@inproceedings{HocherTsuprykovAlteretal.2013, author = {Hocher, Berthold and Tsuprykov, Oleg and Alter, Markus L. and von Websky, Karoline and Chaykovska, Lyubov and Antonenko, V. and Rahnenf{\"u}hrer, Jan and Klein, T. and Reichetzeder, Christoph}, title = {Linagliptin and the angiotensin II receptor blocker telmisartan show comparable efficacy but different renoprotective pathways in rats with 5/6 nephrectomy}, series = {Diabetologia : journal of the European Association for the Study of Diabetes (EASD)}, volume = {56}, booktitle = {Diabetologia : journal of the European Association for the Study of Diabetes (EASD)}, number = {15-16}, publisher = {Springer}, address = {New York}, issn = {0012-186X}, pages = {S66 -- S66}, year = {2013}, language = {en} } @article{ChaykovskaAltervonWebskyetal.2013, author = {Chaykovska, Lyubov and Alter, Markus L. and von Websky, Karoline and Hohmann, Margarete and Tsuprykov, Oleg and Reichetzeder, Christoph and Kutil, Barbara and Kraft, Robin and Klein, Thomas and Hocher, Berthold}, title = {Effects of telmisartan and linagliptin when used in combination on blood pressure and oxidative stress in rats with 2-kidney-1-clip hypertension}, series = {Journal of hypertension}, volume = {31}, journal = {Journal of hypertension}, number = {11}, publisher = {Lippincott Williams \& Wilkins}, address = {Philadelphia}, issn = {0263-6352}, doi = {10.1097/HJH.0b013e3283649b4d}, pages = {2290 -- 2299}, year = {2013}, abstract = {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.}, language = {en} } @article{TepelArmbrusterGroenetal.2013, author = {Tepel, Martin and Armbruster, Franz Paul and Groen, Hans Juergen and Scholze, Alexandra and Reichetzeder, Christoph and Roth, Heinz J{\"u}rgen and Hocher, Berthold}, title = {Nonoxidized, biologically active parathyroid hormone determines mortality in hemodialysis patients}, series = {The journal of clinical endocrinology \& metabolism}, volume = {98}, journal = {The journal of clinical endocrinology \& metabolism}, number = {12}, publisher = {Endocrine Society}, address = {Chevy Chase}, issn = {0021-972X}, doi = {10.1210/jc.2013-2139}, pages = {4744 -- 4751}, year = {2013}, abstract = {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.}, language = {en} } @inproceedings{HocherArmbrusterScholzeetal.2013, author = {Hocher, Berthold and Armbruster, Franz Paul and Scholze, Alexandra and Marckmann, Peter and Reichetzeder, Christoph and Roth, Heinz J{\"u}rgen and Tepel, Martin}, title = {Non-oxidized, biological active parathyroid hormone determines motality in hemodialsysis patients}, series = {Nephrology, dialysis, transplantation}, volume = {28}, booktitle = {Nephrology, dialysis, transplantation}, publisher = {Oxford Univ. Press}, address = {Oxford}, issn = {0931-0509}, pages = {33 -- 33}, year = {2013}, language = {en} } @article{PutraNeuberReichetzederetal.2014, author = {Putra, Sulistyo Emantoko Dwi and Neuber, Corinna and Reichetzeder, Christoph and Hocher, Berthold and Kleuser, Burkhard}, title = {Analysis of genomic DNA methylation levels in human placenta using liquid Chromatography-Electrospray ionization tandem mass spectrometry}, series = {Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry and pharmacology}, volume = {33}, journal = {Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry and pharmacology}, number = {4}, publisher = {Karger}, address = {Basel}, issn = {1015-8987}, doi = {10.1159/000358666}, pages = {945 -- 952}, year = {2014}, abstract = {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.}, language = {en} } @inproceedings{HocherReichetzedervonWebskyetal.2014, author = {Hocher, Berthold and Reichetzeder, Christoph and von Websky, Karoline and Tsuprykov, Oleg and Klein, T.}, title = {Dipeptidyl peptidase-4 inhibition in a rat model of ischaemia-reperfusion injury may accelerate tubular regeneration but does not improve glomerular filtration rate}, series = {Diabetologia : journal of the European Association for the Study of Diabetes (EASD)}, volume = {57}, booktitle = {Diabetologia : journal of the European Association for the Study of Diabetes (EASD)}, publisher = {Springer}, address = {New York}, issn = {0012-186X}, pages = {S538 -- S538}, year = {2014}, language = {en} } @inproceedings{ReichetzederPaschvonWebskyetal.2014, author = {Reichetzeder, Christoph and Pasch, A. and von Websky, Karoline and Tsuprykov, Oleg and Klein, T. and Hocher, Berthold}, title = {The DPP-4 inhibitor linagliptin increases plasma fetuin-A concentrations in a rat model of uraemic calcification}, series = {Diabetologia : journal of the European Association for the Study of Diabetes (EASD)}, volume = {57}, booktitle = {Diabetologia : journal of the European Association for the Study of Diabetes (EASD)}, publisher = {Springer}, address = {New York}, issn = {0012-186X}, pages = {S522 -- S522}, year = {2014}, language = {en} } @article{SharkovskaReichetzederAlteretal.2014, author = {Sharkovska, Yuliya and Reichetzeder, Christoph and Alter, Markus L. and Tsuprykov, Oleg and Bachmann, Sebastian and Secher, Thomas and Klein, Thomas and Hocher, Berthold}, title = {Blood pressure and glucose independent renoprotective effects of dipeptidyl peptidase-4 inhibition in a mouse model of type-2 diabetic nephropathy}, series = {Journal of hypertension}, volume = {32}, journal = {Journal of hypertension}, number = {11}, publisher = {Lippincott Williams \& Wilkins}, address = {Philadelphia}, issn = {0263-6352}, doi = {10.1097/HJH.0000000000000328}, pages = {2211 -- 2223}, year = {2014}, abstract = {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.}, language = {en} } @article{ReichetzederChenFoelleretal.2014, author = {Reichetzeder, Christoph and Chen, Hong and Foeller, Michael and Slowinski, Torsten and Li, Jian and Chen, You-Peng and Lang, Florian and Hocher, Berthold}, title = {Maternal vitamin D deficiency and fetal programming - lessons learned from humans and mice}, series = {Kidney \& blood pressure research : official organ of the Gesellschaft f{\"u}r Nephrologie}, volume = {39}, journal = {Kidney \& blood pressure research : official organ of the Gesellschaft f{\"u}r Nephrologie}, number = {4}, publisher = {Karger}, address = {Basel}, issn = {1420-4096}, doi = {10.1159/000355809}, pages = {315 -- 329}, year = {2014}, abstract = {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.}, language = {en} } @article{PutraTsuprykovVonWebskyetal.2014, author = {Putra, Sulistyo Emantoko Dwi and Tsuprykov, Oleg and Von Websky, Karoline and Ritter, Teresa and Reichetzeder, Christoph and Hocher, Berthold}, title = {Dealing with large sample sizes: comparison of a new one spot dot blot method to western blot}, series = {Clinical laboratory : the peer reviewed journal for clinical laboratories and laboratories related to blood transfusion}, volume = {60}, journal = {Clinical laboratory : the peer reviewed journal for clinical laboratories and laboratories related to blood transfusion}, number = {11}, publisher = {Clin Lab Publ., Verl. Klinisches Labor}, address = {Heidelberg}, issn = {1433-6510}, doi = {10.7754/Clin.Lab.2014.140317}, pages = {1871 -- 1877}, year = {2014}, abstract = {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.}, language = {en} }