@article{VignonZellwegerRahnenfuehrerTheuringetal.2012, author = {Vignon-Zellweger, Nicolas and Rahnenf{\"u}hrer, Jan and Theuring, Franz and Hocher, Berthold}, title = {Analysis of cardiac and renal endothelin receptors by in situ hybridization in mice}, series = {Clinical laboratory : the peer reviewed journal for clinical laboratories and laboratories related to blood transfusion}, volume = {58}, journal = {Clinical laboratory : the peer reviewed journal for clinical laboratories and laboratories related to blood transfusion}, number = {9-10}, publisher = {Clin Lab Publ., Verl. Klinisches Labor}, address = {Heidelberg}, issn = {1433-6510}, doi = {10.7754/Clin.Lab.2012.120216}, pages = {939 -- 949}, year = {2012}, abstract = {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.}, language = {en} } @article{VickersCheethamBirminghametal.2012, author = {Vickers, Steven P. and Cheetham, Sharon C. and Birmingham, Gareth D. and Rowley, Helen L. and Headland, Katie R. and Dickinson, Keith and Grempler, Rolf and Hocher, Berthold and Mark, Michael and Klein, Thomas}, title = {Effects of the DPP-4 Inhibitor, Linagliptin, in Diet-Induced obese rats a comparison in Naive and Exenatide-Treated Animals}, series = {Clinical laboratory : the peer reviewed journal for clinical laboratories and laboratories related to blood transfusion}, volume = {58}, journal = {Clinical laboratory : the peer reviewed journal for clinical laboratories and laboratories related to blood transfusion}, number = {7-8}, publisher = {Clin Lab Publ., Verl. Klinisches Labor}, address = {Heidelberg}, issn = {1433-6510}, doi = {10.7754/Clin.Lab.2011.110919}, pages = {787 -- 799}, year = {2012}, abstract = {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.}, language = {en} } @article{TaalStPourcainThieringetal.2012, author = {Taal, H. Rob and St Pourcain, Beate and Thiering, Elisabeth and Das, Shikta and Mook-Kanamori, Dennis O. and Warrington, Nicole M. and Kaakinen, Marika and Kreiner-Moller, Eskil and Bradfield, Jonathan P. and Freathy, Rachel M. and Geller, Frank and Guxens, Monica and Cousminer, Diana L. and Kerkhof, Marjan and Timpson, Nicholas J. and Ikram, M. Arfan and Beilin, Lawrence J. and Bonnelykke, Klaus and Buxton, Jessica L. and Charoen, Pimphen and Chawes, Bo Lund Krogsgaard and Eriksson, Johan and Evans, David M. and Hofman, Albert and Kemp, John P. and Kim, Cecilia E. and Klopp, Norman and Lahti, Jari and Lye, Stephen J. and McMahon, George and Mentch, Frank D. and Mueller-Nurasyid, Martina and O'Reilly, Paul F. and Prokopenko, Inga and Rivadeneira, Fernando and Steegers, Eric A. P. and Sunyer, Jordi and Tiesler, Carla and Yaghootkar, Hanieh and Breteler, Monique M. B. and Debette, Stephanie and Fornage, Myriam and Gudnason, Vilmundur and Launer, Lenore J. and van der Lugt, Aad and Mosley, Thomas H. and Seshadri, Sudha and Smith, Albert V. and Vernooij, Meike W. and Blakemore, Alexandra I. F. and Chiavacci, Rosetta M. and Feenstra, Bjarke and Fernandez-Banet, Julio and Grant, Struan F. A. and Hartikainen, Anna-Liisa and van der Heijden, Albert J. and Iniguez, Carmen and Lathrop, Mark and McArdle, Wendy L. and Molgaard, Anne and Newnham, John P. and Palmer, Lyle J. and Palotie, Aarno and Pouta, Annneli and Ring, Susan M. and Sovio, Ulla and Standl, Marie and Uitterlinden, Andre G. and Wichmann, H-Erich and Vissing, Nadja Hawwa and DeCarli, Charles and van Duijn, Cornelia M. and McCarthy, Mark I. and Koppelman, Gerard H. and Estivill, Xavier and Hattersley, Andrew T. and Melbye, Mads and Bisgaard, Hans and Pennell, Craig E. and Widen, Elisabeth and Hakonarson, Hakon and Smith, George Davey and Heinrich, Joachim and Jarvelin, Marjo-Riitta and Jaddoe, Vincent W. V. and Adair, Linda S. and Ang, Wei and Atalay, Mustafa and van Beijsterveldt, Toos and Bergen, Nienke and Benke, Kelly and Berry, Diane J. and Bradfield, Jonathan P. and Charoen, Pimphen and Coin, Lachlan and Cousminer, Diana L. and Das, Shikta and Davis, Oliver S. P. and Elliott, Paul and Evans, David M. and Feenstra, Bjarke and Flexeder, Claudia and Frayling, Tim and Freathy, Rachel M. and Gaillard, Romy and Geller, Frank and Groen-Blokhuis, Maria and Goh, Liang-Kee and Guxens, Monica and Haworth, Claire M. A. and Hadley, Dexter and Hebebrand, Johannes and Hinney, Anke and Hirschhorn, Joel N. and Holloway, John W. and Holst, Claus and Hottenga, Jouke Jan and Horikoshi, Momoko and Huikari, Ville and Hypponen, Elina and Iniguez, Carmen and Kaakinen, Marika and Kilpelainen, Tuomas O. and Kirin, Mirna and Kowgier, Matthew and Lakka, Hanna-Maaria and Lange, Leslie A. and Lawlor, Debbie A. and Lehtimaki, Terho and Lewin, Alex and Lindgren, Cecilia and Lindi, Virpi and Maggi, Reedik and Marsh, Julie and Middeldorp, Christel and Millwood, Iona and Mook-Kanamori, Dennis O. and Murray, Jeffrey C. and Nivard, Michel and Nohr, Ellen Aagaard and Ntalla, Ioanna and Oken, Emily and O'Reilly, Paul F. and Palmer, Lyle J. and Panoutsopoulou, Kalliope and Pararajasingham, Jennifer and Prokopenko, Inga and Rodriguez, Alina and Salem, Rany M. and Sebert, Sylvain and Siitonen, Niina and Sovio, Ulla and St Pourcain, Beate and Strachan, David P. and Sunyer, Jordi and Taal, H. Rob and Teo, Yik-Ying and Thiering, Elisabeth and Tiesler, Carla and Uitterlinden, Andre G. and Valcarcel, Beatriz and Warrington, Nicole M. and White, Scott and Willemsen, Gonneke and Yaghootkar, Hanieh and Zeggini, Eleftheria and Boomsma, Dorret I. and Cooper, Cyrus and Estivill, Xavier and Gillman, Matthew and Grant, Struan F. A. and Hakonarson, Hakon and Hattersley, Andrew T. and Heinrich, Joachim and Hocher, Berthold and Jaddoe, Vincent W. V. and Jarvelin, Marjo-Riitta and Lakka, Timo A. and McCarthy, Mark I. and Melbye, Mads and Mohlke, Karen L. and Dedoussis, George V. and Ong, Ken K. and Pearson, Ewan R. and Pennell, Craig E. and Price, Thomas S. and Power, Chris and Raitakari, Olli T. and Saw, Seang-Mei and Scherag, Andre and Simell, Olli and Sorensen, Thorkild I. A. and Timpson, Nicholas J. and Widen, Elisabeth and Wilson, James F. and Ang, Wei and van Beijsterveldt, Toos and Bergen, Nienke and Benke, Kelly and Berry, Diane J. and Bradfield, Jonathan P. and Charoen, Pimphen and Coin, Lachlan and Cousminer, Diana L. and Das, Shikta and Elliott, Paul and Evans, David M. and Frayling, Tim and Freathy, Rachel M. and Gaillard, Romy and Groen-Blokhuis, Maria and Guxens, Monica and Hadley, Dexter and Hottenga, Jouke Jan and Huikari, Ville and Hypponen, Elina and Kaakinen, Marika and Kowgier, Matthew and Lawlor, Debbie A. and Lewin, Alex and Lindgren, Cecilia and Marsh, Julie and Middeldorp, Christel and Millwood, Iona and Mook-Kanamori, Dennis O. and Nivard, Michel and O'Reilly, Paul F. and Palmer, Lyle J. and Prokopenko, Inga and Rodriguez, Alina and Sebert, Sylvain and Sovio, Ulla and St Pourcain, Beate and Standl, Marie and Strachan, David P. and Sunyer, Jordi and Taal, H. Rob and Thiering, Elisabeth and Tiesler, Carla and Uitterlinden, Andre G. and Valcarcel, Beatriz and Warrington, Nicole M. and White, Scott and Willemsen, Gonneke and Yaghootkar, Hanieh and Boomsma, Dorret I. and Estivill, Xavier and Grant, Struan F. A. and Hakonarson, Hakon and Hattersley, Andrew T. and Heinrich, Joachim and Jaddoe, Vincent W. V. and Jarvelin, Marjo-Riitta and McCarthy, Mark I. and Pennell, Craig E. and Power, Chris and Timpson, Nicholas J. and Widen, Elisabeth and Ikram, M. Arfan and Fornage, Myriam and Smith, Albert V. and Seshadri, Sudha and Schmidt, Reinhold and Debette, Stephanie and Vrooman, Henri A. and Sigurdsson, Sigurdur and Ropele, Stefan and Coker, Laura H. and Longstreth, W. T. and Niessen, Wiro J. and DeStefano, Anita L. and Beiser, Alexa and Zijdenbos, Alex P. and Struchalin, Maksim and Jack, Clifford R. and Nalls, Mike A. and Au, Rhoda and Hofman, Albert and Gudnason, Haukur and van der Lugt, Aad and Harris, Tamara B. and Meeks, William M. and Vernooij, Meike W. and van Buchem, Mark A. and Catellier, Diane and Gudnason, Vilmundur and Windham, B. Gwen and Wolf, Philip A. and van Duijn, Cornelia M. and Mosley, Thomas H. and Schmidt, Helena and Launer, Lenore J. and Breteler, Monique M. B. and DeCarli, Charles}, title = {Common variants at 12q15 and 12q24 are associated with infant head circumference}, series = {Nature genetics}, volume = {44}, journal = {Nature genetics}, number = {5}, publisher = {Nature Publ. Group}, address = {New York}, organization = {Cohorts Heart Aging Res Genetic Ep, Early Genetics Lifecourse Epidemio, Early Growth Genetics EGG Consorti}, issn = {1061-4036}, doi = {10.1038/ng.2238}, pages = {532 -- +}, year = {2012}, abstract = {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.}, language = {en} } @article{SunHuangMengetal.2012, author = {Sun, Sheng-Yun and Huang, Jin and Meng, Min-Jie and Lu, Jia-Hai and Hocher, Berthold and Liu, Kang-Li and Yang, Qin-He and Zhu, Xiao-Feng}, title = {Improvement of lipid profile and reduction of body weight by Shan He Jian Fei Granules in high fat diet-induced obese rats}, series = {Clinical laboratory : the peer reviewed journal for clinical laboratories and laboratories related to blood transfusion}, volume = {58}, journal = {Clinical laboratory : the peer reviewed journal for clinical laboratories and laboratories related to blood transfusion}, number = {1-2}, publisher = {Clin Lab Publ., Verl. Klinisches Labor}, address = {Heidelberg}, issn = {1433-6510}, pages = {81 -- 87}, year = {2012}, abstract = {Background: The goal was to study lipid profiles (TG, TC, LDL, HDL), effects on serum leptin, and fat tissue adiponectin, and resistin as well as body weight effects of Shan He Jian Fei Granules (SHJFG) in rats on a high fat diet. Methods: Rats were randomly divided into five groups: normal control group fed with normal fat diet, rats on high fat diet receiving low dosage, middle dosage, high dosage of Shan He Jian Fei Granules (SHJFG) as well as a high fat diet group receiving placebo. Rats were treated for 8 weeks. Body weight and naso-anal length of each rat were recorded and Lee's index was calculated. Serum TG, TC, LDL, HDL and leptin concentrations were analyzed. The gene expressions of adiponectin and resistin in adipose tissues were tested by RT-PCR. Results: Compared to the high-fat diet group, body weights, Lee's indexes, weight of fat tissues and serum TG, TC, LDL and leptin of SHJFG groups significantly decreased (p<0.05), whereas mRNA expressions of adiponectin and resistin of SHJFG groups significantly increased (p<0.05). Conclusions: SHJFG could significantly lower body weight and serum TG, TC, and LDL of obese rats. The effects of SHJFG in lowering leptin synthesis and raising mRNA expression of adiponectin and resistin in fat tissues may act as part of the mechanisms in lowering body weight of obese rats. Further studies are needed to demonstrate whether SHJFG may also reduce overall cardiovascular morbidity and mortality like other lipid lowering drugs.}, language = {en} } @article{SchmerbachKalkWengenmayeretal.2012, author = {Schmerbach, K. and Kalk, Philipp. and Wengenmayer, Christina and Lucht, K. and Unger, T. and Hocher, Berthold and Thoene-Reineke, C.}, title = {Renal outcome in equipotent Antihypertensive Treatment with Telmisartan, Ramipril and in combination in SHR-SP Rats}, series = {Clinical laboratory : the peer reviewed journal for clinical laboratories and laboratories related to blood transfusion}, volume = {58}, journal = {Clinical laboratory : the peer reviewed journal for clinical laboratories and laboratories related to blood transfusion}, number = {7-8}, publisher = {Clin Lab Publ., Verl. Klinisches Labor}, address = {Heidelberg}, issn = {1433-6510}, doi = {10.7754/Clin.Lab.2011.110622}, pages = {625 -- 633}, year = {2012}, abstract = {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.}, language = {en} } @article{RokutanSuckowvonHaehlingetal.2012, author = {Rokutan, Hirofumi and Suckow, Christian and von H{\"a}hling, Stephan and Strassburg, Sabine and Bockmeyer, Barbara and D{\"o}hner, Wolfram and Waller, Christiane and Bauersachs, Johann and von Websky, Karoline and Hocher, Berthold and Anker, Stefan D. and Springer, Jochen}, title = {Furosemide induces mortality in a rat model of chronic heart failure}, series = {International journal of cardiology}, volume = {160}, journal = {International journal of cardiology}, number = {1}, publisher = {Elsevier}, address = {Clare}, issn = {0167-5273}, doi = {10.1016/j.ijcard.2011.03.005}, pages = {20 -- 25}, year = {2012}, abstract = {Objectives: In an experimental heart failure model, we tested the hypothesis that furosemide causes excess mortality. Background: Post-hoc analysis of large clinical heart failure trails revealed that furosemide treatment might be associated with worsening of morbidity and even mortality in heart failure patients. Methods and results: Myocardial infarction was induced in 7 +/- 1 week old male Wistar rats by ligation of the left coronary artery. In study 1, animals were randomly assigned to treatment with furosemide (10 mg/kg/d via drinking water, n = 33) or placebo (n = 33) starting 18 days after surgery. In study 2, animals received furosemide from day 18 and were then randomized to ongoing treatment with either furosemide only (n = 38) or furosemide plus ACE-inhibitor Ramipril (1 mg/kg/d, n = 38) starting on day 42. In study 1 survival rate in the furosemide group was lower than in the placebo group (hazard ratio {HR} 3.39, 95\% confidence interval {CI} 1.14 to 10.09, p = 0.028). The furosemide group had a lower body weight (-6\%, p = 0.028) at the end of the study and a higher sclerosis index of the glomeruli (+9\%, p=0.026) than the placebo group. Wet lung weight, infarct size, and cardiac function were similar between the groups. In study 2, the furosemide group had a higher mortality rate than the furosemide + ramipril group (HR 4.55, 95\% CI 2.0 to 10.0, p = 0.0003). Conclusion: In our rat model of heart failure furosemide, provided at a standard dose, was associated with increased mortality. This increased mortality could be prevented by additional administration of an ACE-inhibitor.}, language = {en} } @article{OttAltervonWebskyetal.2012, author = {Ott, Ina M. and Alter, Markus L. and von Websky, Karoline and Kretschmer, Axel and Tsuprykov, Oleg and Sharkovska, Yuliya and Krause-Relle, Katharina and Raila, Jens and Henze, Andrea and Stasch, Johannes-Peter and Hocher, Berthold}, title = {Effects of Stimulation of Soluble Guanylate Cyclase on Diabetic Nephropathy in Diabetic eNOS Knockout Mice on Top of Angiotensin II Receptor Blockade}, series = {PLOS ONE}, volume = {7}, journal = {PLOS ONE}, number = {8}, publisher = {PUBLIC LIBRARY SCIENCE}, address = {SAN FRANCISCO}, issn = {1932-6203}, doi = {10.1371/journal.pone.0042623}, pages = {9}, year = {2012}, abstract = {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.}, language = {en} } @article{NairHocherVerkaartetal.2012, author = {Nair, Anil V. and Hocher, Berthold and Verkaart, Sjoerd and van Zeeland, Femke and Pfab, Thiemo and Slowinski, Torsten and Chen, You-Peng and Schlingmann, Karl Peter and Schaller, Andre and Gallati, Sabina and Bindels, Rene J. and Konrad, Martin and H{\"o}nderop, Joost G.}, title = {Loss of insulin-induced activation of TRPM6 magnesium channels results in impaired glucose tolerance during pregnancy}, series = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {109}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, number = {28}, publisher = {National Acad. of Sciences}, address = {Washington}, issn = {0027-8424}, doi = {10.1073/pnas.1113811109}, pages = {11324 -- 11329}, year = {2012}, abstract = {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.}, language = {en} } @article{LiWangChenetal.2012, author = {Li, Jian and Wang, Zi-Neng and Chen, You-Peng and Dong, Yun-Peng and Shuai, Han-Lin and Xiao, Xiao-Min and Reichetzeder, Christoph and Hocher, Berthold}, title = {Late gestational maternal serum cortisol is inversely associated with fetal brain growth}, series = {Neuroscience \& biobehavioral reviews : official journal of the International Behavioral Neuroscience Society}, volume = {36}, journal = {Neuroscience \& biobehavioral reviews : official journal of the International Behavioral Neuroscience Society}, number = {3}, publisher = {Elsevier}, address = {Oxford}, issn = {0149-7634}, doi = {10.1016/j.neubiorev.2011.12.006}, pages = {1085 -- 1092}, year = {2012}, abstract = {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.}, language = {en} } @article{LiWangChenetal.2012, author = {Li, Jian and Wang, Zi-Neng and Chen, You-Peng and Dong, Yun-Peng and Mao, Xiao-Min and Hocher, Berthold}, title = {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}, series = {Clinical laboratory : the peer reviewed journal for clinical laboratories and laboratories related to blood transfusion}, volume = {58}, journal = {Clinical laboratory : the peer reviewed journal for clinical laboratories and laboratories related to blood transfusion}, number = {9-10}, publisher = {Clin Lab Publ., Verl. Klinisches Labor}, address = {Heidelberg}, issn = {1433-6510}, doi = {10.7754/Clin.Lab.2012.110920}, pages = {1085 -- 1089}, year = {2012}, abstract = {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.}, language = {en} } @article{IkramFornageSmithetal.2012, author = {Ikram, M. Arfan and Fornage, Myriam and Smith, Albert V. and Seshadri, Sudha and Schmidt, Reinhold and Debette, Stephanie and Vrooman, Henri A. and Sigurdsson, Sigurdur and Ropele, Stefan and Taal, H. Rob and Mook-Kanamori, Dennis O. and Coker, Laura H. and Longstreth, W. T. and Niessen, Wiro J. and DeStefano, Anita L. and Beiser, Alexa and Zijdenbos, Alex P. and Struchalin, Maksim and Jack, Clifford R. and Rivadeneira, Fernando and Uitterlinden, Andre G. and Knopman, David S. and Hartikainen, Anna-Liisa and Pennell, Craig E. and Thiering, Elisabeth and Steegers, Eric A. P. and Hakonarson, Hakon and Heinrich, Joachim and Palmer, Lyle J. and Jarvelin, Marjo-Riitta and McCarthy, Mark I. and Grant, Struan F. A. and St Pourcain, Beate and Timpson, Nicholas J. and Smith, George Davey and Sovio, Ulla and Nalls, Mike A. and Au, Rhoda and Hofman, Albert and Gudnason, Haukur and van der Lugt, Aad and Harris, Tamara B. and Meeks, William M. and Vernooij, Meike W. and van Buchem, Mark A. and Catellier, Diane and Jaddoe, Vincent W. V. and Gudnason, Vilmundur and Windham, B. Gwen and Wolf, Philip A. and van Duijn, Cornelia M. and Mosley, Thomas H. and Schmidt, Helena and Launer, Lenore J. and Breteler, Monique M. B. and DeCarli, Charles and Adair, Linda S. and Ang, Wei and Atalay, Mustafa and vanBeijsterveldt, Toos and Bergen, Nienke and Benke, Kelly and Berry, Diane J. and Coin, Lachlan and Davis, Oliver S. P. and Elliott, Paul and Flexeder, Claudia and Frayling, Tim and Gaillard, Romy and Groen-Blokhuis, Maria and Goh, Liang-Kee and Haworth, Claire M. A. and Hadley, Dexter and Hebebrand, Johannes and Hinney, Anke and Hirschhorn, Joel N. and Holloway, John W. and Holst, Claus and Hottenga, Jouke Jan and Horikoshi, Momoko and Huikari, Ville and Hypponen, Elina and Kilpelainen, Tuomas O. and Kirin, Mirna and Kowgier, Matthew and Lakka, Hanna-Maaria and Lange, Leslie A. and Lawlor, Debbie A. and Lehtimaki, Terho and Lewin, Alex and Lindgren, Cecilia and Lindi, Virpi and Maggi, Reedik and Marsh, Julie and Middeldorp, Christel and Millwood, Iona and Murray, Jeffrey C. and Nivard, Michel and Nohr, Ellen Aagaard and Ntalla, Ioanna and Oken, Emily and Panoutsopoulou, Kalliope and Pararajasingham, Jennifer and Rodriguez, Alina and Salem, Rany M. and Sebert, Sylvain and Siitonen, Niina and Strachan, David P. and Teo, Yik-Ying and Valcarcel, Beatriz and Willemsen, Gonneke and Zeggini, Eleftheria and Boomsma, Dorret I. and Cooper, Cyrus and Gillman, Matthew and Hocher, Berthold and Lakka, Timo A. and Mohlke, Karen L. and Dedoussis, George V. and Ong, Ken K. and Pearson, Ewan R. and Price, Thomas S. and Power, Chris and Raitakari, Olli T. and Saw, Seang-Mei and Scherag, Andre and Simell, Olli and Sorensen, Thorkild I. A. and Wilson, James F.}, title = {Common variants at 6q22 and 17q21 are associated with intracranial volume}, series = {Nature genetics}, volume = {44}, journal = {Nature genetics}, number = {5}, publisher = {Nature Publ. Group}, address = {New York}, organization = {Early Growth Genetics EGG Consorti, Cohorts Heart Aging Res Genomic Ep}, issn = {1061-4036}, doi = {10.1038/ng.2245}, pages = {539 -- +}, year = {2012}, abstract = {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.}, language = {en} } @article{HocherGroenSchumannetal.2012, author = {Hocher, Berthold and Groen, Hans J{\"u}rgen and Schumann, Claudia and Tsuprykov, Oleg and Seifert, Susanne and Hitzler, Walter E. and Armbruster, Franz Paul}, title = {Vitamin D status from dried capillary blood samples}, series = {Clinical laboratory : the peer reviewed journal for clinical laboratories and laboratories related to blood transfusion}, volume = {58}, journal = {Clinical laboratory : the peer reviewed journal for clinical laboratories and laboratories related to blood transfusion}, number = {7-8}, publisher = {Clin Lab Publ., Verl. Klinisches Labor}, address = {Heidelberg}, issn = {1433-6510}, doi = {10.7754/Clin.Lab.2012.120429}, pages = {851 -- 855}, year = {2012}, abstract = {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.}, language = {en} } @article{HocherArmbrusterStoevaetal.2012, author = {Hocher, Berthold and Armbruster, Franz Paul and St{\"o}va, Stanka and Reichetzeder, Christoph and Groen, Hans J{\"u}rgen and Lieker, Ina and Khadzhynov, Dmytro and Slowinski, Torsten and Roth, Heinz J{\"u}rgen}, title = {Measuring Parathyroid Hormone (PTH) in patients with oxidative stress - do we need a fourth generation Parathyroid Hormone assay?}, series = {PLoS one}, volume = {7}, journal = {PLoS one}, number = {7}, publisher = {PLoS}, address = {San Fransisco}, issn = {1932-6203}, doi = {10.1371/journal.pone.0040242}, pages = {10}, year = {2012}, abstract = {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.}, language = {en} } @article{HenzeEspeWanneretal.2012, author = {Henze, Andrea and Espe, Katharina M. and Wanner, Christoph and Krane, Vera and Raila, Jens and Hocher, Berthold and Schweigert, Florian J. and Drechsler, Christiane}, title = {Transthyretin predicts cardiovascular outcome in hemodialysis patients with type 2 diabetes}, series = {Diabetes care}, volume = {35}, journal = {Diabetes care}, number = {11}, publisher = {American Diabetes Association}, address = {Alexandria}, issn = {0149-5992}, doi = {10.2337/dc12-0455}, pages = {2365 -- 2372}, year = {2012}, abstract = {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.}, language = {en} } @article{ChenXiaoLietal.2012, author = {Chen, You-Peng and Xiao, Xiao-Min and Li, Jian and Reichetzeder, Christoph and Wang, Zi-Neng and Hocher, Berthold}, title = {Paternal body mass index (BMI) is associated with offspring intrauterine growth in a gender dependent manner}, series = {PLoS one}, volume = {7}, journal = {PLoS one}, number = {5}, publisher = {PLoS}, address = {San Fransisco}, issn = {1932-6203}, doi = {10.1371/journal.pone.0036329}, pages = {9}, year = {2012}, abstract = {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.}, language = {en} } @article{ChenLiWangetal.2012, author = {Chen, You-Peng and Li, Jian and Wang, Zi-Neng and Reichetzeder, Christoph and Xu, Hao and Gong, Jian and Chen, Guang-Ji and Pfab, Thiemo and Xiao, Xiao-Min and Hocher, Berthold}, title = {Renin angiotensin aldosterone system and glycemia in pregnancy}, series = {Clinical laboratory : the peer reviewed journal for clinical laboratories and laboratories related to blood transfusion}, volume = {58}, journal = {Clinical laboratory : the peer reviewed journal for clinical laboratories and laboratories related to blood transfusion}, number = {5-6}, publisher = {Clin Lab Publ., Verl. Klinisches Labor}, address = {Heidelberg}, issn = {1433-6510}, pages = {527 -- 533}, year = {2012}, abstract = {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.}, language = {en} } @article{AlterOttvonWebskyetal.2012, author = {Alter, Markus L. and Ott, Ina M. and von Websky, Karoline and Tsuprykov, Oleg and Sharkovska, Yuliya and Krause-Relle, Katharina and Raila, Jens and Henze, Andrea and Klein, Thomas and Hocher, Berthold}, title = {DPP-4 Inhibition on top of angiotensin receptor blockade offers a new therapeutic approach for diabetic nephropathy}, series = {Kidney \& blood pressure research : official organ of the Gesellschaft f{\"u}r Nephrologie}, volume = {36}, journal = {Kidney \& blood pressure research : official organ of the Gesellschaft f{\"u}r Nephrologie}, number = {1}, publisher = {Karger}, address = {Basel}, issn = {1420-4096}, doi = {10.1159/000341487}, pages = {119 -- 130}, year = {2012}, abstract = {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.}, language = {en} } @article{AlterKretschmerVonWebskyetal.2012, author = {Alter, Markus L. and Kretschmer, Axel and Von Websky, Karoline and Tsuprykov, Oleg and Reichetzeder, Christoph and Simon, Alexandra and Stasch, Johannes-Peter and Hocher, Berthold}, title = {Early urinary and plasma biomarkers for experimental diabetic Nephropathy}, series = {Clinical laboratory : the peer reviewed journal for clinical laboratories and laboratories related to blood transfusion}, volume = {58}, journal = {Clinical laboratory : the peer reviewed journal for clinical laboratories and laboratories related to blood transfusion}, number = {7-8}, publisher = {Clin Lab Publ., Verl. Klinisches Labor}, address = {Heidelberg}, issn = {1433-6510}, doi = {10.7754/Clin.Lab.2011.111010}, pages = {659 -- 671}, year = {2012}, abstract = {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.}, language = {en} }