Jian A1 - Wang, Zi-Neng A1 - Chen, You-Peng A1 - Dong, Yun-Peng A1 - Mao, Xiao-Min A1 - Hocher, Berthold T1 - Association of fetal but not maternal P-glycoprotein C3435T polymorphism with fetal growth and birth weight, a possible risk factor for cardiovascular diseases in later life JF - Clinical laboratory : the peer reviewed journal for clinical laboratories and laboratories related to blood transfusion N2 - Background: The multidrug transporter P-glycoprotein (PGP) is expressed in the human placenta. In particular the C3435T ABCB1 polymorphism was associated with altered tissue expression of PGP in the human placenta. However, the potential functional impact of this polymorphism on the offspring is unknown so far. Methods: We analyzed the impact of the ABCB1/C3435T polymorphism on fetal growth in 262 mother/child pairs. Fetal growth was assessed by differential ultrasound examination of the fetal body prior to birth and by measuring birth weight. Results: The maternal ABCB1/C3435T polymorphism showed no trend for an association with birth weight or any ultrasound parameter describing late gestational fetal body shape. Genotyping the newborns, however, demonstrated that newborns carrying two copies of the T allele had a birth weight of 3176.39 g, whereas CT and CC newborns had a birth weight of 3345.04 g (p = 0.022). Adjusting for gestational age at delivery, child's gender, maternal BM1, maternal age and body weight at delivery confirmed this finding (p = 0.009). Considering gestational day of late ultrasound examination, gestational age at delivery, child's gender, maternal BMI, maternal age and maternal body weight at delivery, the fetal ABCB1/C3435T genotype revealed likewise a significant negative correlation with abdominal diameter and abdominal circumference (R-2 = 0.538, p = 0.010 and R-2 = 0.534, p = 0.005, respectively). Conclusions: Low birth weight may be a risk factor for cardiovascular diseases in later life. The fetal ABCB1/C3435T gene polymorphism may contribute to this risk. Since PGP controls transport of various biological agents, we suggest that PGP is involved in the transport of biological agents to the fetus that are important for normal fetal growth. Y1 - 2012 U6 - https://doi.org/10.7754/Clin.Lab.2012.110920 SN - 1433-6510 VL - 58 IS - 9-10 SP - 1085 EP - 1089 PB - Clin Lab Publ., Verl. Klinisches Labor CY - Heidelberg ER - TY - JOUR A1 - Li, Jian A1 - Tsuprykov, Oleg A1 - Yang, Xiaoping A1 - Hocher, Berthold T1 - Paternal programming of offspring cardiometabolic diseases in later life JF - Journal of hypertension KW - cardiometabolic diseases KW - epigenetics KW - offspring KW - paternal programming KW - spermatogenesis KW - transgenerational effects Y1 - 2016 U6 - https://doi.org/10.1097/HJH.0000000000001051 SN - 0263-6352 SN - 1473-5598 VL - 34 SP - 2111 EP - 2126 PB - Wiley-Blackwell CY - Philadelphia ER - TY - JOUR A1 - Li, Jian A1 - Shen, Jinhua A1 - Zhang, Xiaoli A1 - Peng, Yangqin A1 - Zhang, Qin A1 - Hu, Liang A1 - Reichetzeder, Christoph A1 - Zeng, Suimin A1 - Li, Jing A1 - Tian, Mei A1 - Gong, Fei A1 - Lin, Ge A1 - Hocher, Berthold T1 - Risk factors associated with preterm birth after IVF/ICSI JF - Scientific reports N2 - In vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI) is associated with an increased risk of preterm (33rd-37th gestational week) and early preterm birth (20th-32nd gestational week). The underlying general and procedure related risk factors are not well understood so far. 4328 infertile women undergoing IVF/ICSI were entered into this study. The study population was divided into three groups: (a) early preterm birth group (n = 66), (b) preterm birth group (n = 675) and (c) full-term birth group (n = 3653). Odds for preterm birth were calculated by stepwise multivariate logistic regression analysis. We identified seven independent risk factors for preterm birth and four independent risk factors for early preterm birth. Older (> 39) or younger (< 25) maternal age (OR: 1.504, 95% CI 1.108-2.042, P = 0.009; OR: 2.125, 95% CI 1.049-4.304, P = 0.036, respectively), multiple pregnancy (OR: 9.780, 95% CI 8.014-11.935, P < 0.001; OR: 8.588, 95% CI 4.866-15.157, P < 0.001, respectively), placenta previa (OR: 14.954, 95% CI 8.053-27.767, P < 0.001; OR: 16.479, 95% CI 4.381-61.976, P < 0.001, respectively), and embryo reduction (OR: 3.547, 95% CI 1.736-7.249, P = 0.001; OR: 7.145, 95% CI 1.990-25.663, P = 0.003, respectively) were associated with preterm birth and early preterm birth, whereas gestational hypertension (OR: 2.494, 95% CI 1.770-3.514, P < 0.001), elevated triglycerides (OR: 1.120, 95% CI 1.011-1.240, P = 0.030) and shorter activated partial thromboplastin time (OR: 0.967, 95% CI 0.949-0.985, P < 0.001) were associated only with preterm birth. In conclusion, preterm and early preterm birth risk factors in patients undergoing assisted IVF/ICSI are in general similar to those in natural pregnancy. The lack of some associations in the early preterm group was most likely due to the lower number of early preterm birth cases. Only embryo reduction represents an IVF/ICSI specific risk factor. Y1 - 2022 U6 - https://doi.org/10.1038/s41598-022-12149-w SN - 2045-2322 VL - 12 IS - 1 PB - Nature Research CY - Berlin ER - TY - JOUR A1 - Li, Jian A1 - Lu, Yong-Ping A1 - Tsuprykov, Oleg A1 - Hasan, Ahmed Abdallah Abdalrahman Mohamed A1 - Reichetzeder, Christoph A1 - Tian, Mei A1 - Zhang, Xiao Li A1 - Zhang, Qin A1 - Sun, Guo-Ying A1 - Guo, Jingli A1 - Gaballa, Mohamed Mahmoud Salem Ahmed A1 - Peng, Xiao-Ning A1 - Lin, Ge A1 - Hocher, Berthold T1 - Folate treatment of pregnant rat dams abolishes metabolic effects in female offspring induced by a paternal pre-conception unhealthy diet JF - Diabetologia : journal of the European Association for the Study of Diabetes (EASD) N2 - Aims/hypothesis Paternal high-fat diet prior to mating programmes impaired glucose tolerance in female offspring. We examined whether the metabolic consequences in offspring could be abolished by folate treatment of either the male rats before mating or the corresponding female rats during pregnancy. Methods Male F0 rats were fed either control diet or high-fat, high-sucrose and high-salt diet (HFSSD), with or without folate, before mating. Male rats were mated with control-diet-fed dams. After mating, the F0 dams were fed control diet with or without folate during pregnancy. KW - Glucose tolerance KW - High-fat-sucrose-salt diet KW - Maternal folate treatment KW - Paternal programming Y1 - 2018 U6 - https://doi.org/10.1007/s00125-018-4635-x SN - 0012-186X SN - 1432-0428 VL - 61 IS - 8 SP - 1862 EP - 1876 PB - Springer CY - New York ER - TY - JOUR A1 - Li, Jian A1 - Lu, Yong Ping A1 - Reichetzeder, Christoph A1 - Kalk, Philipp A1 - Kleuser, Burkhard A1 - Adamski, Jerzy A1 - Hocher, Berthold T1 - Maternal PCaaC38:6 is Associated With Preterm Birth - a Risk Factor for Early and Late Adverse Outcome of the Offspring JF - Journal of European public policy N2 - Background/Aims: Preterm birth (PTB) and low birth weight (LBW) significantly influence mortality and morbidity of the offspring in early life and also have long-term consequences in later life. A better understanding of the molecular mechanisms of preterm birth could provide new insights regarding putative preventive strategies. Metabolomics provides a powerful analytic tool to readout complex interactions between genetics, environment and health and may serve to identify relevant biomarkers. In this study, the association between 163 targeted maternal blood metabolites and gestational age was investigated in order to find candidate biomarkers for PTB. Methods: Five hundred twenty-three women were included into this observational study. Maternal blood was obtained before delivery. The concentration of 163 maternal serum metabolites was measured by flow injection tandem mass spectrometry. To find putative biomarkers for preterm birth, a three-step analysis was designed: bivariate correlation analysis followed by multivariable regression analysis and a comparison of mean values among gestational age groups. Results: Bivariate correlation analysis showed that 2 acylcarnitines (C16:2, C2), 1 amino acids (xLeu), 8 diacyl-PCs (PCaaC36:4, PCaaC38:4, PCaaC38:5, PCaaC38:6, PCaaC40:4, PCaaC40:5, PCaaC40:6, PCaaC42:4), and 1 Acylalkyl-PCs (PCaeC40:5) were inversely correlated with gestational age. Multivariable regression analysis confounded for PTB history, maternal body mass index (BMI) before pregnancy, systolic blood pressure at the third trimester, and maternal body weight at the third trimester, showed that the diacyl-PC PCaaC38:6 was the only metabolite inversely correlated with gestational age. Conclusions: Maternal blood concentrations of PCaaC38:6 are independently associated with gestational age. (C) 2016 The Author(s) Published by S. Karger AG, Basel KW - Metabolomics KW - PCaaC38:6 KW - Biomarker KW - Preterm birth Y1 - 2016 U6 - https://doi.org/10.1159/000443428 SN - 1420-4096 SN - 1423-0143 VL - 41 SP - 250 EP - 257 PB - Karger CY - Basel ER - TY - JOUR A1 - Li, Jian A1 - Chen, You-Peng A1 - Wang, Zi-Neng A1 - Liu, Tie-Bin A1 - Chen, Dan A1 - Dong, Yun-Peng A1 - Hocher, Berthold T1 - A functional fetal HSD11B2[CA]n microsatellite polymorphism is associated with maternal serum cortisol concentrations in pregnant women JF - Kidney & blood pressure research : official organ of the Gesellschaft für Nephrologie N2 - Background/Aims: Cortisol plays an important role during pregnancy. It controls maternal glucose metabolism and fetal development. Cortisol metabolism is partially controlled by the 11b-HSD2. This enzyme is expressed in the kidney and human placenta. The activity of the enzyme is partially controlled by functional polymorphisms: the HSD11B2[CA]n microsatellite polymorphism. The impact of this functional gene polymorphism on cortisol metabolism and potential effects on the newborn's is unknown so far. Methods: In the current prospective birth cohort study in southern Asia, we analyzed the association of the HSD11B2[CA]n microsatellite polymorphisms in 187 mothers and their newborn's on maternal and newborn's serum cortisol concentrations. Results: Using multivariable regression analyses considering known confounding ( gestational age, newborn's gender, the labor uterine contraction states and the timing during the day of blood taking), we showed that the fetal HSD11B2[CA]n microsatellite polymorphisms in the first intron was related to maternal cortisol concentration ( R2=0.26, B=96.27, p=0.007), whereas as the newborn's cortisol concentrations were independent of fetal and maternal HSD11B2[CA] n microsatellite polymorphism. Conclusions: Our study showed for the first time that the fetal HSD11B2[CA]n microsatellite polymorphism of the HSD11B2 gene in healthy uncomplicated human pregnancy is associated with maternal cortisol concentration. This indicates that fetal genes controlling cortisol metabolism may affect maternal cortisol concentration and hence physiology in healthy pregnant women. KW - Pregnancy KW - Placenta KW - Cortisol vertical bar metabolism KW - 11 beta-hydroxysteroid dehydrogenase 2 KW - HSD11B2[CA]n polymorphism Y1 - 2013 U6 - https://doi.org/10.1159/000355761 SN - 1420-4096 SN - 1423-0143 VL - 38 IS - 1 SP - 132 EP - 141 PB - Karger CY - Basel ER - TY - JOUR A1 - Li, Jian A1 - Chen, You-Peng A1 - Dong, Yun-Peng A1 - Yu, Cal-Hong A1 - Lu, Yong-Ping A1 - Xiao, Xiao-Min A1 - Hocher, Berthold T1 - The impact of umbilical blood flow regulation on fetal development differs in diabetic and non-diabetic pregnancy JF - Kidney & blood pressure research : official organ of the Gesellschaft für Nephrologie N2 - Background/Aims: Diabetes is well-known to influence endothelial function. Endothelial function and blood flow regulation might be different in diabetic and non-diabetic pregnancy. However, the impact of umbilical blood flow regulation in gestational diabetes on fetal development is unknown so far. Methods: In a prospective birth cohort study, we analyzed the association of the umbilical artery Doppler indices (pulsatility index, resistance index and systolic/diastolic ratio) and fetal size measures (biparietal diameter, head circumference, abdominal circumference, femur length and birth weight) in 519 non-gestational diabetes mellitus pregnancies (controls) and 226 gestational diabetes mellitus pregnancies in middle (day 160.32 +/- 16.29 of gestation) and late (day 268.12 +/- 13.04 of gestation) pregnancy. Results: Multiple regression analysis considering confounding factors (gestational day of ultrasound examination, offspring sex, maternal body mess index before pregnancy, maternal age at delivery, maternal body weight at delivery and maternal hypertension) showed that umbilical artery Doppler indices (pulsatility index, resistance index and systolic/diastolic ratio) were associated with fetal head circumference and femur length in middle gestational diabetes mellitus pregnancy but not in non-gestational diabetes mellitus pregnancy. Head circumference, biparietal diameter, abdominal circumference and femur length in mid gestation were smaller in fetus of gestational diabetes mellitus pregnancy versus non-gestational diabetes mellitus pregnancy. In contrast to non-gestational diabetes mellitus pregnancy in late gestation, umbilical artery Doppler indices in gestational diabetes mellitus pregnancy were not associated with ultrasound measures of fetal growth. Birth weight was slightly increased in gestational diabetes mellitus pregnancy as compared to non-gestational diabetes mellitus pregnancy. Conclusions: The impact of umbilical blood flow on fetal growth is time dependent in human gestational diabetes mellitus and non-gestational diabetes mellitus pregnancy. In gestational diabetes mellitus pregnancy umbilical blood flow is critical for organ development in much earlier stages of pregnancy as compared to non-gestational diabetes mellitus pregnancy. The physiological and molecular pathways why there is a catch up growth in later times of gestational diabetes mellitus pregnancy resulting in larger gestational diabetes mellitus babies at birth needs to be addressed in further studies. KW - Umbilical artery Doppler KW - Blood flow resistance KW - Gestational diabetes mellitus KW - Fetal development Y1 - 2014 U6 - https://doi.org/10.1159/000355815 SN - 1420-4096 SN - 1423-0143 VL - 39 IS - 4 SP - 369 EP - 377 PB - Karger CY - Basel ER - TY - JOUR A1 - Kalk, Philipp A1 - Sharkovska, Yuliya A1 - Kashina, Elena A1 - von Websky, Karoline A1 - Relle, Katharina A1 - Pfab, Thiemo A1 - Alter, Markus L. A1 - Guillaume, Philippe A1 - Provost, Daniel A1 - Hoffmann, Katrin A1 - Fischer, Yvan A1 - Hocher, Berthold T1 - Endothelin-Converting Enzyme/Neutral Endopeptidase Inhibitor SLV338 Prevents Hypertensive Cardiac Remodeling in a Blood Pressure-Independent Manner JF - HYPERTENSION N2 - Hypertensive heart disease is a major contributor to cardiovascular mortality. Endothelin is a potent vasoconstrictive and profibrotic mediator produced by the endothelin-converting enzyme (ECE), whereas natriuretic peptides, degraded by the neutral endopeptidase (NEP), have diuretic, vasodilatory, and antifibrotic properties. Thus, combined ECE/NEP inhibition may halt hypertensive cardiac remodeling. This study examined effects of SLV338, a novel ECE/NEP inhibitor, on cardiac protection in experimental renovascular hypertension (2-kidney, 1-clip [2K1C]). Male rats were allocated to 5 groups: sham-operated rats, untreated animals with 2K1C, 2K1C animals treated with oral SLV338 (30 and 100 mg/kg per day), and 2K1C animals treated with oral losartan (20 mg/kg per day). Treatment duration was 12 weeks. Blood pressure was assessed every 4 weeks. At study end, hearts were taken for histology/computer-aided histomorphometry/immunohistochemistry. Pharmacological properties of SLV338 are described. SLV338 is a dual ECE/NEP inhibitor, as demonstrated both in vitro and in vivo. In the 2K1C study, losartan lowered blood pressure by <= 46 mm Hg, whereas both dosages of SLV338 had no effect. However, SLV338 (both dosages) completely normalized cardiac interstitial fibrosis, perivascular fibrosis, myocyte diameter, and media: lumen ratio of cardiac arteries, as did losartan. Cardiac transforming growth factor-beta 1 expression was significantly enhanced in untreated 2K1C rats versus controls, whereas treatment with SLV338 and losartan prevented this effect. Taken together, dual ECE/NEP inhibitor SLV338 prevents cardiac remodeling to the same extent as losartan, but in a blood pressure-independent manner, in a rat model of renovascular hypertension. This effect is at least partially mediated via suppression of cardiac transforming growth factor-beta 1 expression. (Hypertension. 2011;57:755-763.) KW - renovascular hypertension KW - cardiac remodeling KW - endothelin-converting enzyme KW - neutral endopeptidase KW - TGF-beta 1 Y1 - 2011 U6 - https://doi.org/10.1161/HYPERTENSIONAHA.110.163972 SN - 0194-911X VL - 57 IS - 4 SP - 755 EP - 763 PB - LIPPINCOTT WILLIAMS & WILKINS CY - PHILADELPHIA ER - TY - JOUR A1 - Ikram, M. Arfan A1 - Fornage, Myriam A1 - Smith, Albert V. A1 - Seshadri, Sudha A1 - Schmidt, Reinhold A1 - Debette, Stephanie A1 - Vrooman, Henri A. A1 - Sigurdsson, Sigurdur A1 - Ropele, Stefan A1 - Taal, H. Rob A1 - Mook-Kanamori, Dennis O. A1 - Coker, Laura H. A1 - Longstreth, W. T. A1 - Niessen, Wiro J. A1 - DeStefano, Anita L. A1 - Beiser, Alexa A1 - Zijdenbos, Alex P. A1 - Struchalin, Maksim A1 - Jack, Clifford R. A1 - Rivadeneira, Fernando A1 - Uitterlinden, Andre G. A1 - Knopman, David S. A1 - Hartikainen, Anna-Liisa A1 - Pennell, Craig E. A1 - Thiering, Elisabeth A1 - Steegers, Eric A. P. A1 - Hakonarson, Hakon A1 - Heinrich, Joachim A1 - Palmer, Lyle J. A1 - Jarvelin, Marjo-Riitta A1 - McCarthy, Mark I. A1 - Grant, Struan F. A. A1 - St Pourcain, Beate A1 - Timpson, Nicholas J. A1 - Smith, George Davey A1 - Sovio, Ulla A1 - Nalls, Mike A. A1 - Au, Rhoda A1 - Hofman, Albert A1 - Gudnason, Haukur A1 - van der Lugt, Aad A1 - Harris, Tamara B. A1 - Meeks, William M. A1 - Vernooij, Meike W. A1 - van Buchem, Mark A. A1 - Catellier, Diane A1 - Jaddoe, Vincent W. V. A1 - Gudnason, Vilmundur A1 - Windham, B. Gwen A1 - Wolf, Philip A. A1 - van Duijn, Cornelia M. A1 - Mosley, Thomas H. A1 - Schmidt, Helena A1 - Launer, Lenore J. A1 - Breteler, Monique M. B. A1 - DeCarli, Charles A1 - Adair, Linda S. A1 - Ang, Wei A1 - Atalay, Mustafa A1 - vanBeijsterveldt, Toos A1 - Bergen, Nienke A1 - Benke, Kelly A1 - Berry, Diane J. A1 - Coin, Lachlan A1 - Davis, Oliver S. P. A1 - Elliott, Paul A1 - Flexeder, Claudia A1 - Frayling, Tim A1 - Gaillard, Romy A1 - Groen-Blokhuis, Maria A1 - Goh, Liang-Kee A1 - Haworth, Claire M. A. A1 - Hadley, Dexter A1 - Hebebrand, Johannes A1 - Hinney, Anke A1 - Hirschhorn, Joel N. A1 - Holloway, John W. A1 - Holst, Claus A1 - Hottenga, Jouke Jan A1 - Horikoshi, Momoko A1 - Huikari, Ville A1 - Hypponen, Elina A1 - Kilpelainen, Tuomas O. A1 - Kirin, Mirna A1 - Kowgier, Matthew A1 - Lakka, Hanna-Maaria A1 - Lange, Leslie A. A1 - Lawlor, Debbie A. A1 - Lehtimaki, Terho A1 - Lewin, Alex A1 - Lindgren, Cecilia A1 - Lindi, Virpi A1 - Maggi, Reedik A1 - Marsh, Julie A1 - Middeldorp, Christel A1 - Millwood, Iona A1 - Murray, Jeffrey C. A1 - Nivard, Michel A1 - Nohr, Ellen Aagaard A1 - Ntalla, Ioanna A1 - Oken, Emily A1 - Panoutsopoulou, Kalliope A1 - Pararajasingham, Jennifer A1 - Rodriguez, Alina A1 - Salem, Rany M. A1 - Sebert, Sylvain A1 - Siitonen, Niina A1 - Strachan, David P. A1 - Teo, Yik-Ying A1 - Valcarcel, Beatriz A1 - Willemsen, Gonneke A1 - Zeggini, Eleftheria A1 - Boomsma, Dorret I. A1 - Cooper, Cyrus A1 - Gillman, Matthew A1 - Hocher, Berthold A1 - Lakka, Timo A. A1 - Mohlke, Karen L. A1 - Dedoussis, George V. A1 - Ong, Ken K. A1 - Pearson, Ewan R. A1 - Price, Thomas S. A1 - Power, Chris A1 - Raitakari, Olli T. A1 - Saw, Seang-Mei A1 - Scherag, Andre A1 - Simell, Olli A1 - Sorensen, Thorkild I. A. A1 - Wilson, James F. T1 - Common variants at 6q22 and 17q21 are associated with intracranial volume JF - Nature genetics N2 - During aging, intracranial volume remains unchanged and represents maximally attained brain size, while various interacting biological phenomena lead to brain volume loss. Consequently, intracranial volume and brain volume in late life reflect different genetic influences. Our genome-wide association study (GWAS) in 8,175 community-dwelling elderly persons did not reveal any associations at genome-wide significance (P < 5 x 10(-8)) for brain volume. In contrast, intracranial volume was significantly associated with two loci: rs4273712 (P = 3.4 x 10(-11)), a known height-associated locus on chromosome 6q22, and rs9915547 (P = 1.5 x 10(-12)), localized to the inversion on chromosome 17q21. We replicated the associations of these loci with intracranial volume in a separate sample of 1,752 elderly persons (P = 1.1 x 10(-3) for 6q22 and 1.2 x 10(-3) for 17q21). Furthermore, we also found suggestive associations of the 17q21 locus with head circumference in 10,768 children (mean age of 14.5 months). Our data identify two loci associated with head size, with the inversion at 17q21 also likely to be involved in attaining maximal brain size. Y1 - 2012 U6 - https://doi.org/10.1038/ng.2245 SN - 1061-4036 VL - 44 IS - 5 SP - 539 EP - + PB - Nature Publ. Group CY - New York ER - TY - JOUR A1 - Horikoshi, Momoko A1 - Yaghootkar, Hanieh A1 - Mook-Kanamori, Dennis O. A1 - Sovio, Ulla A1 - Taal, H. Rob A1 - Hennig, Branwen J. A1 - Bradfield, Jonathan P. A1 - St Pourcain, Beate A1 - Evans, David M. A1 - Charoen, Pimphen A1 - Kaakinen, Marika A1 - Cousminer, Diana L. A1 - Lehtimaki, Terho A1 - Kreiner-Moller, Eskil A1 - Warrington, Nicole M. A1 - Bustamante, Mariona A1 - Feenstra, Bjarke A1 - Berry, Diane J. A1 - Thiering, Elisabeth A1 - Pfab, Thiemo A1 - Barton, Sheila J. A1 - Shields, Beverley M. A1 - Kerkhof, Marjan A1 - van Leeuwen, Elisabeth M. A1 - Fulford, Anthony J. A1 - Kutalik, Zoltan A1 - Zhao, Jing Hua A1 - den Hoed, Marcel A1 - Mahajan, Anubha A1 - Lindi, Virpi A1 - Goh, Liang-Kee A1 - Hottenga, Jouke-Jan A1 - Wu, Ying A1 - Raitakari, Olli T. A1 - Harder, Marie N. A1 - Meirhaeghe, Aline A1 - Ntalla, Ioanna A1 - Salem, Rany M. A1 - Jameson, Karen A. A1 - Zhou, Kaixin A1 - Monies, Dorota M. A1 - Lagou, Vasiliki A1 - Kirin, Mirna A1 - Heikkinen, Jani A1 - Adair, Linda S. A1 - Alkuraya, Fowzan S. A1 - Al-Odaib, Ali A1 - Amouyel, Philippe A1 - Andersson, Ehm Astrid A1 - Bennett, Amanda J. A1 - Blakemore, Alexandra I. F. A1 - Buxton, Jessica L. A1 - Dallongeville, Jean A1 - Das, Shikta A1 - de Geus, Eco J. C. A1 - Estivill, Xavier A1 - Flexeder, Claudia A1 - Froguel, Philippe A1 - Geller, Frank A1 - Godfrey, Keith M. A1 - Gottrand, Frederic A1 - Groves, Christopher J. A1 - Hansen, Torben A1 - Hirschhorn, Joel N. A1 - Hofman, Albert A1 - Hollegaard, Mads V. A1 - Hougaard, David M. A1 - Hyppoenen, Elina A1 - Inskip, Hazel M. A1 - Isaacs, Aaron A1 - Jorgensen, Torben A1 - Kanaka-Gantenbein, Christina A1 - Kemp, John P. A1 - Kiess, Wieland A1 - Kilpelainen, Tuomas O. A1 - Klopp, Norman A1 - Knight, Bridget A. A1 - Kuzawa, Christopher W. A1 - McMahon, George A1 - Newnham, John P. A1 - Niinikoski, Harri A1 - Oostra, Ben A. A1 - Pedersen, Louise A1 - Postma, Dirkje S. A1 - Ring, Susan M. A1 - Rivadeneira, Fernando A1 - Robertson, Neil R. A1 - Sebert, Sylvain A1 - Simell, Olli A1 - Slowinski, Torsten A1 - Tiesler, Carla M. T. A1 - Toenjes, Anke A1 - Vaag, Allan A1 - Viikari, Jorma S. A1 - Vink, Jacqueline M. A1 - Vissing, Nadja Hawwa A1 - Wareham, Nicholas J. A1 - Willemsen, Gonneke A1 - Witte, Daniel R. A1 - Zhang, Haitao A1 - Zhao, Jianhua A1 - Wilson, James F. A1 - Stumvoll, Michael A1 - Prentice, Andrew M. A1 - Meyer, Brian F. A1 - Pearson, Ewan R. A1 - Boreham, Colin A. G. A1 - Cooper, Cyrus A1 - Gillman, Matthew W. A1 - Dedoussis, George V. A1 - Moreno, Luis A. A1 - Pedersen, Oluf A1 - Saarinen, Maiju A1 - Mohlke, Karen L. A1 - Boomsma, Dorret I. A1 - Saw, Seang-Mei A1 - Lakka, Timo A. A1 - Koerner, Antje A1 - Loos, Ruth J. F. A1 - Ong, Ken K. A1 - Vollenweider, Peter A1 - van Duijn, Cornelia M. A1 - Koppelman, Gerard H. A1 - Hattersley, Andrew T. A1 - Holloway, John W. A1 - Hocher, Berthold A1 - Heinrich, Joachim A1 - Power, Chris A1 - Melbye, Mads A1 - Guxens, Monica A1 - Pennell, Craig E. A1 - Bonnelykke, Klaus A1 - Bisgaard, Hans A1 - Eriksson, Johan G. A1 - Widen, Elisabeth A1 - Hakonarson, Hakon A1 - Uitterlinden, Andre G. A1 - Pouta, Anneli A1 - Lawlor, Debbie A. A1 - Smith, George Davey A1 - Frayling, Timothy M. A1 - McCarthy, Mark I. A1 - Grant, Struan F. A. A1 - Jaddoe, Vincent W. V. A1 - Jarvelin, Marjo-Riitta A1 - Timpson, Nicholas J. A1 - Prokopenko, Inga A1 - Freathy, Rachel M. T1 - New loci associated with birth weight identify genetic links between intrauterine growth and adult height and metabolism JF - Nature genetics N2 - Birth weight within the normal range is associated with a variety of adult-onset diseases, but the mechanisms behind these associations are poorly understood(1). Previous genome-wide association studies of birth weight identified a variant in the ADCY5 gene associated both with birth weight and type 2 diabetes and a second variant, near CCNL1, with no obvious link to adult traits(2). In an expanded genome-wide association metaanalysis and follow-up study of birth weight (of up to 69,308 individuals of European descent from 43 studies), we have now extended the number of loci associated at genome-wide significance to 7, accounting for a similar proportion of variance as maternal smoking. Five of the loci are known to be associated with other phenotypes: ADCY5 and CDKAL1 with type 2 diabetes, ADRB1 with adult blood pressure and HMGA2 and LCORL with adult height. Our findings highlight genetic links between fetal growth and postnatal growth and metabolism. Y1 - 2013 U6 - https://doi.org/10.1038/ng.2477 SN - 1061-4036 VL - 45 IS - 1 SP - 76 EP - U115 PB - Nature Publ. Group CY - New York ER - TY - GEN A1 - Hoffmann, Linda Sarah A1 - Kretschmer, Axel A1 - Lawrenz, Bettina A1 - Hocher, Berthold A1 - Stasch, Johannes-Peter T1 - Chronic activation of heme free Guanylate Cyclase leads to renal protection in Dahl salt-sensitive rats T2 - Postprints der Universität Potsdam : Mathematisch naturwissenschaftliche Reihe N2 - The nitric oxide (NO)/soluble guanylate cyclase (sGC)/cyclic guanosine monophasphate (cGMP)-signalling pathway is impaired under oxidative stress conditions due to oxidation and subsequent loss of the prosthetic sGC heme group as observed in particular in chronic renal failure. Thus, the pool of heme free sGC is increased under pathological conditions. sGC activators such as cinaciguat selectively activate the heme free form of sGC and target the disease associated enzyme. In this study, a therapeutic effect of long-term activation of heme free sGC by the sGC activator cinaciguat was investigated in an experimental model of salt-sensitive hypertension, a condition that is associated with increased oxidative stress, heme loss from sGC and development of chronic renal failure. For that purpose Dahl/ss rats, which develop severe hypertension upon high salt intake, were fed a high salt diet (8% NaCl) containing either placebo or cinaciguat for 21 weeks. Cinaciguat markedly improved survival and ameliorated the salt-induced increase in blood pressure upon treatment with cinaciguat compared to placebo. Renal function was significantly improved in the cinaciguat group compared to the placebo group as indicated by a significantly improved glomerular filtration rate and reduced urinary protein excretion. This was due to anti-fibrotic and antiinflammatory effects of the cinaciguat treatment. Taken together, this is the first study showing that long-term activation of heme free sGC leads to renal protection in an experimental model of hypertension and chronic kidney disease. These results underline the promising potential of cinaciguat to treat renal diseases by targeting the disease associated heme free form of sGC. T3 - Zweitveröffentlichungen der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe - 489 KW - signal-transduction system KW - nitric-oxide KW - oxidative stress KW - independent activation KW - endothelial dysfunction KW - pulmonary-hypertension KW - cardiovascular-disease KW - therapeutic target KW - heart-failure KW - cyclic-GMP Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:kobv:517-opus4-408088 SN - 1866-8372 IS - 489 ER - TY - GEN A1 - Hocher, Berthold A1 - Zeng, Shufei T1 - Clear the fog around parathyroid hormone assays BT - what do iPTH assays really measure? T2 - Clinical journal of the American Society of Nephrology KW - Assays KW - Biological Assay KW - CKD KW - oxidative stress KW - PTH Y1 - 2018 U6 - https://doi.org/10.2215/CJN.01730218 SN - 1555-9041 SN - 1555-905X VL - 13 IS - 4 SP - 524 EP - 526 PB - American Society of Nephrology CY - Washington ER - TY - GEN A1 - Hocher, Berthold A1 - Zeng, Shufei T1 - Need for better PTH assays for clinical research and patient treatment T2 - Clinical chemistry and laboratory medicine : journal of the Forum of the European Societies of Clinical Chemistry - the European Branch of the International Federation of Clinical Chemistry and Laboratory Medicine Y1 - 2017 U6 - https://doi.org/10.1515/cclm-2017-0617 SN - 1434-6621 SN - 1437-4331 VL - 56 IS - 2 SP - 183 EP - 185 PB - De Gruyter CY - Berlin ER - TY - GEN A1 - Hocher, Berthold A1 - Yin, Lianghong T1 - Why Current PTH Assays Mislead Clinical Decision Making in Patients with Secondary Hyperparathyroidism T2 - Nephron N2 - Preclinical studies in cell culture systems as well as in whole animal chronic kidney disease (CKD) models showed that parathyroid hormone (PTH), oxidized at the 2 methionine residues (positions 8 and 18), caused a loss of function. This was so far not considered in the development of PTH assays used in current clinical practice. Patients with advanced CKD are subject to oxidative stress, and plasma proteins (including PTH) are targets for oxidants. In patients with CKD, a considerable but variable fraction (about 70 to 90%) of measured PTH appears to be oxidized. Oxidized PTH (oxPTH) does not interact with the PTH receptor resulting in loss of biological activity. Currently used intact PTH (iPTH) assays detect both oxidized and non-oxPTH (n-oxPTH). Clinical studies demonstrated that bioactive, n-oxPTH, but not iPTH nor oxPTH, is associated with mortality in CKD patients. KW - Serum intact-parathyroid hormone level KW - Dialysis patients KW - Mortality Y1 - 2017 U6 - https://doi.org/10.1159/000455289 SN - 1660-8151 SN - 2235-3186 SN - 0028-2766 VL - 136 IS - 2 SP - 137 EP - 142 PB - Karger CY - Basel ER - TY - CHAP A1 - Hocher, Berthold A1 - Tsuprykov, Oleg A1 - Alter, Markus L. A1 - von Websky, Karoline A1 - Chaykovska, Lyubov A1 - Antonenko, V. A1 - Rahnenführer, Jan A1 - Klein, T. A1 - Reichetzeder, Christoph T1 - Linagliptin and the angiotensin II receptor blocker telmisartan show comparable efficacy but different renoprotective pathways in rats with 5/6 nephrectomy T2 - Diabetologia : journal of the European Association for the Study of Diabetes (EASD) Y1 - 2013 SN - 0012-186X SN - 1432-0428 VL - 56 IS - 15-16 SP - S66 EP - S66 PB - Springer CY - New York ER - TY - GEN A1 - Hocher, Berthold A1 - Tsuprykov, Oleg T1 - Renoprotective effects of GLP1R agonists and SGLT2 inhibitors T2 - Nature reviews nephroloy N2 - New data from the LEADER trial show that the glucagon-like peptide 1 receptor agonist liraglutide protects against diabetic nephropathy in patients with type 2 diabetes mellitus. The renoprotective efficacy of liraglutide is not, however, as great as that reported for the sodium-glucose cotransporter 2 inhibitor emplagiflozin in the EMPA-REG OUTCOME trial. Y1 - 2017 U6 - https://doi.org/10.1038/nrneph.2017.140 SN - 1759-5061 SN - 1759-507X VL - 13 SP - 728 EP - 729 PB - Nature Publ. Group CY - New York ER - TY - JOUR A1 - Hocher, Berthold A1 - Sharkovska, Yuliya A1 - Mark, Michael A1 - Klein, Thomas A1 - Pfab, Thiemo T1 - The novel DPP-4 inhibitors linagliptin and BI 14361 reduce infarct size after myocardial ischemia/reperfusion in rats JF - International journal of cardiology N2 - Background: Dipeptidylpeptidase-4 inhibition is reported to have beneficial effects on myocardial ischemia. Mechanisms might include a reduced degradation of stromal cell-derived factor-1 alpha with subsequent increased recruitment of circulating stem cells and/or incretin receptor-dependent pathways. This study evaluated the novel xanthine-based dipeptidylpeptidase-4 inhibitors linagliptin (BI 1356) and BI 14361 in cardiac ischemia. Methods: Male Wistar rats were pretreated with linagliptin or BI 14361 and subjected to ligation of the left anterior descending coronary artery for 30 min. Results: Dipeptidylpeptidase-4 inhibition significantly reduced the infarct size after 7 days (-27.7%, p<0.05) and 8 weeks (-18.0%, p<0.05). There was a significantly improved maximum rate of left ventricular pressure decline (dP/dt min) in linagliptin-treated animals 8 weeks after ischemia/reperfusion. Apart from that, treatment did not improve cardiac function as determined by echocardiography and cardiac catheterization. Immunohistological staining revealed an increased number of cells positive for stromal cell-derived factor-1 alpha, CXCR-4 and CD34 within and around the infarcted area of BI 14361-treated animals. Conclusions: Linagliptin and BI 14361 are able to reduce infarct size after myocardial ischemia. The immunohistological findings support the hypothesis that dipeptidylpeptidase-4 inhibition via reduced cleavage of stromal cell-derived factor-1 alpha might lead to an enhanced recruitment of CXCR-4+ circulating progenitor cells. KW - Dipeptidylpeptidase-4 KW - Stromal cell-derived factor-1 KW - Cardiac ischemia/reperfusion KW - Myocardial ischemia KW - Infarct size KW - Rats Y1 - 2013 U6 - https://doi.org/10.1016/j.ijcard.2011.12.007 SN - 0167-5273 VL - 167 IS - 1 SP - 87 EP - 93 PB - Elsevier CY - Clare ER - TY - JOUR A1 - Hocher, Berthold A1 - Schlemm, Ludwig A1 - Haumann, Hannah A1 - Li, Jian A1 - Rahnenführer, Jan A1 - Guthmann, Florian A1 - Bamberg, Christian A1 - Kalk, Philipp A1 - Pfab, Thiemo A1 - Chen, You-Peng T1 - Offspring sex determines the impact of the maternal ACE I/D polymorphism on maternal glycaemic control during the last weeks of pregnancy JF - Journal of the renin angiotensin aldosterone system N2 - Hypothesis/Introduction: We recently demonstrated that fetal sex may affect maternal glycaemic control in genetically prone mothers. We tested the hypothesis that fetal sex/fetal Y/X chromosomes might affect maternal glycaemic control during pregnancy depending on the maternal angiotensin converting enzyme (ACE) I/D polymorphism. Material and methods: One thousand, three hundred and thirty-two Caucasian women without pre-existing diabetes and pre-existing hypertension with singleton pregnancies delivering consecutively at the Charite obstetrics department were genotyped. Glycaemic control was analysed by measuring total glycated haemoglobin at birth. Correction for confounding factors and multiple testing was done. Results: Maternal ACE I/D polymorphism showed significant interaction with fetal sex concerning maternal total glycated haemoglobin. Total glycated haemoglobin in DD mothers delivering boys was 6.42 +/- 0.70% vs. 6.21 +/- 0.66% in DD mother delivering girls (p < 0.005), whereas the II carrying mothers showed the opposite effect. II mothers delivering a girl had a higher (p = 0.044) total glycated haemoglobin at birth (6.40 +/- 0.80%) compared to II mothers delivering boys (6.21 +/- 0.81%). There was no interaction of the ACE I/D polymorphism and fetal sex with respect to new onset proteinuria, new onset edema and pregnancy-induced hypertension. Conclusions: Maternal glycaemic control during the last weeks of pregnancy seems to be influenced by an interaction of the ACE I/D genotyp and fetal sex. KW - ACE I/D polymorphism KW - pregnancy KW - fetal sex KW - pregnancy induced diabetes KW - total glycated hemoglobin KW - glycemic control during pregnancy Y1 - 2011 U6 - https://doi.org/10.1177/1470320310387843 SN - 1470-3203 VL - 12 IS - 3 SP - 254 EP - 261 PB - Sage Publ. CY - London ER - TY - CHAP A1 - Hocher, Berthold A1 - Reichetzeder, Christoph A1 - von Websky, Karoline A1 - Tsuprykov, Oleg A1 - Klein, T. T1 - Dipeptidyl peptidase-4 inhibition in a rat model of ischaemia-reperfusion injury may accelerate tubular regeneration but does not improve glomerular filtration rate T2 - Diabetologia : journal of the European Association for the Study of Diabetes (EASD) Y1 - 2014 SN - 0012-186X SN - 1432-0428 VL - 57 SP - S538 EP - S538 PB - Springer CY - New York ER - TY - GEN A1 - Hocher, Berthold A1 - Reichetzeder, Christoph A1 - Dwi Putra, Sulistyo Emantoko A1 - Slowinski, Torsten A1 - Neuber, Corinna A1 - Kleuser, Burkhard A1 - Pfab, Thiemo T1 - Increased global placental DNA methylation levels are associated with gestational diabetes N2 - Background: Gestational diabetes mellitus (GDM) is associated with adverse pregnancy outcomes. It is known that GDM is associated with an altered placental function and changes in placental gene regulation. More recent studies demonstrated an involvement of epigenetic mechanisms. So far, the focus regarding placental epigenetic changes in GDM was set on gene-specific DNA methylation analyses. Studies that robustly investigated placental global DNA methylation are lacking. However, several studies showed that tissue-specific alterations in global DNA methylation are independently associated with type 2 diabetes. Thus, the aim of this study was to characterize global placental DNA methylation by robustly measuring placental DNA 5-methylcytosine (5mC) content and to examine whether differences in placental global DNA methylation are associated with GDM. Methods: Global DNA methylation was quantified by the current gold standard method, LC-MS/MS. In total, 1030 placental samples were analyzed in this single-center birth cohort study. Results: Mothers with GDM displayed a significantly increased global placental DNA methylation (3.22 ± 0.63 vs. 3.00 ± 0.46 %; p = 0.013; ±SD). Bivariate logistic regression showed a highly significant positive correlation between global placental DNA methylation and the presence of GDM (p = 0.0009). Quintile stratification according to placental DNA 5mC levels revealed that the frequency of GDM was evenly distributed in quintiles 1–4 (2.9–5.3 %), whereas the frequency in the fifth quintile was significantly higher (10.7 %; p = 0.003). Bivariate logistic models adjusted for maternal age, BMI, ethnicity, recurrent miscarriages, and familiar diabetes predisposition clearly demonstrated an independent association between global placental DNA hypermethylation and GDM. Furthermore, an ANCOVA model considering known predictors of DNA methylation substantiated an independent association between GDM and placental DNA methylation. Conclusions: This is the first study that employed a robust quantitative assessment of placental global DNA methylation in over a thousand placental samples. The study provides large scale evidence that placental global DNA hypermethylation is associated with GDM, independent of established risk factors. T3 - Zweitveröffentlichungen der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe - 370 KW - Placenta KW - Gestational diabetes KW - Insulin resistance KW - LC-MS/MS KW - Global DNA methylation KW - Epigenetics KW - Hypermethylation Y1 - 2017 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:kobv:517-opus4-400914 ER - TY - JOUR A1 - Hocher, Berthold A1 - Reichetzeder, Christoph A1 - Alter, Markus L. T1 - Renal and cardiac effects of DPP-4 inhibitors - from preclinical development to clinical research JF - Kidney & blood pressure research : official organ of the Gesellschaft für Nephrologie N2 - Inhibitors of type 4 dipeptidyl peptidase (DDP-4) were developed and approved for the oral treatment of type 2 diabetes. Its mode of action is to inhibit the degradation of incretins, such as type 1 glucagon like peptide (GLP-1), and GIP. GLP-1 stimulates glucose-dependent insulin secretion from pancreatic beta-cells and suppresses glucagon release from alpha-cells, thereby improving glucose control. Besides its action on the pancreas type 1 glucagon like peptide has direct effects on the heart, vessels and kidney mainly via the type 1 glucagon like peptide receptor (GLP-1R). Moreover, there are substrates of DPP-4 beyond incretins that have proven renal and cardiovascular effects such as BNP/ANP, NPY, PYY or SDF-1 alpha. Preclinical evidence suggests that DPP-4 inhibitors may be effective in acute and chronic renal failure as well as in cardiac diseases like myocardial infarction and heart failure. Interestingly, large cardiovascular meta-analyses of combined Phase II/III clinical trials with DPP-4 inhibitors point all in the same direction: a potential reduction of cardiovascular events in patients treated with these agents. A pooled analysis of pivotal Phase III, placebo-controlled, registration studies of linagliptin further showed a significant reduction of urinary albumin excretion after 24 weeks of treatment. The observation suggests direct renoprotective effects of DPP-4 inhibition that may go beyond its glucose-lowering potential. Type 4 dipeptidyl peptidase inhibitors have been shown to be very well tolerated in general, but for those excreted via the kidney dose adjustments according to renal function are needed to avoid side effects. In conclusion, the direct cardiac and renal effects seen in preclinical studies as well as meta-analysis of clinical trials may offer additional potentials - beyond improvement of glycemic control - for this newer class of drugs, such as acute kidney failure, chronic kidney failure as well as acute myocardial infarction and heart failure. KW - DDP-4 inhibition KW - Diabetes KW - GLP-1 KW - Cardiovascular effects KW - Myocardial infarction KW - Kidney KW - Diabetic nephropathy KW - Acute renal failure Y1 - 2012 U6 - https://doi.org/10.1159/000339028 SN - 1420-4096 VL - 36 IS - 1 SP - 65 EP - 84 PB - Karger CY - Basel ER - TY - INPR A1 - Hocher, Berthold A1 - Reichetzeder, Christoph T1 - Vitamin D and cardiovascular risk in postmenopausal women how to translate preclinical evidence into benefit for patients T2 - Kidney international : official journal of the International Society of Nephrology N2 - Preclinical work indicates that calcitriol restores vascular function by normalizing the endothelial expression of cyclooxygenase-2 and thromboxane-prostanoid receptors in conditions of estrogen deficiency and thus prevents the thromboxane-prostanoid receptor activation-induced inhibition of nitric oxide synthase. Since endothelial dysfunction is a key factor in the pathogenesis of cardiovascular diseases, this finding may have an important translational impact. It provides a clear rationale to use endothelial function in clinical trials aiming to find the optimal dose of vitamin D for the prevention of cardiovascular events in postmenopausal women. Y1 - 2013 U6 - https://doi.org/10.1038/ki.2013.139 SN - 0085-2538 VL - 84 IS - 1 SP - 9 EP - 11 PB - Nature Publ. Group CY - New York ER - TY - JOUR A1 - Hocher, Berthold A1 - Oberthür, Dominik A1 - Slowinski, Torsten A1 - Querfeld, Uwe A1 - Schäfer, Franz A1 - Doyon, Anke A1 - Tepel, Martin A1 - Roth, Heinz J. A1 - Grön, Hans J. A1 - Reichetzeder, Christoph A1 - Betzel, Christian A1 - Armbruster, Franz Paul T1 - Modeling of Oxidized PTH (oxPTH) and Non-oxidized PTH (n-oxPTH) Receptor Binding and Relationship of Oxidized to Non-Oxidized PTH in Children with Chronic Renal Failure, Adult Patients on Hemodialysis and Kidney Transplant Recipients JF - Kidney & blood pressure research : official organ of the Gesellschaft für Nephrologie N2 - Background: The biological properties of oxidized and non-oxidized PTH are substantially different. Oxidized PTH (oxPTH) loses its PTH receptor-stimulating properties, whereas non-oxidized PTH (n-oxPTH) is a full agonist of the receptor. This was described in more than 20 well published studies in the 1970(s) and 80(s). However, PTH oxidation has been ignored during the development of PTH assays for clinical use so far. Even the nowadays used third generation assay systems do not consider oxidation of PTH. We recently developed an assay to differentiate between oxPTH and n-oxPTH. In the current study we established normal values for this assay system. Furthermore, we compare the ratio of oxPTH to n-oxPTH in different population with chronic renal failure: 620 children with renal failure stage 2-4 of the 4C study, 342 adult patients on dialysis, and 602 kidney transplant recipients. In addition, we performed modeling of the interaction of either oxPTH or n-oxPTH with the PTH receptor using biophysical structure approaches. Results: The children had the highest mean as well as maximum n-oxPTH concentrations as compared to adult patients (both patients on dialysis as well as kidney transplant recipients). The relationship between oxPTH and n-oxPTH of individual patients varied substantially in all three populations with renal impairment. The analysis of n-oxPTH in 89 healthy control subjects revealed that n-oxPTH concentrations in patient with renal failure were higher as compared to healthy adult controls (2.25-fold in children with renal failure, 1.53-fold in adult patients on dialysis, and 1.56-fold in kidney transplant recipients, respectively). Computer assisted biophysical structure modeling demonstrated, however, minor sterical- and/or electrostatic changes in oxPTH and n-oxPTH. This indicated that PTH oxidation may induce refolding of PTH and hence alters PTH-PTH receptor interaction via oxidation induced three-dimensional structure alteration of PTH. Conclusion: A huge proportion of circulating PTH measured by current state-of-the-art assay systems is oxidized and thus not biologically active. The relationship between oxPTH and n-oxPTH of individual patients varied substantially. Non-oxidized PTH concentrations are 1.5 - 2.25 fold higher in patients with renal failure as compared to health controls. Measurements of n-oxPTH may reflect the hormone status more precise. The iPTH measures describes most likely oxidative stress in patients with renal failure rather than the PTH hormone status. This, however, needs to be demonstrated in further clinical studies. KW - n-oxPTH KW - Chronic Renal Failure KW - Kidney Transplantation KW - Hemodialysis KW - Oxidation KW - PTH KW - Chronic Renal Failure in Children Y1 - 2013 U6 - https://doi.org/10.1159/000350149 SN - 1420-4096 SN - 1423-0143 VL - 37 IS - 4-5 SP - 240 EP - 251 PB - Karger CY - Basel ER - TY - GEN A1 - Hocher, Berthold A1 - Oberthür, Dominik A1 - Slowinski, Torsten A1 - Querfeld, Uwe A1 - Schaefer, Franz A1 - Doyon, Anke A1 - Tepel, Martin A1 - Roth, Heinz J. A1 - Grön, Hans J. A1 - Reichetzeder, Christoph A1 - Betzel, Christian A1 - Armbruster, Franz Paul T1 - Modeling of oxidized PTH (oxPTH) and non-oxidized PTH (n-oxPTH) receptor binding and relationship of oxidized to non-oxidized PTH in children with chronic renal failure, adult patients on hemodialysis and kidney transplant recipients N2 - Background: The biological properties of oxidized and non-oxidized PTH are substantially different. Oxidized PTH (oxPTH) loses its PTH receptor-stimulating properties, whereas non-oxidized PTH (n-oxPTH) is a full agonist of the receptor. This was described in more than 20 well published studies in the 1970(s) and 80(s). However, PTH oxidation has been ignored during the development of PTH assays for clinical use so far. Even the nowadays used third generation assay systems do not consider oxidation of PTH. We recently developed an assay to differentiate between oxPTH and n-oxPTH. In the current study we established normal values for this assay system. Furthermore, we compare the ratio of oxPTH to n-oxPTH in different population with chronic renal failure: 620 children with renal failure stage 2-4 of the 4C study, 342 adult patients on dialysis, and 602 kidney transplant recipients. In addition, we performed modeling of the interaction of either oxPTH or n-oxPTH with the PTH receptor using biophysical structure approaches. Results: The children had the highest mean as well as maximum n-oxPTH concentrations as compared to adult patients (both patients on dialysis as well as kidney transplant recipients). The relationship between oxPTH and n-oxPTH of individual patients varied substantially in all three populations with renal impairment. The analysis of n-oxPTH in 89 healthy control subjects revealed that n-oxPTH concentrations in patient with renal failure were higher as compared to healthy adult controls (2.25-fold in children with renal failure, 1.53-fold in adult patients on dialysis, and 1.56-fold in kidney transplant recipients, respectively). Computer assisted biophysical structure modeling demonstrated, however, minor sterical- and/or electrostatic changes in oxPTH and n-oxPTH. This indicated that PTH oxidation may induce refolding of PTH and hence alters PTH-PTH receptor interaction via oxidation induced three-dimensional structure alteration of PTH. Conclusion: A huge proportion of circulating PTH measured by current state-of-the-art assay systems is oxidized and thus not biologically active. The relationship between oxPTH and n-oxPTH of individual patients varied substantially. Non-oxidized PTH concentrations are 1.5 - 2.25 fold higher in patients with renal failure as compared to health controls. Measurements of n-oxPTH may reflect the hormone status more precise. The iPTH measures describes most likely oxidative stress in patients with renal failure rather than the PTH hormone status. This, however, needs to be demonstrated in further clinical studies. T3 - Zweitveröffentlichungen der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe - 343 KW - n-oxPTH KW - chronic renal failure KW - kidney transplantation KW - hemodialysis KW - oxidation KW - PTH KW - chronic renal failure in children Y1 - 2017 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:kobv:517-opus4-399980 ER - TY - JOUR A1 - Hocher, Berthold A1 - Lu, Yong-Ping A1 - Reichetzeder, Christoph A1 - Zhang, Xiaoli A1 - Tsuprykov, Oleg A1 - Rahnenführer, Jan A1 - Xie, Li A1 - Li, Jian A1 - Hu, Liang A1 - Krämer, Bernhard K. A1 - Hasan, Ahmed A. T1 - Paternal eNOS deficiency in mice affects glucose homeostasis and liver glycogen in male offspring without inheritance of eNOS deficiency itself JF - Diabetologia N2 - Aims/hypothesis It was shown that maternal endothelial nitric oxide synthase (eNOS) deficiency causes fatty liver disease and numerically lower fasting glucose in female wild-type offspring, suggesting that parental genetic variants may influence the offspring's phenotype via epigenetic modifications in the offspring despite the absence of a primary genetic defect. The aim of the current study was to analyse whether paternal eNOS deficiency may cause the same phenotype as seen with maternal eNOS deficiency. Methods Heterozygous (+/-) male eNOS (Nos3) knockout mice or wild-type male mice were bred with female wild-type mice. The phenotype of wild-type offspring of heterozygous male eNOS knockout mice was compared with offspring from wild-type parents. Results Global sperm DNA methylation decreased and sperm microRNA pattern altered substantially. Fasting glucose and liver glycogen storage were increased when analysing wild-type male and female offspring of +/- eNOS fathers. Wild-type male but not female offspring of +/- eNOS fathers had increased fasting insulin and increased insulin after glucose load. Analysing candidate genes for liver fat and carbohydrate metabolism revealed that the expression of genes encoding glucocorticoid receptor (Gr; also known as Nr3c1) and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (Pgc1a; also known as Ppargc1a) was increased while DNA methylation of Gr exon 1A and Pgc1a promoter was decreased in the liver of male wild-type offspring of +/- eNOS fathers. The endocrine pancreas in wild-type offspring was not affected.
Conclusions/interpretation Our study suggests that paternal genetic defects such as eNOS deficiency may alter the epigenome of the sperm without transmission of the paternal genetic defect itself. In later life wild-type male offspring of +/- eNOS fathers developed increased fasting insulin and increased insulin after glucose load. These effects are associated with increased Gr and Pgc1a gene expression due to altered methylation of these genes. KW - eNOS KW - Glucocorticoid receptor KW - Insulin resistance KW - Paternal programming; KW - PGC1a Y1 - 2022 U6 - https://doi.org/10.1007/s00125-022-05700-x SN - 0012-186X SN - 1432-0428 VL - 65 IS - 7 SP - 1222 EP - 1236 PB - Springer CY - New York ER - TY - JOUR A1 - Hocher, Berthold A1 - Heimerl, Dirk A1 - Slowinski, Torsten A1 - Godes, Michael A1 - Halle, Horst A1 - Priem, Friedrich A1 - Pfab, Thiemo T1 - Birthweight and Fetal Glycosylated Hemoglobin at Birth in Newborns Carrying the GLUT1 XbaI Gene Polymorphism JF - Clinical laboratory : the peer reviewed journal for clinical laboratories and laboratories related to blood transfusion N2 - Background: Low birthweight is an independent risk factor of glucose intolerance and type 2 diabetes in later life. Genetically determined insulin resistance and subsequently impaired glucose uptake might explain both reduced fetal growth and elevated blood glucose. The glucose transporter 1 (GLUT!) plays an important role for fetal glucose uptake as well as for maternal-fetal glucose transfer, and it has been associated with insulin resistance in adults. The present study hypothesized that the common fetal GLUT1 XbaI polymorphism might reduce fetal insulin sensitivity and/or glucose supply in utero, thus affecting fetal blood glucose and fetal growth. Methods: A genetic association study was conducted at the obstetrics department of the Charite University Hospital, Berlin, Germany. 119.1 white women were included after delivery, and all newborns were genotyped for the GLUT1 XbaI polymorphism. Total glycosylated hemoglobin was quantified, serving as a surrogate of glycemia during the last weeks of pregnancy. Results: The analysis of this large population showed no significant differences in fetal glycosylated hemoglobin or birthweight for the different fetal GLUT1 XbaI genotypes. Only newborns carrying the mutated allele show the previously published inverse association between birthweight and glycosylated hemoglobin. Conclusions: The results suggest that there is no prenatal effect of the fetal GLUT1 XbaI polymorphism on fetal insulin sensitivity, intrauterine fetal glucose supply or fetal growth. However, the polymorphism seems to modulate the inverse interaction between birthweight and fetal glycemia. KW - GLUT1 XbaI gene polymorphism KW - birthweight KW - total glycosylated hemoglobin KW - insulin resistance KW - fetal programming Y1 - 2011 SN - 1433-6510 VL - 57 IS - 9-10 SP - 651 EP - 657 PB - Clin Lab Publ., Verl. Klinisches Labor CY - Heidelberg ER - TY - JOUR A1 - Hocher, Berthold A1 - Heiden, Susi A1 - von Websky, Karoline A1 - Arafat, Ayman M. A1 - Rahnenführer, Jan A1 - Alter, Markus L. A1 - Kalk, Philipp A1 - Ziegler, Dieter A1 - Fischer, Yvan A1 - Pfab, Thiemo T1 - Renal effects of the novel selective adenosine A(1) receptor blocker SLV329 in experimental liver cirrhosis in rats JF - PLoS one N2 - Liver cirrhosis is often complicated by an impaired renal excretion of water and sodium. Diuretics tend to further deteriorate renal function. It is unknown whether chronic selective adenosine A(1) receptor blockade, via inhibition of the hepatorenal reflex and the tubuloglomerular feedback, might exert diuretic and natriuretic effects without a reduction of the glomerular filtration rate. In healthy animals intravenous treatment with the novel A(1) receptor antagonist SLV329 resulted in a strong dose-dependent diuretic (up to 3.4-fold) and natriuretic (up to 13.5-fold) effect without affecting creatinine clearance. Male Wistar rats with thioacetamide-induced liver cirrhosis received SLV329, vehicle or furosemide for 12 weeks. The creatinine clearance of cirrhotic animals decreased significantly (-36.5%, p < 0.05), especially in those receiving furosemide (-41.9%, p < 0.01). SLV329 was able to prevent this decline of creatinine clearance. Mortality was significantly lower in cirrhotic animals treated with SLV329 in comparison to animals treated with furosemide (17% vs. 54%, p < 0.05). SLV329 did not relevantly influence the degree of liver fibrosis, kidney histology or expression of hepatic or renal adenosine receptors. In conclusion, chronic treatment with SLV329 prevented the decrease of creatinine clearance in a rat model of liver cirrhosis. Further studies will have to establish whether adenosine A(1) receptor antagonists are clinically beneficial at different stages of liver cirrhosis. Y1 - 2011 U6 - https://doi.org/10.1371/journal.pone.0017891 SN - 1932-6203 VL - 6 IS - 3 PB - PLoS CY - San Fransisco ER - TY - JOUR A1 - Hocher, Berthold A1 - Heiden, S. A1 - von Websky, Karoline A1 - Rahnenführer, Jörg A1 - Kalk, Philipp A1 - Pfab, T. T1 - Dual endothelin-converting enzyme/neutral endopeptidase blockade in rats with D-galactosamine-induced liver failure JF - European journal of medical research : official organ "Deutsche AIDS-Gesellschaft" N2 - Secondary activation of the endothelin system is thought to be involved in toxic liver injury. This study tested the hypothesis that dual endothelin-converting enzyme / neutral endopeptidase blockade might: be able to attenuate acute toxic liver injury. Male Sprague-Dawley rats were implanted with subcutaneous minipumps to deliver the novel compound SLV338 (10 mg/kg*d) or vehicle. Four days later they received two intraperitoneal injections of D-galactosamine (1.3 g/kg each) or vehicle at an interval of 12 hours. The animals were sacrificed 48 hours after the first injection. Injection of D-galactosamine resulted in very severe liver injury, reflected by strongly elevated plasma liver enzymes, hepatic necrosis and inflammation, and a mortality rate of 42.9 %. SLV338 treatment did not show any significant effect on the extent of acute liver injury as judged from plasma parameters, hepatic histology and mortality. Plasma measurements of SLV338 confirmed adequate drug delivery. Plasma concentrations of big endothelin-1 and endothelin-1 were significantly elevated in animals with liver injury (5-fold and 62-fold, respectively). Plasma endothelin-1 was significantly correlated with several markers of liver injury. SLV338 completely prevented the rise of plasma big endothelin-1 (p<0.05) and markedly attenuated the rise of endothelin-1 (p = 0.055). In conclusion, dual endothelin-converting enzyme / neutral endopeptidase blockade by SLV338 did not significantly attenuate D-galactosamine-induced acute liver injury, although it largely prevented the activation of the endothelin system. An evaluation of SLV338 in a less severe model of liver injury would be of interest, since very severe intoxication might not be relevantly amenable to pharmacological interventions. KW - endothelin KW - endothelin-converting enzyme KW - neutral endopeptidase KW - D-galactosamine KW - acute liver failure Y1 - 2011 SN - 0949-2321 VL - 16 IS - 6 SP - 275 EP - 279 PB - Med. Scientific Publ. Holzapfel CY - München ER - TY - JOUR A1 - Hocher, Berthold A1 - Haumann, Hannah A1 - Rahnenführer, Jan A1 - Reichetzeder, Christoph A1 - Kalk, Philipp A1 - Pfab, Thiemo A1 - Tsuprykov, Oleg A1 - Winter, Stefan A1 - Hofmann, Ute A1 - Li, Jian A1 - Püschel, Gerhard Paul A1 - Lang, Florian A1 - Schuppan, Detlef A1 - Schwab, Matthias A1 - Schaeffeler, Elke T1 - Maternal eNOS deficiency determines a fatty liver phenotype of the offspring in a sex dependent manner JF - Epigenetics : the official journal of the DNA Methylation Society N2 - Maternal environmental factors can impact on the phenotype of the offspring via the induction of epigenetic adaptive mechanisms. The advanced fetal programming hypothesis proposes that maternal genetic variants may influence the offspring's phenotype indirectly via epigenetic modification, despite the absence of a primary genetic defect. To test this hypothesis, heterozygous female eNOS knockout mice and wild type mice were bred with male wild type mice. We then assessed the impact of maternal eNOS deficiency on the liver phenotype of wild type offspring. Birth weight of male wild type offspring born to female heterozygous eNOS knockout mice was reduced compared to offspring of wild type mice. Moreover, the offspring displayed a sex specific liver phenotype, with an increased liver weight, due to steatosis. This was accompanied by sex specific differences in expression and DNA methylation of distinct genes. Liver global DNA methylation was significantly enhanced in both male and female offspring. Also, hepatic parameters of carbohydrate metabolism were reduced in male and female offspring. In addition, male mice displayed reductions in various amino acids in the liver. Maternal genetic alterations, such as partial deletion of the eNOS gene, can affect liver metabolism of wild type offspring without transmission of the intrinsic defect. This occurs in a sex specific way, with more detrimental effects in females. This finding demonstrates that a maternal genetic defect can epigenetically alter the phenotype of the offspring, without inheritance of the defect itself. Importantly, these acquired epigenetic phenotypic changes can persist into adulthood. KW - Epigenetics KW - eNOS KW - Fetal programming KW - fatty liver KW - metabolism Y1 - 2016 U6 - https://doi.org/10.1080/15592294.2016.1184800 SN - 1559-2294 SN - 1559-2308 VL - 11 SP - 539 EP - 552 PB - Routledge, Taylor & Francis Group CY - Philadelphia ER -