Dokument-ID Dokumenttyp Verfasser/Autoren Herausgeber Haupttitel Abstract Auflage Verlagsort Verlag Erscheinungsjahr Seitenzahl Schriftenreihe Titel Schriftenreihe Bandzahl ISBN Quelle der Hochschulschrift Konferenzname Quelle:Titel Quelle:Jahrgang Quelle:Heftnummer Quelle:Erste Seite Quelle:Letzte Seite URN DOI Abteilungen OPUS4-51918 misc Tammen, Harald; Koemhoff, Martin; Mark, Michael; Hocher, Berthold; Delic, Denis; Hess, Rüdiger; von Eynatten, Maximilian; Klein, Thomas Linagliptin treatment is associated with improved cobalamin (vitamin B-12) storage in mice and potentially in humans New York Springer 2018 2 Diabetologia : journal of the European Association for the Study of Diabetes (EASD) 61 S252 S253 Department Sport- und Gesundheitswissenschaften OPUS4-49351 Wissenschaftlicher Artikel Groop, Per-Henrik; Cooper, Mark E.; Perkovic, Vlado; Hocher, Berthold; Kanasaki, Keizo; Haneda, Masakazu; Schernthaner, Guntram; Sharma, Kumar; Stanton, Robert C.; Toto, Robert; Cescutti, Jessica; Gordat, Maud; Meinicke, Thomas; Koitka-Weber, Audrey; Thiemann, Sandra; von Eynatten, Maximilian Linagliptin and its effects on hyperglycaemia and albuminuria in patients with type 2 diabetes and renal dysfunction Aims: The MARLINA-T2D study (ClinicalTrials. gov, NCT01792518) was designed to investigate the glycaemic and renal effects of linagliptin added to standard-of-care in individuals with type 2 diabetes and albuminuria. Methods: A total of 360 individuals with type 2 diabetes, HbA1c 6.5% to 10.0% (48-86 mmol/ mol), estimated glomerular filtration rate (eGFR) >= 30 mL/min/1.73 m(2) and urinary albumin-tocreatinine ratio (UACR) 30-3000 mg/g despite single agent renin-angiotensin-system blockade were randomized to double-blind linagliptin (n = 182) or placebo (n = 178) for 24 weeks. The primary and key secondary endpoints were change from baseline in HbA1c at week 24 and time-weighted average of percentage change from baseline in UACR over 24 weeks, respectively. Results: Baseline mean HbA1c and geometric mean (gMean) UACR were 7.8% +/- 0.9% (62.2 +/- 9.6 mmol/mol) and 126 mg/g, respectively; 73.7% and 20.3% of participants had microalbuminuria or macroalbuminuria, respectively. After 24 weeks, the placebo-adjusted mean change in HbA1c from baseline was -0.60% (-6.6 mmol/mol) (95% confidence interval [CI], -0.78 to -0.43 [-8.5 to -4.7 mmol/mol]; P <.0001). The placebo-adjusted gMean for time-weighted average of percentage change in UACR from baseline was -6.0% (95% CI, -15.0 to 3.0; P =.1954). The adverse-event profile, including renal safety and change in eGFR, was similar between the linagliptin and placebo groups. Conclusions: In individuals at early stages of diabetic kidney disease, linagliptin significantly improved glycaemic control but did not significantly lower albuminuria. There was no significant change in placebo-adjusted eGFR. Detection of clinically relevant renal effects of linagliptin may require longer treatment, as its main experimental effects in animal studies have been to reduce interstitial fibrosis rather than alter glomerular haemodynamics. Hoboken Wiley 2017 10 Diabetes obesity & metabolism : a journal of pharmacology and therapeutics 19 11 1610 1619 10.1111/dom.13041 Institut für Ernährungswissenschaft OPUS4-49312 misc Hocher, Berthold; Tsuprykov, Oleg Renoprotective effects of GLP1R agonists and SGLT2 inhibitors 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. New York Nature Publ. Group 2017 2 Nature reviews nephroloy 13 728 729 10.1038/nrneph.2017.140 Institut für Ernährungswissenschaft OPUS4-49661 Wissenschaftlicher Artikel Warrington, Nicole; Beaumont, Robin; Horikoshi, Momoko; Day, Felix R.; Helgeland, Øyvind; Laurin, Charles; Bacelis, Jonas; Peng, Shouneng; Hao, Ke; Feenstra, Bjarke; Wood, Andrew R.; Mahajan, Anubha; Tyrrell, Jessica; Robertson, Neil R.; Rayner, N. William; Qiao, Zhen; Moen, Gunn-Helen; Vaudel, Marc; Marsit, Carmen; Chen, Jia; Nodzenski, Michael; Schnurr, Theresia M.; Zafarmand, Mohammad Hadi; Bradfield, Jonathan P.; Grarup, Niels; Kooijman, Marjolein N.; Li-Gao, Ruifang; Geller, Frank; Ahluwalia, Tarunveer Singh; Paternoster, Lavinia; Rueedi, Rico; Huikari, Ville; Hottenga, Jouke-Jan; Lyytikäinen, Leo-Pekka; Cavadino, Alana; Metrustry, Sarah; Cousminer, Diana L.; Wu, Ying; Thiering, Elisabeth Paula; Wang, Carol A.; Have, Christian Theil; Vilor-Tejedor, Natalia; Joshi, Peter K.; Painter, Jodie N.; Ntalla, Ioanna; Myhre, Ronny; Pitkänen, Niina; van Leeuwen, Elisabeth M.; Joro, Raimo; Lagou, Vasiliki; Richmond, Rebecca C.; Espinosa, Ana; Barton, Sheila J.; Inskip, Hazel M.; Holloway, John W.; Santa-Marina, Loreto; Estivill, Xavier; Ang, Wei; Marsh, Julie A.; Reichetzeder, Christoph; Marullo, Letizia; Hocher, Berthold; Lunetta, Kathryn L.; Murabito, Joanne M.; Relton, Caroline L.; Kogevinas, Manolis; Chatzi, Leda; Allard, Catherine; Bouchard, Luigi; Hivert, Marie-France; Zhang, Ge; Muglia, Louis J.; Heikkinen, Jani; Morgen, Camilla S.; van Kampen, Antoine H. C.; van Schaik, Barbera D. C.; Mentch, Frank D.; Langenberg, Claudia; Scott, Robert A.; Zhao, Jing Hua; Hemani, Gibran; Ring, Susan M.; Bennett, Amanda J.; Gaulton, Kyle J.; Fernandez-Tajes, Juan; van Zuydam, Natalie R.; Medina-Gomez, Carolina; de Haan, Hugoline G.; Rosendaal, Frits R.; Kutalik, Zoltán; Marques-Vidal, Pedro; Das, Shikta; Willemsen, Gonneke; Mbarek, Hamdi; Müller-Nurasyid, Martina; Standl, Marie; Appel, Emil V. R.; Fonvig, Cilius Esmann; Trier, Caecilie; van Beijsterveldt, Catharina E. M.; Murcia, Mario; Bustamante, Mariona; Bonàs-Guarch, Sílvia; Hougaard, David M.; Mercader, Josep M.; Linneberg, Allan; Schraut, Katharina E.; Lind, Penelope A.; Medland, Sarah Elizabeth; Shields, Beverley M.; Knight, Bridget A.; Chai, Jin-Fang; Panoutsopoulou, Kalliope; Bartels, Meike; Sánchez, Friman; Stokholm, Jakob; Torrents, David; Vinding, Rebecca K.; Willems, Sara M.; Atalay, Mustafa; Chawes, Bo L.; Kovacs, Peter; Prokopenko, Inga; Tuke, Marcus A.; Yaghootkar, Hanieh; Ruth, Katherine S.; Jones, Samuel E.; Loh, Po-Ru; Murray, Anna; Weedon, Michael N.; Tönjes, Anke; Stumvoll, Michael; Michaelsen, Kim Fleischer; Eloranta, Aino-Maija; Lakka, Timo A.; van Duijn, Cornelia M.; Kiess, Wieland; Koerner, Antje; Niinikoski, Harri; Pahkala, Katja; Raitakari, Olli T.; Jacobsson, Bo; Zeggini, Eleftheria; Dedoussis, George V.; Teo, Yik-Ying; Saw, Seang-Mei; Montgomery, Grant W.; Campbell, Harry; Wilson, James F.; Vrijkotte, Tanja G. M.; Vrijheid, Martine; de Geus, Eco J. C. N.; Hayes, M. Geoffrey; Kadarmideen, Haja N.; Holm, Jens-Christian; Beilin, Lawrence J.; Pennell, Craig E.; Heinrich, Joachim; Adair, Linda S.; Borja, Judith B.; Mohlke, Karen L.; Eriksson, Johan G.; Widen, Elisabeth E.; Hattersley, Andrew T.; Spector, Tim D.; Kaehoenen, Mika; Viikari, Jorma S.; Lehtimaeki, Terho; Boomsma, Dorret I.; Sebert, Sylvain; Vollenweider, Peter; Sorensen, Thorkild I. A.; Bisgaard, Hans; Bonnelykke, Klaus; Murray, Jeffrey C.; Melbye, Mads; Nohr, Ellen A.; Mook-Kanamori, Dennis O.; Rivadeneira, Fernando; Hofman, Albert; Felix, Janine F.; Jaddoe, Vincent W. V.; Hansen, Torben; Pisinger, Charlotta; Vaag, Allan A.; Pedersen, Oluf; Uitterlinden, Andre G.; Jarvelin, Marjo-Riitta; Power, Christine; Hypponen, Elina; Scholtens, Denise M.; Lowe, William L.; Smith, George Davey; Timpson, Nicholas J.; Morris, Andrew P.; Wareham, Nicholas J.; Hakonarson, Hakon; Grant, Struan F. A.; Frayling, Timothy M.; Lawlor, Debbie A.; Njolstad, Pal R.; Johansson, Stefan; Ong, Ken K.; McCarthy, Mark I.; Perry, John R. B.; Evans, David M.; Freathy, Rachel M. Maternal and fetal genetic effects on birth weight and their relevance to cardio-metabolic risk factors 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. New York Nature Publ. Group 2019 17 Nature genetics 51 5 804 + Institut für Ernährungswissenschaft OPUS4-52142 Wissenschaftlicher Artikel Gao, Lin-rui; Wang, Guang; Zhang, Jing; Li, Shuai; Chuai, Manli; Bao, Yongping; Hocher, Berthold; Yang, Xuesong High salt-induced excess reactive oxygen species production resulted in heart tube malformation during gastrulation An association has been proved between high salt consumption and cardiovascular mortality. In vertebrates, the heart is the first functional organ to be formed. However, it is not clear whether high-salt exposure has an adverse impact on cardiogenesis. Here we report high-salt exposure inhibited basement membrane breakdown by affecting RhoA, thus disturbing the expression of Slug/E-cadherin/N-cadherin/Laminin and interfering with mesoderm formation during the epithelial-mesenchymal transition(EMT). Furthermore, the DiI(+) cell migration trajectory in vivo and scratch wound assays in vitro indicated that high-salt exposure restricted cell migration of cardiac progenitors, which was caused by the weaker cytoskeleton structure and unaltered corresponding adhesion junctions at HH7. Besides, down-regulation of GATA4/5/6, Nkx2.5, TBX5, and Mef2c and up-regulation of Wnt3a/-catenin caused aberrant cardiomyocyte differentiation at HH7 and HH10. High-salt exposure also inhibited cell proliferation and promoted apoptosis. Most importantly, our study revealed that excessive reactive oxygen species(ROS)generated by high salt disturbed the expression of cardiac-related genes, detrimentally affecting the above process including EMT, cell migration, differentiation, cell proliferation and apoptosis, which is the major cause of malformation of heart tubes. Hoboken Wiley 2018 14 Journal of Cellular Physiology 233 9 7120 7133 10.1002/jcp.26528 Institut für Ernährungswissenschaft OPUS4-52126 Wissenschaftlicher Artikel Glosse, Philipp; Feger, Martina; Mutig, Kerim; Chen, Hong; Hirche, Frank; Hasan, Ahmed Abdallah Abdalrahman Mohamed; Gaballa, Mohamed Mahmoud Salem Ahmed; Hocher, Berthold; Lang, Florian; Föller, Michael AMP-activated kinase is a regulator of fibroblast growth factor 23 production Fibroblast growth factor 23 (FGF23) is a proteohormone regulating renal phosphate transport and vitamin D metabolism as well as inducing left heart hypertrophy. FGF23-deficient mice suffer from severe tissue calcification, accelerated aging and a myriad of aging-associated diseases. Bone cells produce FGF23 upon store-operated calcium ion entry (SOCE) through the calcium selective ion channel Orai1. AMP-activated kinase (AMPK) is a powerful energy sensor helping cells survive states of energy deficiency, and AMPK down-regulates Orai1. Here we investigated the role of AMPK in FGF23 production. Fgf23 gene transcription was analyzed by qRT-PCR and SOCE by fluorescence optics in UMR106 osteoblast-like cells while the serum FGF23 concentration and phosphate metabolism were assessed in AMPKa1-knockout and wild-type mice. The AMPK activator, 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR) down-regulated, whereas the AMPK inhibitor, dorsomorphin dihydrochloride (compound C) and AMPK gene silencing induced Fgf23 transcription. AICAR decreased membrane abundance of Orai1 and SOCE. SOCE inhibitors lowered Fgf23 gene expression induced by AMPK inhibition. AMPKa1-knockout mice had a higher serum FGF23 concentration compared to wild-type mice. Thus, AMPK participates in the regulation of FGF23 production in vitro and in vivo. The inhibitory effect of AMPK on FGF23 production is at least in part mediated by Orai1-involving SOCE. New York Elsevier 2018 11 Kidney international : official journal of the International Society of Nephrology 94 3 491 501 10.1016/j.kint.2018.03.006 Institut für Geowissenschaften OPUS4-53521 Wissenschaftlicher Artikel Beaumont, Robin N.; Warrington, Nicole M.; Cavadino, Alana; Tyrrell, Jessica; Nodzenski, Michael; Horikoshi, Momoko; Geller, Frank; Myhre, Ronny; Richmond, Rebecca C.; Paternoster, Lavinia; Bradfield, Jonathan P.; Kreiner-Moller, Eskil; Huikari, Ville; Metrustry, Sarah; Lunetta, Kathryn L.; Painter, Jodie N.; Hottenga, Jouke-Jan; Allard, Catherine; Barton, Sheila J.; Espinosa, Ana; Marsh, Julie A.; Potter, Catherine; Zhang, Ge; Ang, Wei; Berry, Diane J.; Bouchard, Luigi; Das, Shikta; Hakonarson, Hakon; Heikkinen, Jani; Helgeland, Oyvind; Hocher, Berthold; Hofman, Albert; Inskip, Hazel M.; Jones, Samuel E.; Kogevinas, Manolis; Lind, Penelope A.; Marullo, Letizia; Medland, Sarah E.; Murray, Anna; Murray, Jeffrey C.; Njolstad, Pal R.; Nohr, Ellen A.; Reichetzeder, Christoph; Ring, Susan M.; Ruth, Katherine S.; Santa-Marina, Loreto; Scholtens, Denise M.; Sebert, Sylvain; Sengpiel, Verena; Tuke, Marcus A.; Vaudel, Marc; Weedon, Michael N.; Willemsen, Gonneke; Wood, Andrew R.; Yaghootkar, Hanieh; Muglia, Louis J.; Bartels, Meike; Relton, Caroline L.; Pennell, Craig E.; Chatzi, Leda; Estivill, Xavier; Holloway, John W.; Boomsma, Dorret I.; Montgomery, Grant W.; Murabito, Joanne M.; Spector, Tim D.; Power, Christine; Jarvelin, Marjo-Ritta; Bisgaard, Hans; Grant, Struan F. A.; Sorensen, Thorkild I. A.; Jaddoe, Vincent W.; Jacobsson, Bo; Melbye, Mads; McCarthy, Mark I.; Hattersley, Andrew T.; Hayes, M. Geoffrey; Frayling, Timothy M.; Hivert, Marie-France; Felix, Janine F.; Hypponen, Elina; Lowe, William L.; Evans, David M.; Lawlor, Debbie A.; Feenstra, Bjarke; Freathy, Rachel M. Genome-wide association study of offspring birth weight in 86 577 women identifies five novel loci and highlights maternal genetic effects that are independent of fetal genetics Genome-wide association studies of birth weight have focused on fetal genetics, whereas relatively little is known about the role of maternal genetic variation. We aimed to identify maternal genetic variants associated with birth weight that could highlight potentially relevant maternal determinants of fetal growth. We meta-analysed data on up to 8.7 million SNPs in up to 86 577 women of European descent from the Early Growth Genetics (EGG) Consortium and the UK Biobank. We used structural equation modelling (SEM) and analyses of mother-child pairs to quantify the separate maternal and fetal genetic effects. Maternal SNPs at 10 loci (MTNR1B, HMGA2, SH2B3, KCNAB1, L3MBTL3, GCK, EBF1, TCF7L2, ACTL9, CYP3A7) were associated with offspring birth weight at P< 5 x 10(-8). In SEM analyses, at least 7 of the 10 associations were consistent with effects of the maternal genotype acting via the intrauterine environment, rather than via effects of shared alleles with the fetus. Variants, or correlated proxies, at many of the loci had been previously associated with adult traits, including fasting glucose (MTNR1B, GCK and TCF7L2) and sex hormone levels (CYP3A7), and one (EBF1) with gestational duration. The identified associations indicate that genetic effects on maternal glucose, cytochrome P450 activity and gestational duration, and potentially on maternal blood pressure and immune function, are relevant for fetal growth. Further characterization of these associations in mechanistic and causal analyses will enhance understanding of the potentially modifiable maternal determinants of fetal growth, with the goal of reducing the morbidity and mortality associated with low and high birth weights. Oxford Oxford Univ. Press 2018 15 Human molecular genetics 27 4 742 756 10.1093/hmg/ddx429 Institut für Biochemie und Biologie OPUS4-53104 misc Hocher, Berthold; Zeng, Shufei Clear the fog around parathyroid hormone assays Washington American Society of Nephrology 2018 3 Clinical journal of the American Society of Nephrology 13 4 524 526 10.2215/CJN.01730218 Institut für Ernährungswissenschaft OPUS4-53406 misc Reichetzeder, Christoph; Hocher, Berthold DPP4 inhibition prevents AKI Orchard Park Impact Journals LLC 2017 2 Oncotarget 8 64655 64656 10.18632/oncotarget.20212 Institut für Ernährungswissenschaft OPUS4-54805 Review Hasan, Ahmed Abdallah Abdalrahman Mohamed; Hocher, Berthold Role of soluble and membrane-bound dipeptidyl peptidase-4 in diabetic nephropathy Diabetic nephropathy is one of the most frequent, devastating and costly complications of diabetes. The available therapeutic approaches are limited. Dipeptidyl peptidase type 4 (DPP-4) inhibitors represent a new class of glucose-lowering drugs that might also have reno-protective properties. DPP-4 exists in two forms: a plasma membranebound form and a soluble form, and can exert many biological actions mainly through its peptidase activity and interaction with extracellular matrix components. The kidneys have the highest DPP-4 expression level in mammalians. DPP-4 expression and urinary activity are up-regulated in diabetic nephropathy, highlighting its role as a potential target to manage diabetic nephropathy. Preclinical animal studies and some clinical data suggest that DPP-4 inhibitors decrease the progression of diabetic nephropathy in a blood pressure-and glucose-independent manner. Many studies reported that these reno-protective effects could be due to increased half-life of DPP-4 substrates such as glucagon-like peptide-1 (GLP-1) and stromal derived factor-1 alpha (SDF-1a). However, the underlying mechanisms are far from being completely understood and clearly need further investigations. Bristol Bioscientifica LTD 2017 10 Journal of Molecular Endocrinology 59 R1 R10 10.1530/JME-17-0005 Institut für Biochemie und Biologie OPUS4-55394 Wissenschaftlicher Artikel Heunisch, Fabian; Chaykovska, Lyubov; von Einem, Gina; Alter, Markus; Dschietzig, Thomas; Kretschmer, Axel; Kellner, Karl-Heinz; Hocher, Berthold ADMA predicts major adverse renal events in patients with mild renal impairment and/or diabetes mellitus undergoing coronary angiography Asymmetric dimethylarginine (ADMA) is a competitive inhibitor of the nitric oxide (NO)-synthase and a biomarker of endothelial dysfunction (ED). ED plays an important role in the pathogenesis of contrast-induced nephropathy (CIN). The aim of our study was to evaluate serum ADMA concentration as a biomarker of an acute renal damage during the follow-up of 90 days after contrast medium (CM) application. Blood samples were obtained from 330 consecutive patients with diabetes mellitus or mild renal impairment immediately before, 24 and 48 hours after the CM application for coronary angiography. The patients were followed for 90 days. The composite endpoints were major adverse renal events (MARE) defined as occurrence of death, initiation of dialysis, or a doubling of serum creatinine concentration. Overall, ADMA concentration in plasma increased after CM application, although, there was no differences between ADMA levels in patients with and without CIN. ADMA concentration 24 hours after the CM application was predictive for dialysis with a specificity of 0.889 and sensitivity of 0.653 at values higher than 0.71 mu mol/L (area under the curve: 0.854, 95% confidential interval: 0.767-0.941, P<0.001). This association remained significant in multivariate Cox regression models adjusted for relevant factors of long-term renal outcome. 24 hours after the CM application, ADMA concentration in plasma was predictive for MARE with a specificity of 0.833 and sensitivity of 0.636 at a value of more than 0.70 mu mol/L (area under the curve: 0.750, 95% confidence interval: 0.602-0.897, P=0.004). Multivariate logistic regression analysis confirmed that ADMA and anemia were significant predictors of MARE. Further analysis revealed that increased ADMA concentration in plasma was highly significant predictor of MARE in patients with CIN. Moreover, patients with CIN and MARE had the highest plasma ADMA levels 24 hours after CM exposure in our study cohort. The impact of ADMA on MARE was independent of such known CIN risk factors as anemia, pre-existing renal failure, pre-existing heart failure, and diabetes. ADMA concentration in plasma is a promising novel biomarker of major contrast-induced nephropathy-associated events 90 days after contrast media exposure. Philadelphia Lippincott Williams & Wilkins 2017 7 Medicine 96 6 10.1097/MD.0000000000006065 Institut für Ernährungswissenschaft OPUS4-52689 Wissenschaftlicher Artikel Tsuprykov, Oleg; Buse, Claudia; Skoblo, Roman; Haq, Afrozul; Hocher, Berthold Reference intervals for measured and calculated free 25-hydroxyvitamin D in normal pregnancy 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. Oxford Elsevier 2018 8 The Journal of Steroid Biochemistry and Molecular Biology 181 80 87 10.1016/j.jsbmb.2018.03.005 Institut für Ernährungswissenschaft OPUS4-52836 Wissenschaftlicher Artikel Tsuprykov, Oleg; Chen, Xin; Hocher, Carl-Friedrich; Skoblo, Roman; Yin, Lianghong; Hocher, Berthold Why should we measure free 25(OH) vitamin D? 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. Oxford Elsevier 2018 18 The Journal of Steroid Biochemistry and Molecular Biology 180 87 104 10.1016/j.jsbmb.2017.11.014 Department Sport- und Gesundheitswissenschaften OPUS4-52797 Wissenschaftlicher Artikel von Websky, Karoline; Hasan, Ahmed Abdallah Abdalrahman Mohamed; Reichetzeder, Christoph; Tsuprykov, Oleg; Hocher, Berthold Impact of vitamin D on pregnancy-related disorders and on offspring outcome 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. Oxford Elsevier 2018 14 The Journal of Steroid Biochemistry and Molecular Biology 180 51 64 10.1016/j.jsbmb.2017.11.008 Institut für Ernährungswissenschaft OPUS4-52874 Wissenschaftlicher Artikel Bär, Ludmilla; Feger, Martina; Fajol, Abul; Klotz, Lars-Oliver; Zeng, Shufei; Lang, Florian; Hocher, Berthold; Föller, Michael Insulin suppresses the production of fibroblast growth factor 23 (FGF23) Fibroblast growth factor 23 (FGF23) is produced by bone cells and regulates renal phosphate and vitamin D metabolism, as well as causing left ventricular hypertrophy. FGF23 deficiency results in rapid aging, whereas high plasma FGF23 levels are found in several disorders, including kidney or cardiovascular diseases. Regulators of FGF23 production include parathyroid hormone (PTH), calcitriol, dietary phosphate, and inflammation. We report that insulin and insulin-like growth factor 1 (IGF1) are negative regulators of FGF23 production. In UMR106 osteoblast-like cells, insulin and IGF1 down-regulated FGF23 production by inhibiting the transcription factor forkhead box protein O1 (FOXO1) through phosphoinositide 3-kinase (PI3K)/protein kinase B (PKB)/Akt signaling. Insulin deficiency caused a surge in the serum FGF23 concentration in mice, which was reversed by administration of insulin. In women, a highly significant negative correlation between FGF23 plasma concentration and increase in plasma insulin level following an oral glucose load was found. Our results provide strong evidence that insulin/IGF1dependent PI3K/PKB/Akt/FOXO1 signaling is a powerful suppressor of FGF23 production in vitro as well as in mice and in humans. Washington National Acad. of Sciences 2018 6 Proceedings of the National Academy of Sciences of the United States of America 115 22 5804 5809 10.1073/pnas.1800160115 Institut für Biochemie und Biologie OPUS4-52294 Wissenschaftlicher Artikel Li, Jian; Lu, Yong-Ping; Tsuprykov, Oleg; Hasan, Ahmed Abdallah Abdalrahman Mohamed; Reichetzeder, Christoph; Tian, Mei; Zhang, Xiao Li; Zhang, Qin; Sun, Guo-Ying; Guo, Jingli; Gaballa, Mohamed Mahmoud Salem Ahmed; Peng, Xiao-Ning; Lin, Ge; Hocher, Berthold Folate treatment of pregnant rat dams abolishes metabolic effects in female offspring induced by a paternal pre-conception unhealthy diet 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. New York Springer 2018 15 Diabetologia : journal of the European Association for the Study of Diabetes (EASD) 61 8 1862 1876 10.1007/s00125-018-4635-x Department Sport- und Gesundheitswissenschaften OPUS4-52354 Wissenschaftlicher Artikel Luo, Ting; Chen, Xiaoyi; Zeng, Shufei; Guan, Baozhang; Hu, Bo; Meng, Yu; Liu, Fanna; Wong, Taksui; Lu, Yongpin; Yun, Chen; Hocher, Berthold; Yin, Lianghong Bioinformatic identification of key genes and analysis of prognostic values in clear cell renal cell carcinoma 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. Athens Spandidos publ LTD 2018 11 Oncology Letters 16 2 1747 1757 10.3892/ol.2018.8842 Department Sport- und Gesundheitswissenschaften OPUS4-49148 Wissenschaftlicher Artikel Hasan, Ahmed Abdallah Abdalrahman Mohamed; von Websky, Karoline; Reichetzeder, Christoph; Tsuprykov, Oleg; Gaballa, Mohamed Mahmoud Salem Ahmed; Guo, Jingli; Zeng, Shufei; Delic, Denis; Tammen, Harald; Klein, Thomas; Kleuser, Burkhard; Hocher, Berthold Mechanisms of GLP-1 receptor-independent renoprotective effects of the dipeptidyl peptidase type 4 inhibitor linagliptin in GLP-1 receptor knockout mice with 5/6 nephrectomy Dipeptidyl peptidase type 4 (DPP-4) inhibitors were reported to have beneficial effects in experimental models of chronic kidney disease. The underlying mechanisms are not completely understood. However, these effects could be mediated via the glucagon-like peptide-1 (GLP-1)/GLP-1 receptor (GLP1R) pathway. Here we investigated the renal effects of the DPP-4 inhibitor linagliptin in Glp1r-/- knock out and wild-type mice with 5/6 nephrectomy (5/6Nx). Mice were allocated to groups: sham + wild type + placebo; 5/6Nx+ wild type + placebo; 5/6Nx+ wild type + linagliptin; sham + knock out+ placebo; 5/6Nx + knock out+ placebo; 5/6Nx + knock out+ linagliptin. 5/6Nx caused the development of renal interstitial fibrosis, significantly increased plasma cystatin C and creatinine levels and suppressed renal gelatinase/collagenase, matrix metalloproteinase-1 and -13 activities; effects counteracted by linagliptin treatment in wildtype and Glp1r-/- mice. Two hundred ninety-eight proteomics signals were differentially regulated in kidneys among the groups, with 150 signals specific to linagliptin treatment as shown by mass spectrometry. Treatment significantly upregulated three peptides derived from collagen alpha-1(I), thymosin beta 4 and heterogeneous nuclear ribonucleoprotein Al (HNRNPA1) and significantly downregulated one peptide derived from Y box binding protein-1 (YB-1). The proteomics results were further confirmed using western blot and immunofluorescence microscopy. Also, 5/6Nx led to significant up-regulation of renal transforming growth factor-beta 1 and pSMAD3 expression in wild type mice and linagliptin significantly counteracted this up-regulation in wild type and GIplr-/- mice. Thus, the renoprotective effects of linagliptin cannot solely be attributed to the GLP-1/GLP1R pathway, highlighting the importance of other signaling pathways (collagen I homeostasis, HNRNPA1,YB-1,thymosin beta 4 and TGF-beta 1) influenced by DPP-4 inhibition. New York Elsevier 2019 16 Kidney international : official journal of the International Society of Nephrology 95 6 1373 1388 10.1016/j.kint.2019.01.010 Institut für Ernährungswissenschaft OPUS4-47882 Review Tian, Mei; Reichetzeder, Christoph; Li, Jian; Hocher, Berthold Low birth weight, a risk factor for diseases in later life, is a surrogate of insulin resistance at birth 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. Philadelphia Kluwer 2019 12 Journal of hypertension 37 11 2123 2134 10.1097/HJH.0000000000002156 Institut für Ernährungswissenschaft OPUS4-54600 Wissenschaftlicher Artikel Lu, Yong-Ping; Reichetzeder, Christoph; Prehn, Cornelia; von Websky, Karoline; Slowinski, Torsten; Chen, You-Peng; Yin, Liang-Hong; Kleuser, Burkhard; Yang, Xue-Song; Adamski, Jerzy; Hocher, Berthold Fetal serum metabolites are independently associated with Gestational diabetes mellitus 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 Basel Karger 2018 14 Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry and pharmacology 45 2 625 638 10.1159/000487119 Institut für Chemie OPUS4-50174 Wissenschaftlicher Artikel Tao, Ting; Su, Qiongli; Xu, Simeng; Deng, Jun; Zhou, Sichun; Zhuang, Yu; Huang, Yanjun; He, Caimei; He, Shanping; Peng, Mei; Hocher, Berthold; Yang, Xiaoping Down-regulation of PKM2 decreases FASN expression in bladder cancer cells through AKT/mTOR/SREBP-1c axis 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. Hoboken Wiley 2018 17 Journal of cellular physiology 234 3 3088 3104 10.1002/jcp.27129 Institut für Ernährungswissenschaft OPUS4-50042 Wissenschaftlicher Artikel Middeldorp, Christel M.; Mahajan, Anubha; Horikoshi, Momoko; Robertson, Neil R.; Beaumont, Robin N.; Bradfield, Jonathan P.; Bustamante, Mariona; Cousminer, Diana L.; Day, Felix R.; De Silva, N. Maneka; Guxens, Monica; Mook-Kanamori, Dennis O.; St Pourcain, Beate; Warrington, Nicole M.; Adair, Linda S.; Ahlqvist, Emma; Ahluwalia, Tarunveer Singh; Almgren, Peter; Ang, Wei; Atalay, Mustafa; Auvinen, Juha; Bartels, Meike; Beckmann, Jacques S.; Bilbao, Jose Ramon; Bond, Tom; Borja, Judith B.; Cavadino, Alana; Charoen, Pimphen; Chen, Zhanghua; Coin, Lachlan; Cooper, Cyrus; Curtin, John A.; Custovic, Adnan; Das, Shikta; Davies, Gareth E.; Dedoussis, George V.; Duijts, Liesbeth; Eastwood, Peter R.; Eliasen, Anders U.; Elliott, Paul; Eriksson, Johan G.; Estivill, Xavier; Fadista, Joao; Fedko, Iryna O.; Frayling, Timothy M.; Gaillard, Romy; Gauderman, W. James; Geller, Frank; Gilliland, Frank; Gilsanz, Vincente; Granell, Raquel; Grarup, Niels; Groop, Leif; Hadley, Dexter; Hakonarson, Hakon; Hansen, Torben; Hartman, Catharina A.; Hattersley, Andrew T.; Hayes, M. Geoffrey; Hebebrand, Johannes; Heinrich, Joachim; Helgeland, Oyvind; Henders, Anjali K.; Henderson, John; Henriksen, Tine B.; Hirschhorn, Joel N.; Hivert, Marie-France; Hocher, Berthold; Holloway, John W.; Holt, Patrick; Hottenga, Jouke-Jan; Hypponen, Elina; Iniguez, Carmen; Johansson, Stefan; Jugessur, Astanand; Kahonen, Mika; Kalkwarf, Heidi J.; Kaprio, Jaakko; Karhunen, Ville; Kemp, John P.; Kerkhof, Marjan; Koppelman, Gerard H.; Korner, Antje; Kotecha, Sailesh; Kreiner-Moller, Eskil; Kulohoma, Benard; Kumar, Ashish; Kutalik, Zoltan; Lahti, Jari; Lappe, Joan M.; Larsson, Henrik; Lehtimaki, Terho; Lewin, Alexandra M.; Li, Jin; Lichtenstein, Paul; Lindgren, Cecilia M.; Lindi, Virpi; Linneberg, Allan; Liu, Xueping; Liu, Jun; Lowe, William L.; Lundstrom, Sebastian; Lyytikainen, Leo-Pekka; Ma, Ronald C. W.; Mace, Aurelien; Magi, Reedik; Magnus, Per; Mamun, Abdullah A.; Mannikko, Minna; Martin, Nicholas G.; Mbarek, Hamdi; McCarthy, Nina S.; Medland, Sarah E.; Melbye, Mads; Melen, Erik; Mohlke, Karen L.; Monnereau, Claire; Morgen, Camilla S.; Morris, Andrew P.; Murray, Jeffrey C.; Myhre, Ronny; Najman, Jackob M.; Nivard, Michel G.; Nohr, Ellen A.; Nolte, Ilja M.; Ntalla, Ioanna; Oberfield, Sharon E.; Oken, Emily; Oldehinkel, Albertine J.; Pahkala, Katja; Palviainen, Teemu; Panoutsopoulou, Kalliope; Pedersen, Oluf; Pennell, Craig E.; Pershagen, Goran; Pitkanen, Niina; Plomin, Robert; Power, Christine; Prasad, Rashmi B.; Prokopenko, Inga; Pulkkinen, Lea; Raikkonen, Katri; Raitakari, Olli T.; Reynolds, Rebecca M.; Richmond, Rebecca C.; Rivadeneira, Fernando; Rodriguez, Alina; Rose, Richard J.; Salem, Rany; Santa-Marina, Loreto; Saw, Seang-Mei; Schnurr, Theresia M.; Scott, James G.; Selzam, Saskia; Shepherd, John A.; Simpson, Angela; Skotte, Line; Sleiman, Patrick M. A.; Snieder, Harold; Sorensen, Thorkild I. A.; Standl, Marie; Steegers, Eric A. P.; Strachan, David P.; Straker, Leon; Strandberg, Timo; Taylor, Michelle; Teo, Yik-Ying; Thiering, Elisabeth; Torrent, Maties; Tyrrell, Jessica; Uitterlinden, Andre G.; van Beijsterveldt, Toos; van der Most, Peter J.; van Duijn, Cornelia M.; Viikari, Jorma; Vilor-Tejedor, Natalia; Vogelezang, Suzanne; Vonk, Judith M.; Vrijkotte, Tanja G. M.; Vuoksimaa, Eero; Wang, Carol A.; Watkins, William J.; Wichmann, H-Erich; Willemsen, Gonneke; Williams, Gail M.; Wilson, James F.; Wray, Naomi R.; Xu, Shujing; Xu, Cheng-Jian; Yaghootkar, Hanieh; Yi, Lu; Zafarmand, Mohammad Hadi; Zeggini, Eleftheria; Zemel, Babette S.; Hinney, Anke; Lakka, Timo A.; Whitehouse, Andrew J. O.; Sunyer, Jordi; Widen, Elisabeth E.; Feenstra, Bjarke; Sebert, Sylvain; Jacobsson, Bo; Njolstad, Pal R.; Stoltenberg, Camilla; Smith, George Davey; Lawlor, Debbie A.; Paternoster, Lavinia; Timpson, Nicholas J.; Ong, Ken K.; Bisgaard, Hans; Bonnelykke, Klaus; Jaddoe, Vincent W. V.; Tiemeier, Henning; Jarvelin, Marjo-Riitta; Evans, David M.; Perry, John R. B.; Grant, Struan F. A.; Boomsma, Dorret I.; Freathy, Rachel M.; McCarthy, Mark I.; Felix, Janine F. The Early Growth Genetics (EGG) and EArly Genetics and Lifecourse Epidemiology (EAGLE) consortia 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. Dordrecht Springer 2019 22 European journal of epidemiology 34 3 279 300 10.1007/s10654-019-00502-9 Institut für Biochemie und Biologie OPUS4-47087 Konferenzveröffentlichung Tsuprykov, Oleg; Buse, Claudia; Skoblo, Roman; Hocher, Berthold Free 25 (OH) vitamin D, but not total 25 (OH) vitamin D, is strongly correlated with gestational age and calcium in normal human pregnancy Hoboken Wiley 2017 1 Journal of bone and mineral research 32 S323 S323 Institut für Ernährungswissenschaft OPUS4-55873 Wissenschaftlicher Artikel He, Jing; Liu, Zhi-Wei; Lu, Yong-Ping; Li, Tao-Yuan; Liang, Xu-Jing; Arck, Petra; Huang, Si-Min; Hocher, Berthold; Chen, You-Peng A systematic review and meta-analysis of influenza a virus infection during pregnancy associated with an increased risk for stillbirth and low birth weight Background/Aims: Impaired pregnancy outcomes, such as low birth weight are associated with increased disease risk in later life, however little is known about the impact of common infectious diseases during pregnancy on birth weight. The study had two aims: a) to investigate risk factors of influenza virus infection during pregnancy, and b) to analyze the impact of influenza virus infection on pregnancy outcome, especially birth weight. Methods: Prospective and retrospective observational studies found in PubMed, MEDLINE, Embase, Google Scholar, and WangFang database were included in this meta analysis. Data of included studies was extracted and analyzed by the RevMan software. Results: Pregnant women with anemia (P=0.004, RR=1.46, 95% CI: 1.13-1.88), obesity (P<0.00001, RR=1.35, 95% CI: 1.25-1.46) and asthma (P<0.00001, RR=1.99, 95% CI: 1.67-2.37) had higher rates of influenza virus infection. Regarding birth outcomes, influenza A virus infection did not affect the likelihood for cesarean section. Mothers with influenza had a higher rate of stillbirth (P=0.04, RR=2.36, 95% CI: 1.05-5.31), and their offspring had low 5-minute APGR Scores (P=0.009, RR=1.39, 95% CI: 1.08-1.79). Furthermore, the rate for birth weight < 2500g (P=0.04, RR=1.71, 95% CI: 1.03-2.84) was increased. Conclusion: Results of this study showed that anemia, asthma and obesity during pregnancy are risk factors influenza A virus infection during pregnancy. Moreover, gestational influenza A infection impairs pregnancy outcomes and increases the risk for low birth weight, a known risk factor for later life disease susceptibility. Basel Karger 2017 12 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 42 2 232 243 10.1159/000477221 Institut für Ernährungswissenschaft OPUS4-55876 Wissenschaftlicher Artikel Xu, Mei; Lu, Yong-Ping; Hasan, Ahmed A.; Hocher, Berthold Plasma ET-1 concentrations are elevated in patients with hypertension meta-analysis of clinical studies 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. Basel Karger 2017 10 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 42 2 304 313 10.1159/000477572 Institut für Ernährungswissenschaft OPUS4-55875 Wissenschaftlicher Artikel Reichetzeder, Christoph; Heunisch, Fabian; von Einem, Gina-Franziska; Tsuprykov, Oleg; Kellner, Karl-Heinz; Dschietzig, Thomas; Kretschmer, Axel; Hocher, Berthold Pre-interventional kynurenine predicts medium-term outcome after contrast media exposure due to coronary angiography 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. Basel Karger 2017 13 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 42 2 244 256 10.1159/000477222 Institut für Ernährungswissenschaft OPUS4-55868 Review Yang, Xiaoping; Darko, Kwame Oteng; Huang, Yanjun; He, Caimei; Yang, Huansheng; He, Shanping; Li, Jianzhong; Li, Jian; Hocher, Berthold; Yin, Yulong Resistant starch regulates gut microbiota 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. Basel Karger 2017 13 Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry and pharmacology 42 1 306 318 10.1159/000477386 Institut für Ernährungswissenschaft OPUS4-38278 Wissenschaftlicher Artikel Putra, Sulistyo Emantoko Dwi; Neuber, Corinna; Reichetzeder, Christoph; Hocher, Berthold; Kleuser, Burkhard Analysis of genomic DNA methylation levels in human placenta using liquid Chromatography-Electrospray ionization tandem mass spectrometry 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. Basel Karger 2014 8 Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry and pharmacology 33 4 945 952 10.1159/000358666 Institut für Ernährungswissenschaft OPUS4-40091 misc Hocher, Berthold; Reichetzeder, Christoph; Dwi Putra, Sulistyo Emantoko; Slowinski, Torsten; Neuber, Corinna; Kleuser, Burkhard; Pfab, Thiemo Increased global placental DNA methylation levels are associated with gestational diabetes 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. 2017 10 urn:nbn:de:kobv:517-opus4-400914 Institut für Ernährungswissenschaft OPUS4-45137 Wissenschaftlicher Artikel Reichetzeder, Christoph; Putra, S. E. Dwi; Pfab, T.; Slowinski, T.; Neuber, Corinna; Kleuser, Burkhard; Hocher, Berthold Increased global placental DNA methylation levels are associated with gestational diabetes 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. London BioMed Central 2016 10 Clinical epigenetics 8 10.1186/s13148-016-0247-9 Institut für Ernährungswissenschaft OPUS4-55589 Wissenschaftlicher Artikel Lu, Yong-Ping; Hasan, Ahmed A.; Zeng, Shufei; Hocher, Berthold Plasma ET-1 concentrations are elevated in pregnant women with hypertension - meta-analysis of clinical studies 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. Basel Karger 2017 10 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 42 4 654 663 10.1159/000482004 Institut für Ernährungswissenschaft OPUS4-42825 misc Alter, Markus L.; Ott, Ina; von Websky, Karoline; Tsuprykov, Oleg; Sharkovska, Yuliya; Krause-Relle, Katharina; Raila, Jens; Henze, Andrea; Kretschmer, Axel; Stasch, Johannes-Peter; Hocher, Berthold Additional stimulation of sGC on top of standard treatment with ARB`s may offer a new therapeutic approach for the treatment of diabetic nephropathy resistant to ARB treatment alone Background Riociguat is the first of a new class of drugs, the soluble guanylate cyclase (sGC) stimulators. Riociguat has a dual mode of action: it sensitizes sGC to the body's own NO and can also increase sGC activity in the absence of NO. The NO-sGC-pathway is impaired in many cardiovascular diseases such as heart failure, pulmonary hypertension and diabetic nephropathy (DN). DN leads to high cardiovascular morbidity and mortality. There is still a high unmet medical need. The urinary albumin excretion rate is a predictive biomarker for these clinical events. Therefore, we investigated the effect of riociguat, alone and in combination with the angiotensin II receptor antagonist (ARB) telmisartan on the progression of DN in diabetic eNOS knock out mice, a new model closely resembling human pathology. Methods Seventy-six male eNOS knockout C57BL/6J mice were divided into 4 groups after receiving intraperitoneal high-dose streptozotocin: telmisartan (1 mg/kg), riociguat (3 mg/kg), riociguat+telmisartan (3 and 1 mg/kg), and vehicle. Fourteen mice were used as non-diabetic controls. After 12 weeks, urine and blood were obtained and blood pressure measured. Glucose concentrations were highly increased and similar in all diabetic groups. Results Riociguat, alone (105.2 ± 2.5 mmHg; mean±SEM; n = 14) and in combination with telmisartan (105.0 ± 3.2 mmHg; n = 12), significantly reduced blood pressure versus diabetic controls (117.1 ± 2.2 mmHg; n = 14; p = 0.002 and p = 0.004, respectively), whereas telmisartan alone (111.2 ± 2.6 mmHg) showed a modest blood pressure lowering trend (p = 0.071; n = 14). The effects of single treatment with either riociguat (97.1 ± 15.7 µg/d; n = 13) or telmisartan (97.8 ± 26.4 µg/d; n = 14) did not significantly lower albumin excretion on its own (p = 0.067 and p = 0.101, respectively). However, the combined treatment led to significantly lower urinary albumin excretion (47.3 ± 9.6 µg/d; n = 12) compared to diabetic controls (170.8 ± 34.2 µg/d; n = 13; p = 0.004), and reached levels similar to non-diabetic controls (31.4 ± 10.1 µg/d, n = 12). Conclusion Riociguat significantly reduced urinary albumin excretion in diabetic eNOS knock out mice that were refractory to treatment with ARB's alone. Patients with diabetic nephropathy refractory to treatment with ARB's have the worst prognosis among all patients with diabetic nephropathy. Our data indicate that additional stimulation of sGC on top of standard treatment with ARB`s may offer a new therapeutic approach for patients with diabetic nephropathy resistant to ARB treatment. 2011 4 Postprints der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe 855 urn:nbn:de:kobv:517-opus4-428250 10.25932/publishup-42825 Mathematisch-Naturwissenschaftliche Fakultät OPUS4-53779 misc Hocher, Berthold; Zeng, Shufei Need for better PTH assays for clinical research and patient treatment Berlin De Gruyter 2018 3 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 56 2 183 185 10.1515/cclm-2017-0617 Institut für Ernährungswissenschaft OPUS4-56740 misc Hocher, Berthold; Yin, Lianghong Why Current PTH Assays Mislead Clinical Decision Making in Patients with Secondary Hyperparathyroidism 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. Basel Karger 2017 6 Nephron 136 2 137 142 10.1159/000455289 Department Sport- und Gesundheitswissenschaften OPUS4-45777 Wissenschaftlicher Artikel Hocher, Berthold; Haumann, Hannah; Rahnenführer, Jan; Reichetzeder, Christoph; Kalk, Philipp; Pfab, Thiemo; Tsuprykov, Oleg; Winter, Stefan; Hofmann, Ute; Li, Jian; Püschel, Gerhard Paul; Lang, Florian; Schuppan, Detlef; Schwab, Matthias; Schaeffeler, Elke Maternal eNOS deficiency determines a fatty liver phenotype of the offspring in a sex dependent manner 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. Philadelphia Routledge, Taylor & Francis Group 2016 14 Epigenetics : the official journal of the DNA Methylation Society 11 539 552 10.1080/15592294.2016.1184800 Institut für Ernährungswissenschaft OPUS4-31471 Wissenschaftlicher Artikel Sharkovska, Yuliya; Kalk, Philipp; Lawrenz, Bettina; Godes, Michael; Hoffmann, Linda Sarah; Wellkisch, Kathrin; Geschka, Sandra; Relle, Katharina; Hocher, Berthold; Stasch, Johannes-Peter Nitric oxide-independent stimulation of soluble guanylate cyclase reduces organ damage in experimental low- renin and high-renin models 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. 2010 10.1097/Hjh.0b013e32833b558c Institut für Ernährungswissenschaft OPUS4-35184 Wissenschaftlicher Artikel Espe, Katharina M.; Raila, Jens; Henze, Andrea; Blouin, Katja; Schneider, Andreas; Schmiedeke, Daniel; Krane, Vera; Pilz, Stefan; Schweigert, Florian J.; Hocher, Berthold; Wanner, Christoph; Drechsler, Christiane Low plasma alpha-tocopherol concentrations and adverse clinical outcomes in diabetic hemodialysis patients Background and objectives Trials with the antioxidant vitamin E have failed to show benefit in the general population. Considering the different causes of death in ESRD, this study investigated the association between plasma concentrations of alpha-tocopherol and specific clinical outcomes in diabetic hemodialysis patients. Design, settings, participants, & measurements In 1046 diabetic hemodialysis patients (participants of the German Diabetes and Dialysis Study), alpha-tocopherol was measured in plasma by reversed-phase HPLC. By Cox regression analyses, hazard ratios were determined for prespecified end points according to baseline plasma alpha-tocopherol levels: sudden death (n=134), myocardial infarction (n=172), stroke (n=89), combined cardiovascular events (n=398), fatal infection (n=107), and all-cause mortality (n=508). Results Patients had a mean age of 66 8 years, and mean plasma alpha-tocopherol level was 22.8+/-9.6 mu mol/L. Levels of alpha-tocopherol were highly correlated to triglycerides (r=0.63, P<0.001). Patients in the lowest alpha-tocopherol quartile had (in unadjusted analyses) a 79% higher risk of stroke and a 31% higher risk of all-cause mortality compared with patients in the highest quartile. The associations were attenuated after adjustment for confounders (hazard ratio(stroke)=1.56, 95% confidence interval=0.75-3.25; hazard ratio(mortality)=1.22, 95% confidence interval=0.89-1.69, respectively). There was no association between alpha-tocopherol and myocardial infarction, sudden death, or infectious death. Conclusions Plasma alpha-tocopherol concentrations were not independently associated with cardiovascular outcomes, infectious deaths, or all-cause mortality in diabetic hemodialysis patients. The lack of association can partly be explained by a confounding influence of malnutrition, which should be considered in the planning of trials to reduce cardiovascular risk in dialysis patients. Washington American Society of Nephrology 2013 7 Clinical journal of the American Society of Nephrology 8 3 452 458 10.2215/CJN.04880511 Institut für Ernährungswissenschaft OPUS4-35298 Wissenschaftlicher Artikel Lu, Yong-Ping; Zeng, De-Ying; Chen, You-Peng; Liang, Xu-Jing; Xu, Jie-Ping; Huang, Si-Min; Lai, Zhi-Wei; Wen, Wang-Rong; von Websky, Karoline; Hocher, Berthold Low birth weight is associated with lower respiratory tract infections in children with hand, foot, and mouth disease 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. Heidelberg Clin Lab Publ., Verl. Klinisches Labor 2013 8 Clinical laboratory : the peer reviewed journal for clinical laboratories and laboratories related to blood transfusion 59 9-10 985 992 10.7754/Clin.Lab.2012.120725 Institut für Ernährungswissenschaft OPUS4-35306 Wissenschaftlicher Artikel Hocher, Berthold; Oberthür, Dominik; Slowinski, Torsten; Querfeld, Uwe; Schäfer, Franz; Doyon, Anke; Tepel, Martin; Roth, Heinz J.; Grön, Hans J.; Reichetzeder, Christoph; Betzel, Christian; Armbruster, Franz Paul 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 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. Basel Karger 2013 12 Kidney & blood pressure research : official organ of the Gesellschaft für Nephrologie 37 4-5 240 251 10.1159/000350149 Institut für Biochemie und Biologie OPUS4-35307 Wissenschaftlicher Artikel Feger, Martina; Fajol, Abul; Lebedeva, Aleksandra; Meissner, Adrian; Michael, Diana; Völkl, Jakob; Alesutan, Ioana; Schleicher, Erwin; Reichetzeder, Christoph; Hocher, Berthold; Qadri, Syed M.; Lang, Florian Effect of Carbon Monoxide Donor CORM-2 on Vitamin D-3 Metabolism Background/Aims: Carbon monoxide (CO) interferes with cytochrome-dependent cellular functions and acts as gaseous transmitter. CO is released from CO-releasing molecules (CORM) including tricarbonyl-dichlororuthenium (II) dimer (CORM-2), molecules considered for the treatment of several disorders including vascular dysfunction, inflammation, tissue ischemia and organ rejection. Cytochrome P450-sensitive function include formation of 1,25-dihydroxyvitamin D-3 (1,25(OH)(2)D-3) by renal 25-hydroxyvitamin D-3 1-alpha-hydroxylase (Cyp27b1). The enzyme is regulated by PTH, FGF23 and klotho. 1,25(OH)(2)D-3 regulates Ca2+ and phosphate transport as well as klotho expression. The present study explored, whether CORM-2 influences 1,25(OH)(2)D-3 formation and klotho expression. Methods: Mice were treated with intravenous CORM-2 (20 mg/kg body weight). Plasma 1,25(OH)(2)D-3 and FGF23 concentrations were determined by ELISA, phosphate, calcium and creatinine concentrations by colorimetric methods, transcript levels by quantitative RT-PCR and protein expression by western blotting. Fgf23 mRNA transcript levels were further determined in rat osteosarcoma UMR106 cells without or with prior treatment for 24 hours with 20 mu M CORM-2. Results: CORM-2 injection within 24 hours significantly increased FGF23 plasma levels and decreased 1,25(OH)(2)D-3 plasma levels, renal Cyp27b1 gene expression as well as renal klotho protein abundance and transcript levels. Moreover, treatment of UMR106 cells with CORM-2 significantly increased Fgf23 transcript levels. Conclusion: CO-releasing molecule CORM-2 enhances FGF23 expression and release and decreases klotho expression and 1,25(OH)(2)D-3 synthesis. Basel Karger 2013 10 Kidney & blood pressure research : official organ of the Gesellschaft für Nephrologie 37 4-5 496 505 10.1159/000355730 Institut für Biochemie und Biologie OPUS4-35280 Wissenschaftlicher Artikel Li, Jian; Chen, You-Peng; Wang, Zi-Neng; Liu, Tie-Bin; Chen, Dan; Dong, Yun-Peng; Hocher, Berthold A functional fetal HSD11B2[CA]n microsatellite polymorphism is associated with maternal serum cortisol concentrations in pregnant women 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. Basel Karger 2013 10 Kidney & blood pressure research : official organ of the Gesellschaft für Nephrologie 38 1 132 141 10.1159/000355761 Institut für Ernährungswissenschaft OPUS4-32161 Wissenschaftlicher Artikel Fischer, Stephanie S.; Kempe, Daniela S.; Leibrock, Christina B.; Rexhepaj, Rexhep; Siraskar, Balasaheb; Boini, Krishna M.; Ackermann, Teresa F.; Foeller, Michael; Hocher, Berthold; Rosenblatt, Kevin P.; Kuro-o, Makoto; Lang, Florian Hyperaldosteronism in Klotho-deficient mice Klotho is a membrane protein participating in the inhibitory effect of FGF23 on the formation of 1,25- dihydroxyvitamin-D-3 [1,25(OH)(2)D-3]. It participates in the regulation of renal tubular phosphate reabsorption and stimulates renal tubular Ca2+ reabsorption. Klotho hypomorphic mice (klotho(hm)) suffer from severe growth deficit, rapid aging, and early death, events largely reversed by a vitamin D-deficient diet. The present study explored the role of Klotho deficiency in mineral and electrolyte metabolism. To this end, klothohm mice and wild-type mice (klotho(+/+)) were subjected to a normal (D+) or vitamin D-deficient (D-) diet or to a vitamin D-deficient diet for 4 wk and then to a normal diet (D-/+). At the age of 8 wk, body weight was significantly lower in klotho(hm)D(+) mice than in klotho(+/ +)D(+) mice, klotho(hm)D(-) mice, and klotho(hm)D(-/+) mice. Plasma concentrations of 1,25(OH)(2)D-3, adrenocorticotropic hormone (ACTH), antidiuretic hormone (ADH), and aldosterone were significantly higher in klotho(hm)D(+) mice than in klotho(+/+)D(+) mice. Plasma volume was significantly smaller in klotho(hm)D(-/+) mice, and plasma urea, Ca2+, phosphate and Na+, but not K+ concentrations were significantly higher in klotho(hm)D(+) mice than in klotho(+/+)D(+) mice. The differences were partially abrogated by a vitamin D-deficient diet. Moreover, the hyperaldosteronism was partially reversed by Ca2+-deficient diet. Ussing chamber experiments revealed a marked increase in amiloride-sensitive current across the colonic epithelium, pointing to enhanced epithelial sodium channel (ENaC) activity. A salt-deficient diet tended to decrease and a salt-rich diet significantly increased the life span of klotho(hm)D(+) mice. In conclusion, the present observation disclose that the excessive formation of 1,25(OH)(2)D-3 in Klotho-deficient mice results in extracellular volume depletion, which significantly contributes to the shortening of life span. 2010 10.1152/ajprenal.00233.2010 Institut für Ernährungswissenschaft OPUS4-32163 Wissenschaftlicher Artikel Foeller, Michael; Mahmud, Hasan; Qadri, Syed M.; Gu, Shuchen; Braun, Manuel; Bobbala, Diwakar; Hocher, Berthold; Lang, Florian Endothelin B receptor stimulation inhibits suicidal erythrocyte death Endothelins (ETs), potent endothelium-derived mediators, stimulate formation of nitric oxide, which, in turn, protects against suicidal erythrocyte death or eryptosis, characterized by phosphatidylserine exposure at the erythrocyte surface and triggered by increase in cytosolic Ca2+ ([Ca2+](i)). The present study explored whether the ET1- receptor ETB influences suicidal erythrocyte death. To this end, [Ca2+](i) (Fluo3-fluorescence) and phosphatidylserine exposure (annexin V-binding) were determined utilizing FACS analysis. Energy depletion increased [Ca2+]i and phosphatidylserine-exposure, effects significantly blunted by ET1 (IC50 approximate to 100 nM) and the ETB receptor- agonist sarafotoxin 6c (IC50 approximate to 10 nM) but not by ET2 and ET3. ET1 and sarafotoxin significantly delayed the kinetics of suicidal erythrocyte death following energy depletion. ETB stimulation did not blunt the effect of Ca2+- ionophore ionomycin (1 mu M) on phosphatidylserine exposure. The in vivo significance was tested using rescued ETB- knockout (etb(-/-)) and wild-type (etb(+/+)) mice. The number of phosphatidylserine-exposing erythrocytes, of reticulocytes and spleen size were significantly larger in etb(-/-) mice than in etb(+/+)-mice. The etb(-/-) erythrocytes were more susceptible to the eryptotic effect of oxidative stress and more rapidly cleared from circulating blood than etb(+/+) erythrocytes. Finally, the spleens from etb(-/-) mice were enlarged and contained markedly more phosphatidylserine- exposing erythrocytes than spleens from etb(+/+) mice. The observations disclose a novel function of ET1, i. e., protection from suicidal erythrocyte death. 2010 10.1096/Fj.10-159483 Institut für Ernährungswissenschaft OPUS4-34907 unpublished Hocher, Berthold; Reichetzeder, Christoph Vitamin D and cardiovascular risk in postmenopausal women how to translate preclinical evidence into benefit for patients 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. New York Nature Publ. Group 2013 3 Kidney international : official journal of the International Society of Nephrology 84 1 9 11 10.1038/ki.2013.139 Institut für Ernährungswissenschaft OPUS4-34746 Konferenzveröffentlichung Hocher, Berthold; Tsuprykov, Oleg; Alter, Markus L.; von Websky, Karoline; Chaykovska, Lyubov; Antonenko, V.; Rahnenführer, Jan; Klein, T.; Reichetzeder, Christoph Linagliptin and the angiotensin II receptor blocker telmisartan show comparable efficacy but different renoprotective pathways in rats with 5/6 nephrectomy New York Springer 2013 1 Diabetologia : journal of the European Association for the Study of Diabetes (EASD) 56 15-16 S66 S66 Institut für Ernährungswissenschaft OPUS4-34630 Wissenschaftlicher Artikel Chaykovska, Lyubov; Alter, Markus L.; von Websky, Karoline; Hohmann, Margarete; Tsuprykov, Oleg; Reichetzeder, Christoph; Kutil, Barbara; Kraft, Robin; Klein, Thomas; Hocher, Berthold Effects of telmisartan and linagliptin when used in combination on blood pressure and oxidative stress in rats with 2-kidney-1-clip hypertension Objective:To investigate the effects of linagliptin alone and in combination with the angiotensin II receptor blocker (ARB), telmisartan on blood pressure (BP), kidney function, heart morphology and oxidative stress in rats with renovascular hypertension.Methods:Fifty-seven male Wistar rats underwent unilateral surgical stenosis of the renal artery [2-kidney-1-clip (2k1c) method]. Animals were randomly divided into four treatment groups (n=14-18 per group) receiving: telmisartan (10mg/kg per day in drinking water), linagliptin (89ppm in chow), combination (linagliptin 89ppm+telmisartan 10mg/kg per day) or placebo. An additional group of 12 rats underwent sham surgery. BP was measured one week after surgery. Hypertensive animals entered a 16-week dosing period. BP was measured 2, 4, 8, 12 and 16 weeks after the initiation of treatment. Blood and urine were tested for assessment of kidney function and oxidative stress 6, 10, 14 and 18 weeks after surgery. Blood and urine sampling and organ harvesting were finally performed.Results:Renal stenosis caused an increase in meanSD systolic BP as compared with the sham group (157.7 +/- 29.3 vs. 106.2 +/- 20.5mmHg, respectively; P<0.001). Telmisartan alone and in combination with linagliptin, normalized SBP (111.1 +/- 24.3mmHg and 100.4 +/- 13.9mmHg, respectively; P<0.001 vs. placebo). Telmisartan alone and in combination with linagliptin significantly prevented cardiac hypertrophy, measured by heart weight and myocyte diameter. Renal function measured by cystatin C was not affected by 2k1c surgery. Telmisartan significantly increased plasma concentration of cystatin C. 2k1c surgery initiated fibrosis in both kidneys. Telmisartan promoted further fibrotic changes in the clipped kidney, as measured by protein expression of Col1a1 and histology for interstitial fibrosis and glomerulosclerosis. In non-clipped kidneys, telmisartan demonstrated antifibrotic properties, reducing Col1a1 protein expression. Plasma levels of oxidized low-density lipoprotein were higher in the placebo-treated 2k1c rats as compared to sham-operated animals. The increase was abolished by linagliptin alone (P=0.03 vs. placebo) and in combination with telmisartan (P=0.02 vs. placebo). Combination therapy also significantly reduced plasma concentration of carbonyl proteins (P=0.04 vs. placebo).Conclusion:Inhibition of type 4 dipeptidyl peptidase with linagliptin did not counter BP-lowering effects of ARB in 2k1c rats. Linagliptin reduced lipid and protein oxidation in 2k1c rats, and this effect was BP-independent. Philadelphia Lippincott Williams & Wilkins 2013 10 Journal of hypertension 31 11 2290 2299 10.1097/HJH.0b013e3283649b4d Institut für Ernährungswissenschaft OPUS4-34540 Wissenschaftlicher Artikel Tepel, Martin; Armbruster, Franz Paul; Groen, Hans Juergen; Scholze, Alexandra; Reichetzeder, Christoph; Roth, Heinz Jürgen; Hocher, Berthold Nonoxidized, biologically active parathyroid hormone determines mortality in hemodialysis patients 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. Chevy Chase Endocrine Society 2013 8 The journal of clinical endocrinology & metabolism 98 12 4744 4751 10.1210/jc.2013-2139 Institut für Ernährungswissenschaft OPUS4-34864 Wissenschaftlicher Artikel Hocher, Berthold; Sharkovska, Yuliya; Mark, Michael; Klein, Thomas; Pfab, Thiemo The novel DPP-4 inhibitors linagliptin and BI 14361 reduce infarct size after myocardial ischemia/reperfusion in rats 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. Clare Elsevier 2013 7 International journal of cardiology 167 1 87 93 10.1016/j.ijcard.2011.12.007 Institut für Ernährungswissenschaft OPUS4-34819 Konferenzveröffentlichung Sharkovska, Y.; Pohl, K. K.; Hocher, Berthold; Dschietzig, T. Cardiac expression of relaxin and its receptor RXFP1 in rats with renovascular hypertension OXFORD OXFORD UNIV PRESS 2013 1 EUROPEAN HEART JOURNAL 34 10 1056 1056 OPUS4-32235 Wissenschaftlicher Artikel Hocher, Berthold Adenosine A1 receptor antagonists in clinical research and development Selective adenosine A1 receptor antagonists targeting renal microcirculation are novel pharmacologic agents that are currently under development for the treatment of acute heart failure as well as for chronic heart failure. Despite several studies showing improvement of renal function and/or increased diuresis with adenosine A1 antagonists, particularly in chronic heart failure, these findings were not confirmed in a large phase III trial in acute heart failure patients. However, lessons can be learned from these and other studies, and there might still be a potential role for the clinical use of adenosine A1 antagonists. We review the role of adenosine A1 receptors in the regulation of renal function, and emerging data regarding the safety and efficacy of A1 adenosine receptor antagonists based on all available completed and reported clinical trials using A1 adenosine receptor antagonists. The majority of trials were done in heart failure patients. However, there is clear clinical evidence for a role of this new class in hepatorenal syndrome, hypotension on dialysis, and radiocontrast media-induced nephropathy. 2010 10.1038/Ki.2010.204 Institut für Ernährungswissenschaft OPUS4-35040 Konferenzveröffentlichung Hocher, Berthold; Armbruster, Franz Paul; Scholze, Alexandra; Marckmann, Peter; Reichetzeder, Christoph; Roth, Heinz Jürgen; Tepel, Martin Non-oxidized, biological active parathyroid hormone determines motality in hemodialsysis patients Oxford Oxford Univ. Press 2013 1 Nephrology, dialysis, transplantation 28 33 33 Department Sport- und Gesundheitswissenschaften OPUS4-35420 Wissenschaftlicher Artikel Horikoshi, Momoko; Yaghootkar, Hanieh; Mook-Kanamori, Dennis O.; Sovio, Ulla; Taal, H. Rob; Hennig, Branwen J.; Bradfield, Jonathan P.; St Pourcain, Beate; Evans, David M.; Charoen, Pimphen; Kaakinen, Marika; Cousminer, Diana L.; Lehtimaki, Terho; Kreiner-Moller, Eskil; Warrington, Nicole M.; Bustamante, Mariona; Feenstra, Bjarke; Berry, Diane J.; Thiering, Elisabeth; Pfab, Thiemo; Barton, Sheila J.; Shields, Beverley M.; Kerkhof, Marjan; van Leeuwen, Elisabeth M.; Fulford, Anthony J.; Kutalik, Zoltan; Zhao, Jing Hua; den Hoed, Marcel; Mahajan, Anubha; Lindi, Virpi; Goh, Liang-Kee; Hottenga, Jouke-Jan; Wu, Ying; Raitakari, Olli T.; Harder, Marie N.; Meirhaeghe, Aline; Ntalla, Ioanna; Salem, Rany M.; Jameson, Karen A.; Zhou, Kaixin; Monies, Dorota M.; Lagou, Vasiliki; Kirin, Mirna; Heikkinen, Jani; Adair, Linda S.; Alkuraya, Fowzan S.; Al-Odaib, Ali; Amouyel, Philippe; Andersson, Ehm Astrid; Bennett, Amanda J.; Blakemore, Alexandra I. F.; Buxton, Jessica L.; Dallongeville, Jean; Das, Shikta; de Geus, Eco J. C.; Estivill, Xavier; Flexeder, Claudia; Froguel, Philippe; Geller, Frank; Godfrey, Keith M.; Gottrand, Frederic; Groves, Christopher J.; Hansen, Torben; Hirschhorn, Joel N.; Hofman, Albert; Hollegaard, Mads V.; Hougaard, David M.; Hyppoenen, Elina; Inskip, Hazel M.; Isaacs, Aaron; Jorgensen, Torben; Kanaka-Gantenbein, Christina; Kemp, John P.; Kiess, Wieland; Kilpelainen, Tuomas O.; Klopp, Norman; Knight, Bridget A.; Kuzawa, Christopher W.; McMahon, George; Newnham, John P.; Niinikoski, Harri; Oostra, Ben A.; Pedersen, Louise; Postma, Dirkje S.; Ring, Susan M.; Rivadeneira, Fernando; Robertson, Neil R.; Sebert, Sylvain; Simell, Olli; Slowinski, Torsten; Tiesler, Carla M. T.; Toenjes, Anke; Vaag, Allan; Viikari, Jorma S.; Vink, Jacqueline M.; Vissing, Nadja Hawwa; Wareham, Nicholas J.; Willemsen, Gonneke; Witte, Daniel R.; Zhang, Haitao; Zhao, Jianhua; Wilson, James F.; Stumvoll, Michael; Prentice, Andrew M.; Meyer, Brian F.; Pearson, Ewan R.; Boreham, Colin A. G.; Cooper, Cyrus; Gillman, Matthew W.; Dedoussis, George V.; Moreno, Luis A.; Pedersen, Oluf; Saarinen, Maiju; Mohlke, Karen L.; Boomsma, Dorret I.; Saw, Seang-Mei; Lakka, Timo A.; Koerner, Antje; Loos, Ruth J. F.; Ong, Ken K.; Vollenweider, Peter; van Duijn, Cornelia M.; Koppelman, Gerard H.; Hattersley, Andrew T.; Holloway, John W.; Hocher, Berthold; Heinrich, Joachim; Power, Chris; Melbye, Mads; Guxens, Monica; Pennell, Craig E.; Bonnelykke, Klaus; Bisgaard, Hans; Eriksson, Johan G.; Widen, Elisabeth; Hakonarson, Hakon; Uitterlinden, Andre G.; Pouta, Anneli; Lawlor, Debbie A.; Smith, George Davey; Frayling, Timothy M.; McCarthy, Mark I.; Grant, Struan F. A.; Jaddoe, Vincent W. V.; Jarvelin, Marjo-Riitta; Timpson, Nicholas J.; Prokopenko, Inga; Freathy, Rachel M. New loci associated with birth weight identify genetic links between intrauterine growth and adult height and metabolism 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. New York Nature Publ. Group 2013 10 Nature genetics 45 1 76 U115 10.1038/ng.2477 Institut für Ernährungswissenschaft OPUS4-35934 Wissenschaftlicher Artikel Taal, H. Rob; St Pourcain, Beate; Thiering, Elisabeth; Das, Shikta; Mook-Kanamori, Dennis O.; Warrington, Nicole M.; Kaakinen, Marika; Kreiner-Moller, Eskil; Bradfield, Jonathan P.; Freathy, Rachel M.; Geller, Frank; Guxens, Monica; Cousminer, Diana L.; Kerkhof, Marjan; Timpson, Nicholas J.; Ikram, M. Arfan; Beilin, Lawrence J.; Bonnelykke, Klaus; Buxton, Jessica L.; Charoen, Pimphen; Chawes, Bo Lund Krogsgaard; Eriksson, Johan; Evans, David M.; Hofman, Albert; Kemp, John P.; Kim, Cecilia E.; Klopp, Norman; Lahti, Jari; Lye, Stephen J.; McMahon, George; Mentch, Frank D.; Mueller-Nurasyid, Martina; O'Reilly, Paul F.; Prokopenko, Inga; Rivadeneira, Fernando; Steegers, Eric A. P.; Sunyer, Jordi; Tiesler, Carla; Yaghootkar, Hanieh; Breteler, Monique M. B.; Debette, Stephanie; Fornage, Myriam; Gudnason, Vilmundur; Launer, Lenore J.; van der Lugt, Aad; Mosley, Thomas H.; Seshadri, Sudha; Smith, Albert V.; Vernooij, Meike W.; Blakemore, Alexandra I. F.; Chiavacci, Rosetta M.; Feenstra, Bjarke; Fernandez-Banet, Julio; Grant, Struan F. A.; Hartikainen, Anna-Liisa; van der Heijden, Albert J.; Iniguez, Carmen; Lathrop, Mark; McArdle, Wendy L.; Molgaard, Anne; Newnham, John P.; Palmer, Lyle J.; Palotie, Aarno; Pouta, Annneli; Ring, Susan M.; Sovio, Ulla; Standl, Marie; Uitterlinden, Andre G.; Wichmann, H-Erich; Vissing, Nadja Hawwa; DeCarli, Charles; van Duijn, Cornelia M.; McCarthy, Mark I.; Koppelman, Gerard H.; Estivill, Xavier; Hattersley, Andrew T.; Melbye, Mads; Bisgaard, Hans; Pennell, Craig E.; Widen, Elisabeth; Hakonarson, Hakon; Smith, George Davey; Heinrich, Joachim; Jarvelin, Marjo-Riitta; Jaddoe, Vincent W. V.; Adair, Linda S.; Ang, Wei; Atalay, Mustafa; van Beijsterveldt, Toos; Bergen, Nienke; Benke, Kelly; Berry, Diane J.; Bradfield, Jonathan P.; Charoen, Pimphen; Coin, Lachlan; Cousminer, Diana L.; Das, Shikta; Davis, Oliver S. P.; Elliott, Paul; Evans, David M.; Feenstra, Bjarke; Flexeder, Claudia; Frayling, Tim; Freathy, Rachel M.; Gaillard, Romy; Geller, Frank; Groen-Blokhuis, Maria; Goh, Liang-Kee; Guxens, Monica; Haworth, Claire M. A.; Hadley, Dexter; Hebebrand, Johannes; Hinney, Anke; Hirschhorn, Joel N.; Holloway, John W.; Holst, Claus; Hottenga, Jouke Jan; Horikoshi, Momoko; Huikari, Ville; Hypponen, Elina; Iniguez, Carmen; Kaakinen, Marika; Kilpelainen, Tuomas O.; Kirin, Mirna; Kowgier, Matthew; Lakka, Hanna-Maaria; Lange, Leslie A.; Lawlor, Debbie A.; Lehtimaki, Terho; Lewin, Alex; Lindgren, Cecilia; Lindi, Virpi; Maggi, Reedik; Marsh, Julie; Middeldorp, Christel; Millwood, Iona; Mook-Kanamori, Dennis O.; Murray, Jeffrey C.; Nivard, Michel; Nohr, Ellen Aagaard; Ntalla, Ioanna; Oken, Emily; O'Reilly, Paul F.; Palmer, Lyle J.; Panoutsopoulou, Kalliope; Pararajasingham, Jennifer; Prokopenko, Inga; Rodriguez, Alina; Salem, Rany M.; Sebert, Sylvain; Siitonen, Niina; Sovio, Ulla; St Pourcain, Beate; Strachan, David P.; Sunyer, Jordi; Taal, H. Rob; Teo, Yik-Ying; Thiering, Elisabeth; Tiesler, Carla; Uitterlinden, Andre G.; Valcarcel, Beatriz; Warrington, Nicole M.; White, Scott; Willemsen, Gonneke; Yaghootkar, Hanieh; Zeggini, Eleftheria; Boomsma, Dorret I.; Cooper, Cyrus; Estivill, Xavier; Gillman, Matthew; Grant, Struan F. A.; Hakonarson, Hakon; Hattersley, Andrew T.; Heinrich, Joachim; Hocher, Berthold; Jaddoe, Vincent W. V.; Jarvelin, Marjo-Riitta; Lakka, Timo A.; McCarthy, Mark I.; Melbye, Mads; Mohlke, Karen L.; Dedoussis, George V.; Ong, Ken K.; Pearson, Ewan R.; Pennell, Craig E.; Price, Thomas S.; Power, Chris; Raitakari, Olli T.; Saw, Seang-Mei; Scherag, Andre; Simell, Olli; Sorensen, Thorkild I. A.; Timpson, Nicholas J.; Widen, Elisabeth; Wilson, James F.; Ang, Wei; van Beijsterveldt, Toos; Bergen, Nienke; Benke, Kelly; Berry, Diane J.; Bradfield, Jonathan P.; Charoen, Pimphen; Coin, Lachlan; Cousminer, Diana L.; Das, Shikta; Elliott, Paul; Evans, David M.; Frayling, Tim; Freathy, Rachel M.; Gaillard, Romy; Groen-Blokhuis, Maria; Guxens, Monica; Hadley, Dexter; Hottenga, Jouke Jan; Huikari, Ville; Hypponen, Elina; Kaakinen, Marika; Kowgier, Matthew; Lawlor, Debbie A.; Lewin, Alex; Lindgren, Cecilia; Marsh, Julie; Middeldorp, Christel; Millwood, Iona; Mook-Kanamori, Dennis O.; Nivard, Michel; O'Reilly, Paul F.; Palmer, Lyle J.; Prokopenko, Inga; Rodriguez, Alina; Sebert, Sylvain; Sovio, Ulla; St Pourcain, Beate; Standl, Marie; Strachan, David P.; Sunyer, Jordi; Taal, H. Rob; Thiering, Elisabeth; Tiesler, Carla; Uitterlinden, Andre G.; Valcarcel, Beatriz; Warrington, Nicole M.; White, Scott; Willemsen, Gonneke; Yaghootkar, Hanieh; Boomsma, Dorret I.; Estivill, Xavier; Grant, Struan F. A.; Hakonarson, Hakon; Hattersley, Andrew T.; Heinrich, Joachim; Jaddoe, Vincent W. V.; Jarvelin, Marjo-Riitta; McCarthy, Mark I.; Pennell, Craig E.; Power, Chris; Timpson, Nicholas J.; Widen, Elisabeth; Ikram, M. Arfan; Fornage, Myriam; Smith, Albert V.; Seshadri, Sudha; Schmidt, Reinhold; Debette, Stephanie; Vrooman, Henri A.; Sigurdsson, Sigurdur; Ropele, Stefan; Coker, Laura H.; Longstreth, W. T.; Niessen, Wiro J.; DeStefano, Anita L.; Beiser, Alexa; Zijdenbos, Alex P.; Struchalin, Maksim; Jack, Clifford R.; Nalls, Mike A.; Au, Rhoda; Hofman, Albert; Gudnason, Haukur; van der Lugt, Aad; Harris, Tamara B.; Meeks, William M.; Vernooij, Meike W.; van Buchem, Mark A.; Catellier, Diane; Gudnason, Vilmundur; Windham, B. Gwen; Wolf, Philip A.; van Duijn, Cornelia M.; Mosley, Thomas H.; Schmidt, Helena; Launer, Lenore J.; Breteler, Monique M. B.; DeCarli, Charles Common variants at 12q15 and 12q24 are associated with infant head circumference 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. New York Nature Publ. Group 2012 9 Nature genetics 44 5 532 + 10.1038/ng.2238 Institut für Biochemie und Biologie OPUS4-35935 Wissenschaftlicher Artikel Ikram, M. Arfan; Fornage, Myriam; Smith, Albert V.; Seshadri, Sudha; Schmidt, Reinhold; Debette, Stephanie; Vrooman, Henri A.; Sigurdsson, Sigurdur; Ropele, Stefan; Taal, H. Rob; Mook-Kanamori, Dennis O.; Coker, Laura H.; Longstreth, W. T.; Niessen, Wiro J.; DeStefano, Anita L.; Beiser, Alexa; Zijdenbos, Alex P.; Struchalin, Maksim; Jack, Clifford R.; Rivadeneira, Fernando; Uitterlinden, Andre G.; Knopman, David S.; Hartikainen, Anna-Liisa; Pennell, Craig E.; Thiering, Elisabeth; Steegers, Eric A. P.; Hakonarson, Hakon; Heinrich, Joachim; Palmer, Lyle J.; Jarvelin, Marjo-Riitta; McCarthy, Mark I.; Grant, Struan F. A.; St Pourcain, Beate; Timpson, Nicholas J.; Smith, George Davey; Sovio, Ulla; Nalls, Mike A.; Au, Rhoda; Hofman, Albert; Gudnason, Haukur; van der Lugt, Aad; Harris, Tamara B.; Meeks, William M.; Vernooij, Meike W.; van Buchem, Mark A.; Catellier, Diane; Jaddoe, Vincent W. V.; Gudnason, Vilmundur; Windham, B. Gwen; Wolf, Philip A.; van Duijn, Cornelia M.; Mosley, Thomas H.; Schmidt, Helena; Launer, Lenore J.; Breteler, Monique M. B.; DeCarli, Charles; Adair, Linda S.; Ang, Wei; Atalay, Mustafa; vanBeijsterveldt, Toos; Bergen, Nienke; Benke, Kelly; Berry, Diane J.; Coin, Lachlan; Davis, Oliver S. P.; Elliott, Paul; Flexeder, Claudia; Frayling, Tim; Gaillard, Romy; Groen-Blokhuis, Maria; Goh, Liang-Kee; Haworth, Claire M. A.; Hadley, Dexter; Hebebrand, Johannes; Hinney, Anke; Hirschhorn, Joel N.; Holloway, John W.; Holst, Claus; Hottenga, Jouke Jan; Horikoshi, Momoko; Huikari, Ville; Hypponen, Elina; Kilpelainen, Tuomas O.; Kirin, Mirna; Kowgier, Matthew; Lakka, Hanna-Maaria; Lange, Leslie A.; Lawlor, Debbie A.; Lehtimaki, Terho; Lewin, Alex; Lindgren, Cecilia; Lindi, Virpi; Maggi, Reedik; Marsh, Julie; Middeldorp, Christel; Millwood, Iona; Murray, Jeffrey C.; Nivard, Michel; Nohr, Ellen Aagaard; Ntalla, Ioanna; Oken, Emily; Panoutsopoulou, Kalliope; Pararajasingham, Jennifer; Rodriguez, Alina; Salem, Rany M.; Sebert, Sylvain; Siitonen, Niina; Strachan, David P.; Teo, Yik-Ying; Valcarcel, Beatriz; Willemsen, Gonneke; Zeggini, Eleftheria; Boomsma, Dorret I.; Cooper, Cyrus; Gillman, Matthew; Hocher, Berthold; Lakka, Timo A.; Mohlke, Karen L.; Dedoussis, George V.; Ong, Ken K.; Pearson, Ewan R.; Price, Thomas S.; Power, Chris; Raitakari, Olli T.; Saw, Seang-Mei; Scherag, Andre; Simell, Olli; Sorensen, Thorkild I. A.; Wilson, James F. Common variants at 6q22 and 17q21 are associated with intracranial volume 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. New York Nature Publ. Group 2012 7 Nature genetics 44 5 539 + 10.1038/ng.2245 Institut für Ernährungswissenschaft OPUS4-36092 Wissenschaftlicher Artikel Li, Jian; Wang, Zi-Neng; Chen, You-Peng; Dong, Yun-Peng; Shuai, Han-Lin; Xiao, Xiao-Min; Reichetzeder, Christoph; Hocher, Berthold Late gestational maternal serum cortisol is inversely associated with fetal brain growth 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. Oxford Elsevier 2012 8 Neuroscience & biobehavioral reviews : official journal of the International Behavioral Neuroscience Society 36 3 1085 1092 10.1016/j.neubiorev.2011.12.006 Institut für Ernährungswissenschaft OPUS4-36787 Wissenschaftlicher Artikel Hocher, Berthold; Heiden, S.; von Websky, Karoline; Rahnenführer, Jörg; Kalk, Philipp; Pfab, T. Dual endothelin-converting enzyme/neutral endopeptidase blockade in rats with D-galactosamine-induced liver failure 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. München Med. Scientific Publ. Holzapfel 2011 5 European journal of medical research : official organ "Deutsche AIDS-Gesellschaft" 16 6 275 279 Institut für Informatik und Computational Science OPUS4-37519 Wissenschaftlicher Artikel Hocher, Berthold More than genes: the advanced fetal programming hypothesis Many lines of data, initial epidemiologic studies as well as subsequent extensive experimental studies, indicate that early-life events play a powerful role in influencing later suceptibility to certain chronic diseases. Such events might be over- or undernutrition, exposure to environmental toxins, but also changes in hormones, in particular stress hormones. Typically, those events are triggered by the environmental challenges of the mother. However, recent studies have shown that paternal environmental or nutritional factors affect the phenotype of the offspring as well. The maternal and paternal environmental factors act on the phenotype of the offspring via epigenetic modification of its genome. The advanced fetal programming hypothesis proposes an additional non-environmentally driven mechanism: maternal and also paternal genes may influence the maturating sperm, the oocyte, and later the embryo/fetus, leading to their epigenetic alteration. Thus, the observed phenotype of the offspring may be altered by maternal/paternal genes independent of the fetal genome. Meanwhile, several independent association studies in humans dealing with metabolic and neurological traits also suggest that maternal genes might affect the offspring phenotype independent of the transmission of that particular gene to the offspring. Considering the implications of this hypothesis, some conclusions drawn from transgenic or knockout animal models and based on the causality between a genetic alteration and a phenotype, need to be challenged. Possible implications for the development, diagnostic and therapy of human genetic diseases have to be investigated. (C) 2014 Elsevier Ireland Ltd. All rights reserved. Clare Elsevier 2014 4 Journal of reproductive immunology : the international journal for experimental and clinical reproductive immunobiology 104 8 11 10.1016/j.jri.2014.03.001 Institut für Ernährungswissenschaft OPUS4-37568 Konferenzveröffentlichung Hocher, Berthold; Reichetzeder, Christoph; von Websky, Karoline; Tsuprykov, Oleg; Klein, T. Dipeptidyl peptidase-4 inhibition in a rat model of ischaemia-reperfusion injury may accelerate tubular regeneration but does not improve glomerular filtration rate New York Springer 2014 1 Diabetologia : journal of the European Association for the Study of Diabetes (EASD) 57 S538 S538 Institut für Ernährungswissenschaft OPUS4-37569 Konferenzveröffentlichung Reichetzeder, Christoph; Pasch, A.; von Websky, Karoline; Tsuprykov, Oleg; Klein, T.; Hocher, Berthold The DPP-4 inhibitor linagliptin increases plasma fetuin-A concentrations in a rat model of uraemic calcification New York Springer 2014 1 Diabetologia : journal of the European Association for the Study of Diabetes (EASD) 57 S522 S522 Institut für Ernährungswissenschaft OPUS4-38224 Wissenschaftlicher Artikel Liang, Xu-Jing; Huang, Si-Min; Li, Jian-Ping; Zhu, Xian-Nv; Lu, Yong-Ping; Hocher, Berthold; Chen, You-Peng Hepatic impairment induced by scrub typhus is associated with new onset of renal dysfunction 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. Heidelberg Clin Lab Publ., Verl. Klinisches Labor 2014 6 Clinical laboratory : the peer reviewed journal for clinical laboratories and laboratories related to blood transfusion 60 1 63 68 10.7754/Clin.Lab.2013.121203 Institut für Ernährungswissenschaft OPUS4-38225 Wissenschaftlicher Artikel Lu, Yong-Ping; Lung, Xu-Jing; Xiao, Xiao-Min; Huang, Si-Min; Liu, Zhi-Wei; Li, Jian; Hocher, Berthold; Chen, You-Peng Telbivudine during the second and third trimester of pregnancy interrupts HBV intrauterine transmission: a systematic review and meta-analysis 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. Heidelberg Clin Lab Publ., Verl. Klinisches Labor 2014 16 Clinical laboratory : the peer reviewed journal for clinical laboratories and laboratories related to blood transfusion 60 4 571 586 10.7754/Clin.Lab.2013.130408 Institut für Ernährungswissenschaft OPUS4-38226 Wissenschaftlicher Artikel Chaykovska, Lyubov; Zientara, Alicja; Reser, Diana; Weise, Alexander; Reichert, Wolfgang; Hocher, Berthold Development and validation of a macroarray system - MutaCHIP (R) ARTERO - for the detection of genetic variants involved in the pathogenesis of atherosclerosis Background: Cardiovascular diseases are the leading cause of death in developed countries. The underlying mechanism is often atherosclerotic remodeling of blood vessels in organs such as heart, kidney, brain, and large arteries in case of peripheral arterial disease. Beside environmental and behavioral factors such as smoking or lack of physical activity, genetic variants in genes involved in lipid metabolism, blood pressure regulation, oxidative stress, and coagulation play a prominent role in the pathogenesis of atherosclerosis. Methods: Thus, we developed and validated for clinical use and research a macroarray system for the simultaneous detection of key genetic variants in genes involved in lipid metabolism, blood pressure regulation, oxidative stress, and coagulation. Results: When compared with standard PCR technologies to determine all these genetic variants in parallel, the macroarray system (MutaCHIP (R) ARTERO) was as accurate but faster, cheaper, and easier to handle compared to classical real time PCR based technologies. Conclusions: MutaCHIP (R) ARTERO is a gene chip for diagnostics of a complex genetic panel involved in the pathogenesis of atherosclerosis. This method is as sensitive and precise as real time PCR and is able to replicate real time PCR data previously validated in evaluation studies. Heidelberg Clin Lab Publ., Verl. Klinisches Labor 2014 6 Clinical laboratory : the peer reviewed journal for clinical laboratories and laboratories related to blood transfusion 60 5 873 878 10.7754/Clin.Lab.2014.140104 Institut für Ernährungswissenschaft OPUS4-36736 Wissenschaftlicher Artikel Geschka, Sandra; Kretschmer, Axel; Sharkovska, Yuliya; Evgenov, Oleg V.; Lawrenz, Bettina; Hucke, Andreas; Hocher, Berthold; Stasch, Johannes-Peter Soluble guanylate cyclase stimulation prevents fibrotic tissue remodeling and improves survival in salt-sensitive dahl rats Background: A direct pharmacological stimulation of soluble guanylate cyclase (sGC) is an emerging therapeutic approach to the management of various cardiovascular disorders associated with endothelial dysfunction. Novel sGC stimulators, including riociguat (BAY 63-2521), have a dual mode of action: They sensitize sGC to endogenously produced nitric oxide (NO) and also directly stimulate sGC independently of NO. Little is known about their effects on tissue remodeling and degeneration and survival in experimental malignant hypertension. Methods and Results: Mortality, hemodynamics and biomarkers of tissue remodeling and degeneration were assessed in Dahl salt-sensitive rats maintained on a high salt diet and treated with riociguat (3 or 10 mg/kg/d) for 14 weeks. Riociguat markedly attenuated systemic hypertension, improved systolic heart function and increased survival from 33% to 85%. Histological examination of the heart and kidneys revealed that riociguat significantly ameliorated fibrotic tissue remodeling and degeneration. Correspondingly, mRNA expression of the pro-fibrotic biomarkers osteopontin (OPN), tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) and plasminogen activator inhibitor-1 (PAI-1) in the myocardium and the renal cortex was attenuated by riociguat. In addition, riociguat reduced plasma and urinary levels of OPN, TIMP-1, and PAI-1. Conclusions: Stimulation of sGC by riociguat markedly improves survival and attenuates systemic hypertension and systolic dysfunction, as well as fibrotic tissue remodeling in the myocardium and the renal cortex in a rodent model of pressure and volume overload. These findings suggest a therapeutic potential of sGC stimulators in diseases associated with impaired cardiovascular and renal functions. San Fransisco PLoS 2011 10 PLoS one 6 7 10.1371/journal.pone.0021853 Institut für Ernährungswissenschaft OPUS4-37459 Wissenschaftlicher Artikel Sharkovska, Yuliya; Reichetzeder, Christoph; Alter, Markus L.; Tsuprykov, Oleg; Bachmann, Sebastian; Secher, Thomas; Klein, Thomas; Hocher, Berthold Blood pressure and glucose independent renoprotective effects of dipeptidyl peptidase-4 inhibition in a mouse model of type-2 diabetic nephropathy 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. Philadelphia Lippincott Williams & Wilkins 2014 13 Journal of hypertension 32 11 2211 2223 10.1097/HJH.0000000000000328 Institut für Ernährungswissenschaft OPUS4-38203 Wissenschaftlicher Artikel Reichetzeder, Christoph; Chen, Hong; Foeller, Michael; Slowinski, Torsten; Li, Jian; Chen, You-Peng; Lang, Florian; Hocher, Berthold Maternal vitamin D deficiency and fetal programming - lessons learned from humans and mice 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. Basel Karger 2014 15 Kidney & blood pressure research : official organ of the Gesellschaft für Nephrologie 39 4 315 329 10.1159/000355809 Institut für Ernährungswissenschaft OPUS4-38204 Wissenschaftlicher Artikel Li, Jian; Chen, You-Peng; Dong, Yun-Peng; Yu, Cal-Hong; Lu, Yong-Ping; Xiao, Xiao-Min; Hocher, Berthold The impact of umbilical blood flow regulation on fetal development differs in diabetic and non-diabetic pregnancy 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. Basel Karger 2014 9 Kidney & blood pressure research : official organ of the Gesellschaft für Nephrologie 39 4 369 377 10.1159/000355815 Institut für Ernährungswissenschaft OPUS4-38206 Wissenschaftlicher Artikel Putra, Sulistyo Emantoko Dwi; Tsuprykov, Oleg; Von Websky, Karoline; Ritter, Teresa; Reichetzeder, Christoph; Hocher, Berthold Dealing with large sample sizes: comparison of a new one spot dot blot method to western blot 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. Heidelberg Clin Lab Publ., Verl. Klinisches Labor 2014 7 Clinical laboratory : the peer reviewed journal for clinical laboratories and laboratories related to blood transfusion 60 11 1871 1877 10.7754/Clin.Lab.2014.140317 Institut für Ernährungswissenschaft OPUS4-38216 Wissenschaftlicher Artikel Chen, Yao; Wang, Guang; Wang, Xiao-yu; Ma, Zheng-lai; Chen, You-peng; Chuai, Manli; von Websky, Karoline; Hocher, Berthold; Yang, Xuesong Effects of high salt-exposure on the development of retina and lens in 5.5-Day Chick Embryo Background/Aims: Excess maternal salt intake during pregnancy may alter fetal development. However; our knowledge on how an increased salt intake during pregnancy influences fetal eye development is limited. In this study, we investigated the effects of high salt treatment on the developing eyes in chick embryos, especially focusing on the development of the retina and the lens. Methods: 5.5 day chick embryos were exposed to 280mosm/l (n=17), or 300mosm/l (n=16) NaCl. The treated embryos were then incubated for 96 hours before they were fixed with 4% paraformaldehyde for H&E staining, whole mount embryo immunostaining and TUNEL staining. BrdU and PH3 incorporation experiments were performed on the chick embryos after high salt treatment. RT-PCR analyses were conducted from chick retina tissues. Results: We demonstrated that high-salt treatment altered the size of eyes in chick embryos, induced malformation of the eyes and impaired the development of the lens and the retina. We found an impaired expression of Paired box 6 (PAX6) and neuronal cells in the developing retina as revealed by neurofilament immunofluorescent staining. There was a reduction in the number of BrdU-positive cells and PH3-positive cells in the retina, indicating an impaired cell proliferation with high salt treatment. High salt treatment also resulted in an increased number of TUNEL-positive cells in the retina, indicating a higher amount of cell death. RT-PCR data displayed that the expression of the pro-apoptotic molecule nerve growth factor (NGF) in chick retina was increased and CyclinD1 was reduced with high-salt treatment. The size of the lens was reduced and Pax6 expression in the lens was significantly inhibited. High salt treatment was detrimental to the migration of neural crest cells. Conclusion: Taken together; our study demonstrated that high salt exposure of 5.5 day chick embryos led to an impairment of retina and lens development, possibly through interfering with Pax6 expression. Basel Karger 2014 14 Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry and pharmacology 34 3 804 817 10.1159/000363044 Institut für Biochemie und Biologie OPUS4-35909 Wissenschaftlicher Artikel Chen, You-Peng; Xiao, Xiao-Min; Li, Jian; Reichetzeder, Christoph; Wang, Zi-Neng; Hocher, Berthold Paternal body mass index (BMI) is associated with offspring intrauterine growth in a gender dependent manner Background: Environmental alternations leading to fetal programming of cardiovascular diseases in later life have been attributed to maternal factors. However, animal studies showed that paternal obesity may program cardio-metabolic diseases in the offspring. In the current study we tested the hypothesis that paternal BMI may be associated with fetal growth. Methods and Results: We analyzed the relationship between paternal body mass index (BMI) and birth weight, ultrasound parameters describing the newborn's body shape as well as parameters describing the newborns endocrine system such as cortisol, aldosterone, renin activity and fetal glycated serum protein in a birth cohort of 899 father/mother/child triplets. Since fetal programming is an offspring sex specific process, male and female offspring were analyzed separately. Multivariable regression analyses considering maternal BMI, paternal and maternal age, hypertension during pregnancy, maternal total glycated serum protein, parity and either gestational age (for birth weight) or time of ultrasound investigation (for ultrasound parameters) as confounding showed that paternal BMI is associated with growth of the male but not female offspring. Paternal BMI correlated with birth parameters of male offspring only: birth weight; biparietal diameter, head circumference; abdominal diameter, abdominal circumference; and pectoral diameter. Cortisol was likewise significantly correlated with paternal BMI in male newborns only. Conclusions: Paternal BMI affects growth of the male but not female offspring. Paternal BMI may thus represent a risk factor for cardiovascular diseases of male offspring in later life. It remains to be demonstrated whether this is linked to an offspring sex specific paternal programming of cortisol secretion. San Fransisco PLoS 2012 9 PLoS one 7 5 10.1371/journal.pone.0036329 Institut für Ernährungswissenschaft OPUS4-36500 Wissenschaftlicher Artikel Chaykovska, Lyubov; von Websky, Karoline; Rahnenführer, Jan; Alter, Markus L.; Heiden, Susi; Fuchs, Holger; Runge, Frank; Klein, Thomas; Hocher, Berthold Effects of DPP-4 Inhibitors on the Heart in a Rat Model of Uremic Cardiomyopathy Background: Uremic cardiomyopathy contributes substantially to mortality in chronic kidney disease (CKD) patients. Glucagon-like peptide-1 (GLP-1) may improve cardiac function, but is mainly degraded by dipeptidyl peptidase-4 (DPP-4). Methodology/Principal Findings: In a rat model of chronic renal failure, 5/6-nephrectomized [5/6N] rats were treated orally with DPP-4 inhibitors (linagliptin, sitagliptin, alogliptin) or placebo once daily for 4 days from 8 weeks after surgery, to identify the most appropriate treatment for cardiac dysfunction associated with CKD. Linagliptin showed no significant change in blood level AUC(0-infinity) in 5/6N rats, but sitagliptin and alogliptin had significantly higher AUC(0-infinity) values; 41% and 28% (p=0.0001 and p=0.0324), respectively. No correlation of markers of renal tubular and glomerular function with AUC was observed for linagliptin, which required no dose adjustment in uremic rats. Linagliptin 7 mu mol/kg caused a 2-fold increase in GLP-1 (AUC 201.0 ng/l*h) in 5/6N rats compared with sham-treated rats (AUC 108.6 ng/l*h) (p=0.01). The mRNA levels of heart tissue fibrosis markers were all significantly increased in 5/6N vs control rats and reduced/normalized by linagliptin. Conclusions/Significance: DPP-4 inhibition increases plasma GLP-1 levels, particularly in uremia, and reduces expression of cardiac mRNA levels of matrix proteins and B-type natriuretic peptides (BNP). Linagliptin may offer a unique approach for treating uremic cardiomyopathy in CKD patients, with no need for dose-adjustment. San Fransisco PLoS 2011 9 PLoS one 6 11 10.1371/journal.pone.0027861 Institut für Ernährungswissenschaft OPUS4-36485 Wissenschaftlicher Artikel Espe, Katharina M.; Raila, Jens; Henze, Andrea; Krane, Vera; Schweigert, Florian J.; Hocher, Berthold; Wanner, Christoph; Drechsler, Christiane Impact of vitamin A on clinical outcomes in haemodialysis patients Background. Patients on maintenance haemodialysis treatment experience an excessive risk of cardiovascular disease and mortality. The vitamin A concentration is known to be higher in these patients compared to the general population where elevated vitamin A concentrations are associated with adverse outcome. The impact of vitamin A on morbidity and mortality in end-stage renal disease patients is controversial and is the topic of this study. Methods. We analysed plasma retinol and retinol-binding protein 4 (RBP4) in 1177 diabetic haemodialysis patients, who participated in the German Diabetes and Dialysis Study (median follow-up 4 years). By Cox regression analyses hazard ratios (HRs) were determined for pre-specified, adjudicated end points according to baseline concentrations. Results. Patients had a mean age of 66 +/- 8 years, mean retinol and RBP4 concentrations of 3.28 (0.71-7.44) and 4.02 (1.28-10.1) mu mol/L, respectively. Patients with retinol concentrations in the first quartile (<2.6 mu mol/L) had an almost 2-fold increased risk of all-cause mortality compared to patients of the fourth quartile [>3.9 mu mol/L; HR 1.81, 95% confidence interval (CI) 1.43-2.30]. There was a strong association between low retinol and the risk of sudden cardiac death (SCD, HR 2.22, 95% CI 1.41-3.50) and fatal infection (HR 2.19, 95% CI 1.26-3.82). Patients with RBP4 concentrations in the lowest quartile (<3.0 mu mol/L) were more likely to die of any cause (HR 1.43, 95% CI 1.14-1.80), experience SCD (HR 1.97, 95% CI 1.28-3.03) and cardiovascular events (HR 1.43, 95% CI 1.10-1.85). Conclusion. This large cohort study shows a strong association of low retinol and RBP4 concentrations with SCD and all-cause mortality in diabetic haemodialysis patients. Oxford Oxford Univ. Press 2011 8 Nephrology, dialysis, transplantation 26 12 4054 U583 10.1093/ndt/gfr171 Institut für Ernährungswissenschaft OPUS4-37384 Review Reichetzeder, Christoph; Tsuprykov, Oleg; Hocher, Berthold Endothelin receptor antagonists in clinical research - Lessons learned from preclinical and clinical kidney studies 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/). Oxford Elsevier 2014 8 Life sciences : molecular, cellular and functional basis of therapy 118 2 141 148 10.1016/j.lfs.2014.02.025 Institut für Ernährungswissenschaft OPUS4-37385 Wissenschaftlicher Artikel Vignon-Zellweger, Nicolas; Relle, Katharina; Rahnenfuehrer, Jan; Schwab, Karima; Hocher, Berthold; Theuring, Franz Endothelin-1 overexpression and endothelial nitric oxide synthase knock-out induce different pathological responses in the heart of male and female mice 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/). Oxford Elsevier 2014 7 Life sciences : molecular, cellular and functional basis of therapy 118 2 219 225 10.1016/j.lfs.2013.12.003 Institut für Ernährungswissenschaft OPUS4-37386 Wissenschaftlicher Artikel Heunisch, Fabian; von Einem, Gina; Alter, Markus L.; Weist, Andreas; Dschietzig, Thomas; Kretschmer, Axel; Hocher, Berthold Urinary ET-1 excretion after exposure to radio-contrast media in diabetic patients and patients with preexisting mild impaired renal function Aims: Contrast media-induced nephropathy (CIN) is associated with increased morbidity and mortality. The renal endothelin system has been associated with disease progression of various acute and chronic renal diseases. However, robust data coming from adequately powered prospective clinical studies analyzing the short and long-term impacts of the renal ET system in patients with CIN are missing so far. We thus performed a prospective study addressing this topic. Main methods: We included 327 patients with diabetes or renal impairment undergoing coronary angiography. Blood and spot urine were collected before and 24 h after contrast media (CM) application. Patients were followed for 90 days for major clinical events like need for dialysis, unplanned rehospitalization or death. Key findings: The concentration of ET-1 and the urinary ET-1/creatinine ratio decreased in spot urine after CM application (ET-1 concentration: 0.91 +/- 1.23pg/ml versus 0.63 +/- 1.03pg/ml, p<0.001; ET-1/creatinine ratio: 0.14 +/- 0.23 versus 0.09 +/- 0.19, p<0.001). The urinary ET-1 concentrations in patients with CIN decreased significantly more than in patients without CIN (-0.26 +/- 1.42pg/ml vs. -0.79 +/- 1.69pg/ml, p=0.041), whereas the decrease of the urinary ET-1/creatinine ratio was not significantly different (non-CIN patients: -0.05 +/- 0.30; CIN patients: -0.11 +/- 0.21, p=0.223). Urinary ET-1 concentrations as well as the urinary ET-1/creatinine ratio were not associated with clinical events (need for dialysis, rehospitalization or death) during the 90day follow-up after contrast media exposure. However, the urinary ET-1 concentration and the urinary ET-1/creatinine ratio after CM application were higher in those patients who had a decrease of GFR of at least 25% after 90days of follow-up. Significance: In general the ET-1 system in the kidney seems to be down-regulated after contrast media application in patients with moderate CIN risk. Major long-term complications of CIN (need for dialysis, rehospitalization or death) are not associated with the renal ET system. (C) 2014 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license. Oxford Elsevier 2014 6 Life sciences : molecular, cellular and functional basis of therapy 118 2 440 445 10.1016/j.lfs.2013.12.233 Institut für Ernährungswissenschaft OPUS4-37387 Wissenschaftlicher Artikel Yang, Fang; Lai, Xinlong; Deng, Li; Liu, Xiaoxiao; Li, Jian; Zeng, Shuixiu; Zhang, Cheng; Hocher, Carl-Friedrich; Hocher, Berthold Association of endothelin-1 gene polymorphisms with the clinical phenotype in primary nephrotic syndrome of children 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. Oxford Elsevier 2014 5 Life sciences : molecular, cellular and functional basis of therapy 118 2 446 450 10.1016/j.lfs.2014.04.010 Institut für Ernährungswissenschaft OPUS4-38939 Wissenschaftlicher Artikel Zirafi, Onofrio; Kim, Kyeong-Ae; Ständker, Ludger; Mohr, Katharina B.; Sauter, Daniel; Heigele, Anke; Kluge, Silvia F.; Wiercinska, Eliza; Chudziak, Doreen; Richter, Rudolf; Möpps, Barbara; Gierschik, Peter; Vas, Virag; Geiger, Hartmut; Lamla, Markus; Weil, Tanja; Burster, Timo; Zgraja, Andreas; Daubeuf, Francois; Frossard, Nelly; Hachet-Haas, Muriel; Heunisch, Fabian; Reichetzeder, Christoph; Galzi, Jean-Luc; Perez-Castells, Javier; Canales-Mayordomo, Angeles; Jimenez-Barbero, Jesus; Gimenez-Gallego, Guillermo; Schneider, Marion; Shorter, James; Telenti, Amalio; Hocher, Berthold; Forssmann, Wolf-Georg; Bonig, Halvard; Kirchhoff, Frank; Münch, Jan Discovery and Characterization of an Endogenous CXCR4 Antagonist 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. Cambridge Cell Press 2015 11 Cell reports 11 5 737 747 10.1016/j.celrep.2015.03.061 Institut für Ernährungswissenschaft OPUS4-35766 Wissenschaftlicher Artikel Nair, Anil V.; Hocher, Berthold; Verkaart, Sjoerd; van Zeeland, Femke; Pfab, Thiemo; Slowinski, Torsten; Chen, You-Peng; Schlingmann, Karl Peter; Schaller, Andre; Gallati, Sabina; Bindels, Rene J.; Konrad, Martin; Hönderop, Joost G. Loss of insulin-induced activation of TRPM6 magnesium channels results in impaired glucose tolerance during pregnancy 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. Washington National Acad. of Sciences 2012 6 Proceedings of the National Academy of Sciences of the United States of America 109 28 11324 11329 10.1073/pnas.1113811109 Institut für Ernährungswissenschaft OPUS4-35769 Wissenschaftlicher Artikel Hocher, Berthold; Armbruster, Franz Paul; Stöva, Stanka; Reichetzeder, Christoph; Groen, Hans Jürgen; Lieker, Ina; Khadzhynov, Dmytro; Slowinski, Torsten; Roth, Heinz Jürgen Measuring Parathyroid Hormone (PTH) in patients with oxidative stress - do we need a fourth generation Parathyroid Hormone assay? Oxidation of PTH at methionine residues results in loss of biological activity. PTH may be oxidized in patients with renal disease. The aim of this study was to develop an assay considering oxidation of PTH. Oxidized hPTH was analyzed by high resolution nano-liquid chromatography coupled to ESI-FTT tandem mass spectrometry (nanoLC-ESI-FT-MS/MS) directly and after proteolytic cleavage. The oxidized hPTH(1-84) sample shows TIC-peaks at 18-20 min and several mass peaks due to mass shifts caused by oxidations. No significant signal for oxidized hPTH(1-84) species after removal of oxidized PTH molecules by a specific column with monoclonal antibodies (MAB) raised against the oxidized hPTH was detectable. By using this column in samples from 18 patients on dialysis we could demonstrate that measured PTH concentrations were substantially lower when considering oxidized forms of PTH. The relationship between PTH concentrations determined directly and those concentrations measured after removal of the oxidized PTH forms varies substantially. In some patients only 7% of traditionally measured PTH was free of oxidation, whereas in other patients 34% of the traditionally measured PTH was real intact PTH. In conclusion, a huge but not constant proportion of PTH molecules are oxidized in patients requiring dialysis. Since oxidized PTH is biologically inactive, the currently used methods to detect PTH in daily clinical practice may not adequately reflect PTH-related bone and cardiovascular abnormalities in patients on dialysis. San Fransisco PLoS 2012 10 PLoS one 7 7 10.1371/journal.pone.0040242 Institut für Ernährungswissenschaft OPUS4-35705 Wissenschaftlicher Artikel Ott, Ina M.; Alter, Markus L.; von Websky, Karoline; Kretschmer, Axel; Tsuprykov, Oleg; Sharkovska, Yuliya; Krause-Relle, Katharina; Raila, Jens; Henze, Andrea; Stasch, Johannes-Peter; Hocher, Berthold Effects of Stimulation of Soluble Guanylate Cyclase on Diabetic Nephropathy in Diabetic eNOS Knockout Mice on Top of Angiotensin II Receptor Blockade 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. SAN FRANCISCO PUBLIC LIBRARY SCIENCE 2012 9 PLOS ONE 7 8 10.1371/journal.pone.0042623 OPUS4-36261 Wissenschaftlicher Artikel Schmerbach, K.; Kalk, Philipp.; Wengenmayer, Christina; Lucht, K.; Unger, T.; Hocher, Berthold; Thoene-Reineke, C. Renal outcome in equipotent Antihypertensive Treatment with Telmisartan, Ramipril and in combination in SHR-SP Rats 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. Heidelberg Clin Lab Publ., Verl. Klinisches Labor 2012 9 Clinical laboratory : the peer reviewed journal for clinical laboratories and laboratories related to blood transfusion 58 7-8 625 633 10.7754/Clin.Lab.2011.110622 Institut für Ernährungswissenschaft OPUS4-36262 Wissenschaftlicher Artikel Alter, Markus L.; Kretschmer, Axel; Von Websky, Karoline; Tsuprykov, Oleg; Reichetzeder, Christoph; Simon, Alexandra; Stasch, Johannes-Peter; Hocher, Berthold Early urinary and plasma biomarkers for experimental diabetic Nephropathy Background: As the prevalence of diabetes rises, its complications such as diabetic nephropathy affect an increaseing number of patients. Consequently, the need for biomarkers in rodent models which reflect the stage and course of diabetic nephropathy is high. This article focuses on Heart-type fatty acid binding protein (H-FABP), osteopontin (OPN), nephrin, and Neutrophil gelatinase-associated lipocalin (NGAL) in urine, and kidney injury molecule (KIM)-1, clusterin, and tissue inhibitior of metalloproteinases (TIMP) 1 in plasma in uni-nephrectomized rats with streptocotozin-induced type 1 diabetes mellitus, a common animal model to explore renal impairment in the setting of diabetes mellitus. Methods: 23 male Wistar rats were uni-nephrectomized and subsequently divided into two study groups. The diabetic group received streptozotocin (STZ) via tail-vein injection, the non-diabetic group received citrate buffer without STZ. Subsequently, blood glucose, body weight, and blood pressure were checked regularly. After 18 weeks, animals were placed in metabolic cages, blood and urine obtained and subsequently organs were harvested after sacrifice. Results: Blood glucose levels were highly increased in diabetic animals throughout the experiment, whereas systolic blood pressure did not differ between the study groups. At study end, classical biomarkers such as urinary albumin and protein and plasma cystatin c were only slightly but not significantly different between groups indicating a very early disease state. In contrast, urinary excretion of H-FABP, OPN, nephrin, and NGAL were highly increased in diabetic animals with a highly significant p-value (p<0.01 each) compared to non-diabetic animals. In plasma, differences were found for calbindin, KIM-1, clusterin, TIMP-1, and OPN. These findings were confirmed by means of the area under the receiver operating characteristic curve (ROC-AUC) analysis. Conclusions: In summary, our study revealed elevated levels of new plasma and urinary biomarkers (urinary osteopontin, urinary nephrin, urinary NGAL, urinary H-FABP, plasma KIM-1, plasma TIMP-1) in uni-nephrectomized diabetic rats, an established rat model of diabetic nephropathy. These biomarkers appeared even before the classical biomarkers of diabetic nephropathy such as albuminuria and urinary protein excretion. The new biomarkers might offer advantage to urinary albumin and plasma cystatin c with respect to early detection. Heidelberg Clin Lab Publ., Verl. Klinisches Labor 2012 13 Clinical laboratory : the peer reviewed journal for clinical laboratories and laboratories related to blood transfusion 58 7-8 659 671 10.7754/Clin.Lab.2011.111010 Institut für Ernährungswissenschaft OPUS4-36244 Wissenschaftlicher Artikel Vignon-Zellweger, Nicolas; Rahnenführer, Jan; Theuring, Franz; Hocher, Berthold Analysis of cardiac and renal endothelin receptors by in situ hybridization in mice 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. Heidelberg Clin Lab Publ., Verl. Klinisches Labor 2012 11 Clinical laboratory : the peer reviewed journal for clinical laboratories and laboratories related to blood transfusion 58 9-10 939 949 10.7754/Clin.Lab.2012.120216 Department Sport- und Gesundheitswissenschaften OPUS4-36245 Wissenschaftlicher Artikel Li, Jian; Wang, Zi-Neng; Chen, You-Peng; Dong, Yun-Peng; Mao, Xiao-Min; Hocher, Berthold 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 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. Heidelberg Clin Lab Publ., Verl. Klinisches Labor 2012 5 Clinical laboratory : the peer reviewed journal for clinical laboratories and laboratories related to blood transfusion 58 9-10 1085 1089 10.7754/Clin.Lab.2012.110920 Institut für Biochemie und Biologie OPUS4-36313 Konferenzveröffentlichung Espe, Katharina M.; Raila, Jens; Henze, Andrea; Blouin, Katja; Schneider, A.; Schmiedeke, D.; Krane, Vera; Schweigert, Florian J.; Hocher, Berthold; Wanner, Christoph; Drechsler, Christiane Low vitamin E plasma levels are associated with cerebrovascular events and mortality in hemodialysis patients Basel Karger 2012 1 Annals of nutrition & metabolism : journal of nutrition, metabolic diseases and dietetics ; an official journal of International Union of Nutritional Sciences (IUNS) 60 2 137 137 Institut für Ernährungswissenschaft OPUS4-36294 Wissenschaftlicher Artikel Chen, You-Peng; Li, Jian; Wang, Zi-Neng; Reichetzeder, Christoph; Xu, Hao; Gong, Jian; Chen, Guang-Ji; Pfab, Thiemo; Xiao, Xiao-Min; Hocher, Berthold Renin angiotensin aldosterone system and glycemia in pregnancy Background: The renin-angiotensin-aldosterone system (RAAS) is involved in the pathogenesis of insulin resistance and type 2 diabetes in the general population. The RAAS is activated during pregnancy. However, it is unknown whether the RAAS contributes to glycemia in pregnant women. Methods: Plasma renin activity (PRA) and plasma aldosterone levels were quantified at delivery in 689 Chinese mothers. An oral glucose tolerance test in fasted women was performed in the second trimester of pregnancy. The diagnosis of gestational diabetes mellitus (GDM) and impaired glucose tolerance during pregnancy were made according to the guidelines of the Chinese Society of Obstetrics. Results: Plasma aldosterone was significantly higher in pregnant women with GDM as compared to those without impairment of glycemic control (normal pregnancies: 0.27 +/- 0.21 ng/mL, GDM: 0.36 +/- 0.30 ng/mL; p<0.05). Regression analyses revealed that PRA was negatively correlated with fasting blood glucose (FBG) (R-2 = 0.03, p = 0.007), whereas plasma aldosterone and aldosterone/PRA ratio were positively correlated with FBG (R-2 = 0.05, p<0.001 and R-2 = 0.03, p = 0.007, respectively). Multivariable regression analysis models considering relevant confounding factors confirmed these findings. Conclusions: This study demonstrated that fasting blood glucose in pregnant women is inversely correlated with the PRA, whereas plasma aldosterone showed a highly significant positive correlation with fasting blood glucose during pregnancy. Moreover, plasma aldosterone is significantly higher in pregnant women with GDM as compared to those women with normal glucose tolerance during pregnancy. Although causality cannot be proven in association studies, these data may indicate that the RAAS during pregnancy contributes to the pathogenesis of insulin resistance/new onset of diabetes during pregnancy. Heidelberg Clin Lab Publ., Verl. Klinisches Labor 2012 7 Clinical laboratory : the peer reviewed journal for clinical laboratories and laboratories related to blood transfusion 58 5-6 527 533 Institut für Ernährungswissenschaft OPUS4-36263 Wissenschaftlicher Artikel Vickers, Steven P.; Cheetham, Sharon C.; Birmingham, Gareth D.; Rowley, Helen L.; Headland, Katie R.; Dickinson, Keith; Grempler, Rolf; Hocher, Berthold; Mark, Michael; Klein, Thomas Effects of the DPP-4 Inhibitor, Linagliptin, in Diet-Induced obese rats a comparison in Naive and Exenatide-Treated Animals 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. Heidelberg Clin Lab Publ., Verl. Klinisches Labor 2012 13 Clinical laboratory : the peer reviewed journal for clinical laboratories and laboratories related to blood transfusion 58 7-8 787 799 10.7754/Clin.Lab.2011.110919 Institut für Ernährungswissenschaft OPUS4-36264 Wissenschaftlicher Artikel Hocher, Berthold; Groen, Hans Jürgen; Schumann, Claudia; Tsuprykov, Oleg; Seifert, Susanne; Hitzler, Walter E.; Armbruster, Franz Paul Vitamin D status from dried capillary blood samples Background: Given the huge impact of vitamin D deficiency on a broad spectrum of diseases such as rickets, osteoporosis, mineral bone disease-vascular calcification syndrome, infectious diseases, but also several types of cancer and CNS diseases, reliable and simple methods to analyze the vitamin D status are urgently needed. Methods: We developed an easy technique to determine the 25-OH vitamin D status from dried blood samples on filter paper. This allows determination of the 25-OH vitamin D status independently of venous blood taking, since only sampling of capillary blood is required for this new method. We compared the results of vitamin D measurements from venous blood of 96 healthy blood donors with those from capillary blood taken from the same patients at the same time. The capillary blood was dried on filter paper using the D-Vital ID dry-blood collection system. Results: 25-OH vitamin D concentration data from extracted dried capillary blood filters correlated very well with data obtained after direct measurement of venous blood samples of the same blood donor (R: 0.7936; p<0.0001). The correlation was linear over the whole range of 25-OH vitamin D concentrations seen in this study. A Bland-Altman plot revealed good agreement between both tests. Conclusions: The D-Vital ID dry-blood collection system showed an excellent performance as compared to the classical way of 25-OH vitamin D measurement from venous blood. This new technique will facilitate easy and reliable measurement for vitamin D status, in particular, in rural or isolated areas, developing countries, and field studies. Heidelberg Clin Lab Publ., Verl. Klinisches Labor 2012 5 Clinical laboratory : the peer reviewed journal for clinical laboratories and laboratories related to blood transfusion 58 7-8 851 855 10.7754/Clin.Lab.2012.120429 Institut für Ernährungswissenschaft OPUS4-36939 Wissenschaftlicher Artikel Kalk, Philipp; Sharkovska, Yuliya; Kashina, Elena; von Websky, Karoline; Relle, Katharina; Pfab, Thiemo; Alter, Markus L.; Guillaume, Philippe; Provost, Daniel; Hoffmann, Katrin; Fischer, Yvan; Hocher, Berthold Endothelin-Converting Enzyme/Neutral Endopeptidase Inhibitor SLV338 Prevents Hypertensive Cardiac Remodeling in a Blood Pressure-Independent Manner 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.) PHILADELPHIA LIPPINCOTT WILLIAMS & WILKINS 2011 9 HYPERTENSION 57 4 755 763 10.1161/HYPERTENSIONAHA.110.163972 OPUS4-36893 Wissenschaftlicher Artikel Vignon-Zellweger, Nicolas; Relle, Katharina; Kienlen, Elodie; Alter, Markus L.; Seider, Patrick; Sharkovska, Juliya; Heiden, Susi; Kalk, Philipp; Schwab, Karima; Albrecht-Kuepper, Barbara; Theuring, Franz; Stasch, Johannes-Peter; Hocher, Berthold Endothelin-1 overexpression restores diastolic function in eNOS knockout mice 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. Philadelphia Lippincott Williams & Wilkins 2011 10 Journal of hypertension 29 5 961 970 10.1097/HJH.0b013e3283450770 Institut für Ernährungswissenschaft OPUS4-38589 Wissenschaftlicher Artikel Satwiko, Muhammad Gahan; Ikeda, Koji; Nakayama, Kazuhiko; Yagi, Keiko; Hocher, Berthold; Hirata, Ken-Ichi; Emoto, Noriaki Targeted activation of endothelin-1 exacerbates hypoxia-induced pulmonary hypertension 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. San Diego Elsevier 2015 7 Biochemical and biophysical research communications 465 3 356 362 10.1016/j.bbrc.2015.08.002 Institut für Ernährungswissenschaft OPUS4-38646 Konferenzveröffentlichung Reichetzeder, Christoph; von Websky, Karoline; Tsuprykov, Oleg; Antonenko, V.; Samarin, Azin Mohagheghi; Hocher, Berthold Effects of DPP-4 inhibition on glomerular and tubular function in a rat model of ischaemia-reperfusion injury New York Springer 2015 2 Diabetologia : journal of the European Association for the Study of Diabetes (EASD) 58 S34 S35 Institut für Ernährungswissenschaft OPUS4-35548 Wissenschaftlicher Artikel Henze, Andrea; Espe, Katharina M.; Wanner, Christoph; Krane, Vera; Raila, Jens; Hocher, Berthold; Schweigert, Florian J.; Drechsler, Christiane Transthyretin predicts cardiovascular outcome in hemodialysis patients with type 2 diabetes OBJECTIVE-BMI and albumin are commonly accepted parameters to recognize wasting in dialysis patients and are powerful predictors of morbidity and mortality. However, both parameters reveal limitations and may not cover the entire range of patients with wasting. The visceral protein transthyretin (TTR) may be helpful in overcoming the diagnostic and prognostic gap. Therefore, the aim of this study was to assess the association of TTR with morbidity and mortality in hemodialysis patients. RESEARCH DESIGN AND METHODS-The TTR concentration was determined in plasma samples of 1,177 hemodialysis patients with type 2 diabetes. Cox regression analyses were used to determine hazard ratios (HRs) for the risk of cardiovascular end points (CVEs) and mortality according to quartiles of TTR concentration for the total study cohort and the subgroups BMI >= 23 kg/m(2), albumin concentration >= 3.8 g/dL, and a combination of both. RESULTS-A low TTR concentration was associated with an increased risk for CVE for the total study cohort (HR 1.65 [95% CI 1.27-2.14]), patients with BMI >= 23 kg/m(2) (1.70 [1.22-2.37]), albumin >= 3.8 g/dL (1.68 [1.17-2.42]), and the combination of both (1.69 [1.13-2.53]). Additionally, a low TTR concentration predicted mortality for the total study cohort (1.79 [1.43-2.24]) and patients with BMI >= 23 kg/m(2) (1.46 [1.09-1.95]). CONCLUSIONS-The current study demonstrated that TTR is a useful predictor for cardiovascular outcome and mortality in diabetic hemodialysis patients. TTR was particularly useful in patients who were not identified to be at risk by BMI or albumin status. Alexandria American Diabetes Association 2012 8 Diabetes care 35 11 2365 2372 10.2337/dc12-0455 Institut für Ernährungswissenschaft OPUS4-36658 Konferenzveröffentlichung Pfab, T.; Sharkovska, Yukiya; Alter, Markus L.; von Websky, Karoline; Mark, M.; Klein, T.; Hocher, Berthold Effect of linagliptin on infarction size and cardiac function in rats after myocardial ischaemia reperfusion New York Springer 2011 1 Diabetologia : journal of the European Association for the Study of Diabetes (EASD) 54 S329 S329 Institut für Ernährungswissenschaft OPUS4-36662 Wissenschaftlicher Artikel Li, Jian; Wang, Zi-Neng; Schlemm, Ludwig; Pfab, Thiemo; Xiao, Xiao-Min; Chen, You-Peng; Hocher, Berthold Low birth weight and elevated head-to-abdominal circumference ratio are associated with elevated fetal glycated serum protein concentrations 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. Philadelphia Lippincott Williams & Wilkins 2011 7 Journal of hypertension 29 9 1712 1718 10.1097/HJH.0b013e328349a2e6 Institut für Ernährungswissenschaft OPUS4-36650 Wissenschaftlicher Artikel Hocher, Berthold; Schlemm, Ludwig; Haumann, Hannah; Li, Jian; Rahnenführer, Jan; Guthmann, Florian; Bamberg, Christian; Kalk, Philipp; Pfab, Thiemo; Chen, You-Peng Offspring sex determines the impact of the maternal ACE I/D polymorphism on maternal glycaemic control during the last weeks of pregnancy 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. London Sage Publ. 2011 8 Journal of the renin angiotensin aldosterone system 12 3 254 261 10.1177/1470320310387843 Institut für Ernährungswissenschaft OPUS4-36989 Wissenschaftlicher Artikel Schildroth, Janice; Rettig-Zimmermann, Juliane; Kalk, Philipp; Steege, Andreas; Faehling, Michael; Sendeski, Mauricio; Paliege, Alexander; Lai, En Yin; Bachmann, Sebastian; Persson, Pontus B.; Hocher, Berthold; Patzak, Andreas Endothelin type A and B receptors in the control of afferent and efferent arterioles in mice 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. Oxford Oxford Univ. Press 2011 11 Nephrology, dialysis, transplantation 26 3 779 789 10.1093/ndt/gfq534 Institut für Ernährungswissenschaft OPUS4-36963 Wissenschaftlicher Artikel Hocher, Berthold; Heiden, Susi; von Websky, Karoline; Arafat, Ayman M.; Rahnenführer, Jan; Alter, Markus L.; Kalk, Philipp; Ziegler, Dieter; Fischer, Yvan; Pfab, Thiemo Renal effects of the novel selective adenosine A(1) receptor blocker SLV329 in experimental liver cirrhosis in rats 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. San Fransisco PLoS 2011 8 PLoS one 6 3 10.1371/journal.pone.0017891 Institut für Ernährungswissenschaft OPUS4-36221 Review Hocher, Berthold; Reichetzeder, Christoph; Alter, Markus L. Renal and cardiac effects of DPP-4 inhibitors - from preclinical development to clinical research 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. Basel Karger 2012 20 Kidney & blood pressure research : official organ of the Gesellschaft für Nephrologie 36 1 65 84 10.1159/000339028 Institut für Ernährungswissenschaft OPUS4-36222 Wissenschaftlicher Artikel Alter, Markus L.; Ott, Ina M.; von Websky, Karoline; Tsuprykov, Oleg; Sharkovska, Yuliya; Krause-Relle, Katharina; Raila, Jens; Henze, Andrea; Klein, Thomas; Hocher, Berthold DPP-4 Inhibition on top of angiotensin receptor blockade offers a new therapeutic approach for diabetic nephropathy Background: The need for an improved treatment for diabetic nephropathy is greatest in patients who do not adequately respond to angiotensin II receptor blockers (ARBs). This study investigated the effect of the novel dipeptidyl peptidase-4 inhibitor linagliptin alone and in combination with the ARB telmisartan on the progression of diabetic nephropathy in diabetic endothelial nitric oxide synthase (eNOS) knockout mice. Methods: Sixty male eNOS knockout C57BL/6J mice were divided into four groups after receiving intraperitoneal high-dose streptozotocin: telmisartan (1 mg/kg), linagliptin (3 mg/kg), linagliptin + telmisartan (3 mg/kg + 1 mg/kg) and vehicle. Fourteen mice were used as non-diabetic controls. Results: After 12 weeks, urine and blood were obtained and blood pressure measured. Glucose concentrations were increased and similar in all diabetic groups. Telmisartan alone reduced systolic blood pressure by 5.9 mmHg versus diabetic controls (111.2 +/- 2.3 mmHg vs 117.1 +/- 2.2 mmHg; mean +/- SEM; P = 0.071). Combined treatment significantly reduced albuminuria compared with diabetic controls (71.7 +/- 15.3 mu g/24 h vs 170.8 +/- 34.2 mu g/24 h; P = 0.017), whereas the effects of single treatment with either telmisartan (97.8 +/- 26.4 mu g/24 h) or linagliptin (120.8 +/- 37.7 mu g/24 h) were not statistically significant. DPP-4 inhibition, alone and in combination, led to significantly lower plasma osteopontin levels compared with telmisartan alone. Histological analysis revealed reduced glomerulosclerosis after Linagliptin alone and in combination with telmisartan in comparison to non treated diabetic animals (p < 0.01 and p < 0.05). Kidney malonaldehyde immune-reactivity, a marker of oxidative stress, was significantly lower in animals treated with linagliptin. Conclusions: DPP-4 inhibition on top of ARB treatment significantly reduced urinary albumin excretion and oxidative stress in diabetic eNOS knockout mice. Linagliptin on top of an angiotensin II receptor blocker may offer a new therapeutic approach for patients with diabetic nephropathy. Basel Karger 2012 12 Kidney & blood pressure research : official organ of the Gesellschaft für Nephrologie 36 1 119 130 10.1159/000341487 Institut für Ernährungswissenschaft OPUS4-37158 Review Chaykovska, Lyubov; Tsuprykov, Oleg; Hocher, Berthold Biomarkers for the prediction of mortality and morbidity in patients with renal replacement therapy The mortality of end-stage renal disease (ESRD) patients on dialysis remains high despite great improvement of dialysis technologies in the past decades. These patients die due to infectious diseases (mainly sepsis), cardiovascular diseases such as myocardial infarction, heart failure, stroke, and, in particular, sudden cardiac death. End stage renal disease is a complex condition, where the failure of kidney function is accompanied by numerous metabolic changes affecting almost all organ systems of the human body. Many of the biomarker characteristics of the individually affected organ systems have been associated with adverse outcomes. These biomarkers are different in patients with ESRD compared to the general population in the prediction of morbidity and mortality. Biomarker research in this field should aim to identify patients at risk for the different disease entities. Traditional biomarkers such as CRP, BNP, and troponins as well as new biomarkers such as fetuin, CD 154, and relaxin were analyzed in patients on dialysis. We will include observational as well as prospective clinical trials in this review. Furthermore, we will also discuss proteomics biomarker studies. The article assess the potential diagnostic value of different biomarkers in daily clinical practice as well as their usefulness for clinical drug development in end stage renal disease patients. Heidelberg Clin Lab Publ., Verl. Klinisches Labor 2011 13 Clinical laboratory : the peer reviewed journal for clinical laboratories and laboratories related to blood transfusion 57 7-8 455 467 Institut für Ernährungswissenschaft