@misc{HocherTsuprykov2017,
  author    = {Hocher, Berthold and Tsuprykov, Oleg},
  title     = {Renoprotective effects of GLP1R agonists and SGLT2 inhibitors},
  series = {Nature reviews nephroloy},
  volume    = {13},
  journal   = {Nature reviews nephroloy},
  publisher = {Nature Publ. Group},
  address   = {New York},
  issn      = {1759-5061},
  doi       = {10.1038/nrneph.2017.140},
  pages     = {728 -- 729},
  year      = {2017},
  abstract  = {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.},
  language  = {en}
}
@article{TsuprykovBuseSkobloetal.2018,
  author    = {Tsuprykov, Oleg and Buse, Claudia and Skoblo, Roman and Haq, Afrozul and Hocher, Berthold},
  title     = {Reference intervals for measured and calculated free 25-hydroxyvitamin D in normal pregnancy},
  series = {The Journal of Steroid Biochemistry and Molecular Biology},
  volume    = {181},
  journal   = {The Journal of Steroid Biochemistry and Molecular Biology},
  publisher = {Elsevier},
  address   = {Oxford},
  issn      = {0960-0760},
  doi       = {10.1016/j.jsbmb.2018.03.005},
  pages     = {80 -- 87},
  year      = {2018},
  abstract  = {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.},
  language  = {en}
}
@article{TsuprykovChenHocheretal.2018,
  author    = {Tsuprykov, Oleg and Chen, Xin and Hocher, Carl-Friedrich and Skoblo, Roman and Yin, Lianghong and Hocher, Berthold},
  title     = {Why should we measure free 25(OH) vitamin D?},
  series = {The Journal of Steroid Biochemistry and Molecular Biology},
  volume    = {180},
  journal   = {The Journal of Steroid Biochemistry and Molecular Biology},
  publisher = {Elsevier},
  address   = {Oxford},
  issn      = {0960-0760},
  doi       = {10.1016/j.jsbmb.2017.11.014},
  pages     = {87 -- 104},
  year      = {2018},
  abstract  = {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.},
  language  = {en}
}
@article{vonWebskyHasanReichetzederetal.2018,
  author    = {von Websky, Karoline and Hasan, Ahmed Abdallah Abdalrahman Mohamed and Reichetzeder, Christoph and Tsuprykov, Oleg and Hocher, Berthold},
  title     = {Impact of vitamin D on pregnancy-related disorders and on offspring outcome},
  series = {The Journal of Steroid Biochemistry and Molecular Biology},
  volume    = {180},
  journal   = {The Journal of Steroid Biochemistry and Molecular Biology},
  publisher = {Elsevier},
  address   = {Oxford},
  issn      = {0960-0760},
  doi       = {10.1016/j.jsbmb.2017.11.008},
  pages     = {51 -- 64},
  year      = {2018},
  abstract  = {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.},
  language  = {en}
}
@article{LiLuTsuprykovetal.2018,
  author    = {Li, Jian and Lu, Yong-Ping and Tsuprykov, Oleg and Hasan, Ahmed Abdallah Abdalrahman Mohamed and Reichetzeder, Christoph and Tian, Mei and Zhang, Xiao Li and Zhang, Qin and Sun, Guo-Ying and Guo, Jingli and Gaballa, Mohamed Mahmoud Salem Ahmed and Peng, Xiao-Ning and Lin, Ge and Hocher, Berthold},
  title     = {Folate treatment of pregnant rat dams abolishes metabolic effects in female offspring induced by a paternal pre-conception unhealthy diet},
  series = {Diabetologia : journal of the European Association for the Study of Diabetes (EASD)},
  volume    = {61},
  journal   = {Diabetologia : journal of the European Association for the Study of Diabetes (EASD)},
  number    = {8},
  publisher = {Springer},
  address   = {New York},
  issn      = {0012-186X},
  doi       = {10.1007/s00125-018-4635-x},
  pages     = {1862 -- 1876},
  year      = {2018},
  abstract  = {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.},
  language  = {en}
}
@article{HasanvonWebskyReichetzederetal.2019,
  author    = {Hasan, Ahmed Abdallah Abdalrahman Mohamed and von Websky, Karoline and Reichetzeder, Christoph and Tsuprykov, Oleg and Gaballa, Mohamed Mahmoud Salem Ahmed and Guo, Jingli and Zeng, Shufei and Delic, Denis and Tammen, Harald and Klein, Thomas and Kleuser, Burkhard and Hocher, Berthold},
  title     = {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},
  series = {Kidney international : official journal of the International Society of Nephrology},
  volume    = {95},
  journal   = {Kidney international : official journal of the International Society of Nephrology},
  number    = {6},
  publisher = {Elsevier},
  address   = {New York},
  issn      = {0085-2538},
  doi       = {10.1016/j.kint.2019.01.010},
  pages     = {1373 -- 1388},
  year      = {2019},
  abstract  = {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.},
  language  = {en}
}
@inproceedings{TsuprykovBuseSkobloetal.2017,
  author    = {Tsuprykov, Oleg and Buse, Claudia and Skoblo, Roman and Hocher, Berthold},
  title     = {Free 25 (OH) vitamin D, but not total 25 (OH) vitamin D, is strongly correlated with gestational age and calcium in normal human pregnancy},
  series = {Journal of bone and mineral research},
  volume    = {32},
  booktitle = {Journal of bone and mineral research},
  publisher = {Wiley},
  address   = {Hoboken},
  issn      = {0884-0431},
  pages     = {S323 -- S323},
  year      = {2017},
  language  = {en}
}
@article{ReichetzederHeunischvonEinemetal.2017,
  author    = {Reichetzeder, Christoph and Heunisch, Fabian and von Einem, Gina-Franziska and Tsuprykov, Oleg and Kellner, Karl-Heinz and Dschietzig, Thomas and Kretschmer, Axel and Hocher, Berthold},
  title     = {Pre-interventional kynurenine predicts medium-term outcome after contrast media exposure due to coronary angiography},
  series = {Kidney \& blood pressure research : official organ of the Gesellschaft f{\"u}r Nephrologie ; official organ of the Deutsche Liga zur Bek{\"a}mpfung des Hohen Blutdruckes e.V., Deutsche Hypertonie-Gesellschaft},
  volume    = {42},
  journal   = {Kidney \& blood pressure research : official organ of the Gesellschaft f{\"u}r Nephrologie ; official organ of the Deutsche Liga zur Bek{\"a}mpfung des Hohen Blutdruckes e.V., Deutsche Hypertonie-Gesellschaft},
  number    = {2},
  publisher = {Karger},
  address   = {Basel},
  issn      = {1420-4096},
  doi       = {10.1159/000477222},
  pages     = {244 -- 256},
  year      = {2017},
  abstract  = {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.},
  language  = {en}
}
@misc{AlterOttvonWebskyetal.2011,
  author    = {Alter, Markus L. and Ott, Ina and von Websky, Karoline and Tsuprykov, Oleg and Sharkovska, Yuliya and Krause-Relle, Katharina and Raila, Jens and Henze, Andrea and Kretschmer, Axel and Stasch, Johannes-Peter and Hocher, Berthold},
  title     = {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},
  series = {Postprints der Universit{\"a}t Potsdam : Mathematisch-Naturwissenschaftliche Reihe},
  journal   = {Postprints der Universit{\"a}t Potsdam : Mathematisch-Naturwissenschaftliche Reihe},
  number    = {855},
  issn      = {1866-8372},
  doi       = {10.25932/publishup-42825},
  url       = {http://nbn-resolving.de/urn:nbn:de:kobv:517-opus4-428250},
  pages     = {4},
  year      = {2011},
  abstract  = {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.},
  language  = {en}
}
@article{HocherHaumannRahnenfuehreretal.2016,
  author    = {Hocher, Berthold and Haumann, Hannah and Rahnenf{\"u}hrer, Jan and Reichetzeder, Christoph and Kalk, Philipp and Pfab, Thiemo and Tsuprykov, Oleg and Winter, Stefan and Hofmann, Ute and Li, Jian and P{\"u}schel, Gerhard Paul and Lang, Florian and Schuppan, Detlef and Schwab, Matthias and Schaeffeler, Elke},
  title     = {Maternal eNOS deficiency determines a fatty liver phenotype of the offspring in a sex dependent manner},
  series = {Epigenetics : the official journal of the DNA Methylation Society},
  volume    = {11},
  journal   = {Epigenetics : the official journal of the DNA Methylation Society},
  publisher = {Routledge, Taylor \& Francis Group},
  address   = {Philadelphia},
  issn      = {1559-2294},
  doi       = {10.1080/15592294.2016.1184800},
  pages     = {539 -- 552},
  year      = {2016},
  abstract  = {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.},
  language  = {en}
}
@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}
}
@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{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}
}
@misc{ReichetzederTsuprykovHocher2014,
  author    = {Reichetzeder, Christoph and Tsuprykov, Oleg and Hocher, Berthold},
  title     = {Endothelin receptor antagonists in clinical research - Lessons learned from preclinical and clinical kidney studies},
  series = {Life sciences : molecular, cellular and functional basis of therapy},
  volume    = {118},
  journal   = {Life sciences : molecular, cellular and functional basis of therapy},
  number    = {2},
  publisher = {Elsevier},
  address   = {Oxford},
  issn      = {0024-3205},
  doi       = {10.1016/j.lfs.2014.02.025},
  pages     = {141 -- 148},
  year      = {2014},
  abstract  = {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/).},
  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{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}
}
@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}
}
@inproceedings{ReichetzedervonWebskyTsuprykovetal.2015,
  author    = {Reichetzeder, Christoph and von Websky, Karoline and Tsuprykov, Oleg and Antonenko, V. and Samarin, Azin Mohagheghi and Hocher, Berthold},
  title     = {Effects of DPP-4 inhibition on glomerular and tubular function in a rat model of ischaemia-reperfusion injury},
  series = {Diabetologia : journal of the European Association for the Study of Diabetes (EASD)},
  volume    = {58},
  booktitle = {Diabetologia : journal of the European Association for the Study of Diabetes (EASD)},
  publisher = {Springer},
  address   = {New York},
  issn      = {0012-186X},
  pages     = {S34 -- S35},
  year      = {2015},
  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}
}
@misc{ChaykovskaTsuprykovHocher2011,
  author    = {Chaykovska, Lyubov and Tsuprykov, Oleg and Hocher, Berthold},
  title     = {Biomarkers for the prediction of mortality and morbidity in patients with renal replacement therapy},
  series = {Clinical laboratory : the peer reviewed journal for clinical laboratories and laboratories related to blood transfusion},
  volume    = {57},
  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},
  pages     = {455 -- 467},
  year      = {2011},
  abstract  = {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.},
  language  = {en}
}
@inproceedings{SharkovskaAlterReichetzederetal.2012,
  author    = {Sharkovska, Y. and Alter, Markus L. and Reichetzeder, Christoph and Tsuprykov, Oleg and Klein, T. and Hocher, Berthold},
  title     = {DPP-4 inhibition with linagliptin delays the progression of diabetic nephropathy in db/db mice},
  series = {Diabetologia : journal of the European Association for the Study of Diabetes (EASD)},
  volume    = {55},
  booktitle = {Diabetologia : journal of the European Association for the Study of Diabetes (EASD)},
  number    = {5},
  publisher = {Springer},
  address   = {New York},
  issn      = {0012-186X},
  pages     = {S20 -- S20},
  year      = {2012},
  language  = {en}
}
@misc{ChaykovskaHeunischvonEinemetal.2016,
  author    = {Chaykovska, Lyubov and Heunisch, Fabian and von Einem, Gina and Alter, Markus L. and Hocher, Carl-Friedrich and Tsuprykov, Oleg and Dschietzig, Thomas and Kretschmer, Axel and Hocher, Berthold},
  title     = {Urinary vitamin D binding protein and KIM-1 are potent new biomarkers of major adverse renal events in patients undergoing coronary angiography},
  series = {Postprints der Universit{\"a}t Potsdam : Mathematisch-Naturwissenschaftliche Reihe},
  journal   = {Postprints der Universit{\"a}t Potsdam : Mathematisch-Naturwissenschaftliche Reihe},
  number    = {558},
  issn      = {1866-8372},
  doi       = {10.25932/publishup-41192},
  url       = {http://nbn-resolving.de/urn:nbn:de:kobv:517-opus4-411928},
  pages     = {11},
  year      = {2016},
  abstract  = {Background Vitamin-D-binding protein (VDBP) is a low molecular weight protein that is filtered through the glomerulus as a 25-(OH) vitamin D 3/VDBP complex. In the normal kidney VDBP is reabsorbed and catabolized by proximal tubule epithelial cells reducing the urinary excretion to trace amounts. Acute tubular injury is expected to result in urinary VDBP loss. The purpose of our study was to explore the potential role of urinary VDBP as a biomarker of an acute renal damage. Method We included 314 patients with diabetes mellitus or mild renal impairment undergoing coronary angiography and collected blood and urine before and 24 hours after the CM application. Patients were followed for 90 days for the composite endpoint major adverse renal events (MARE: need for dialysis, doubling of serum creatinine after 90 days, unplanned emergency rehospitalization or death). Results Increased urine VDBP concentration 24 hours after contrast media exposure was predictive for dialysis need (no dialysis: 113.06 +/- 299.61ng/ml, n = 303; need for dialysis: 613.07 +/- 700.45 ng/ml, n = 11, Mean +/- SD, p < 0.001), death (no death during follow-up: 121.41 +/- 324.45 ng/ml, n = 306; death during follow-up: 522.01 +/- 521.86 ng/ml, n = 8; Mean +/- SD, p < 0.003) and MARE (no MARE: 112.08 +/- 302.00ng/ml, n = 298; MARE: 506.16 +/- 624.61 ng/ml, n = 16, Mean +/- SD, p < 0.001) during the follow-up of 90 days after contrast media exposure. Correction of urine VDBP concentrations for creatinine excretion confirmed its predictive value and was consistent with increased levels of urinary Kidney Injury Molecule1 (KIM-1) and baseline plasma creatinine in patients with above mentioned complications. The impact of urinary VDBP and KIM-1 on MARE was independent of known CIN risk factors such as anemia, preexisting renal failure, preexisting heart failure, and diabetes. Conclusions Urinary VDBP is a promising novel biomarker of major contrast induced nephropathy-associated events 90 days after contrast media exposure.},
  language  = {en}
}
@misc{LiTsuprykovYangetal.2016,
  author    = {Li, Jian and Tsuprykov, Oleg and Yang, Xiaoping and Hocher, Berthold},
  title     = {Paternal programming of offspring cardiometabolic diseases in later life},
  series = {Journal of hypertension},
  volume    = {34},
  journal   = {Journal of hypertension},
  publisher = {Wiley-Blackwell},
  address   = {Philadelphia},
  issn      = {0263-6352},
  doi       = {10.1097/HJH.0000000000001051},
  pages     = {2111 -- 2126},
  year      = {2016},
  language  = {en}
}
@article{TsuprykovAndoReichetzederetal.2016,
  author    = {Tsuprykov, Oleg and Ando, Ryotaro and Reichetzeder, Christoph and von Websky, Karoline and Antonenko, Viktoriia and Sharkovska, Yuliya and Chaykovska, Lyubov and Rahnenfuehrer, Jan and Hasan, Ahmed Abdallah Abdalrahman Mohamed and Tammen, Harald and Alter, Markus L. and Klein, Thomas and Ueda, Seiji and Yamagishi, Sho-ichi and Okuda, Seiya and Hocher, Berthold},
  title     = {The dipeptidyl peptidase inhibitor linagliptin and the angiotensin II receptor blocker telmisartan show renal benefit by different pathways in rats with 5/6 nephrectomy},
  series = {Kidney international : official journal of the International Society of Nephrology},
  volume    = {89},
  journal   = {Kidney international : official journal of the International Society of Nephrology},
  publisher = {Nature Publ. Group},
  address   = {New York},
  issn      = {0085-2538},
  doi       = {10.1016/j.kint.2016.01.016},
  pages     = {1049 -- 1061},
  year      = {2016},
  abstract  = {Dipeptidyl peptidase (DPP)-4 inhibitors delay chronic kidney disease (CKD) progression in experimental diabetic nephropathy in a glucose-independent manner. Here we compared the effects of the DPP-4 inhibitor linagliptin versus telmisartan in preventing CKD progression in non-diabetic rats with 5/6 nephrectomy. Animals were allocated to 1 of 4 groups: sham operated plus placebo; 5/6 nephrectomy plus placebo; 5/6 nephrectomy plus linagliptin; and 5/6 nephrectomy plus telmisartan. Interstitial fibrosis was significantly decreased by 48\% with linagliptin but a non-significant 24\% with telmisartan versus placebo. The urine albumin-to-creatinine ratio was significantly decreased by 66\% with linagliptin and 92\% with telmisartan versus placebo. Blood pressure was significantly lowered by telmisartan, but it was not affected by linagliptin. As shown by mass spectrometry, the number of altered peptide signals for linagliptin in plasma was 552 and 320 in the kidney. For telmisartan, there were 108 peptide changes in plasma and 363 in the kidney versus placebo. Linagliptin up-regulated peptides derived from collagen type I, apolipoprotein C1, and heterogeneous nuclear ribonucleoproteins A2/B1, a potential downstream target of atrial natriuretic peptide, whereas telmisartan up-regulated angiotensin II. A second study was conducted to confirm these findings in 5/6 nephrectomy wild-type and genetically deficient DPP-4 rats treated with linagliptin or placebo. Linagliptin therapy in wild-type rats was as effective as DPP-4 genetic deficiency in terms of albuminuria reduction. Thus, linagliptin showed comparable efficacy to telmisartan in preventing CKD progression in non-diabetic rats with 5/6 nephrectomy. However, the underlying pathways seem to be different. Copyright (C) 2016, International Society of Nephrology. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).},
  language  = {en}
}
@article{ChaykovskaHeunischvonEinemetal.2016,
  author    = {Chaykovska, Lyubov and Heunisch, Fabian and von Einem, Gina and Alter, Markus L. and Hocher, Carl-Friedrich and Tsuprykov, Oleg and Dschietzig, Thomas and Kretschmer, Axel and Hocher, Berthold},
  title     = {Urinary Vitamin D Binding Protein and KIM-1 Are Potent New Biomarkers of Major Adverse Renal Events in Patients Undergoing Coronary Angiography},
  series = {PLoS one},
  volume    = {11},
  journal   = {PLoS one},
  publisher = {PLoS},
  address   = {San Fransisco},
  issn      = {1932-6203},
  doi       = {10.1371/journal.pone.0145723},
  pages     = {11},
  year      = {2016},
  abstract  = {Background Vitamin-D-binding protein (VDBP) is a low molecular weight protein that is filtered through the glomerulus as a 25-(OH) vitamin D 3/VDBP complex. In the normal kidney VDBP is reabsorbed and catabolized by proximal tubule epithelial cells reducing the urinary excretion to trace amounts. Acute tubular injury is expected to result in urinary VDBP loss. The purpose of our study was to explore the potential role of urinary VDBP as a biomarker of an acute renal damage. Method We included 314 patients with diabetes mellitus or mild renal impairment undergoing coronary angiography and collected blood and urine before and 24 hours after the CM application. Patients were followed for 90 days for the composite endpoint major adverse renal events (MARE: need for dialysis, doubling of serum creatinine after 90 days, unplanned emergency rehospitalization or death). Results Increased urine VDBP concentration 24 hours after contrast media exposure was predictive for dialysis need (no dialysis: 113.06 +/- 299.61ng/ml, n = 303; need for dialysis: 613.07 +/- 700.45 ng/ml, n = 11, Mean +/- SD, p < 0.001), death (no death during follow-up: 121.41 +/- 324.45 ng/ml, n = 306; death during follow-up: 522.01 +/- 521.86 ng/ml, n = 8; Mean +/- SD, p < 0.003) and MARE (no MARE: 112.08 +/- 302.00ng/ml, n = 298; MARE: 506.16 +/- 624.61 ng/ml, n = 16, Mean +/- SD, p < 0.001) during the follow-up of 90 days after contrast media exposure. Correction of urine VDBP concentrations for creatinine excretion confirmed its predictive value and was consistent with increased levels of urinary Kidney Injury Molecule1 (KIM-1) and baseline plasma creatinine in patients with above mentioned complications. The impact of urinary VDBP and KIM-1 on MARE was independent of known CIN risk factors such as anemia, preexisting renal failure, preexisting heart failure, and diabetes. Conclusions Urinary VDBP is a promising novel biomarker of major contrast induced nephropathy-associated events 90 days after contrast media exposure.},
  language  = {en}
}
@article{LuTsuprykovVignonZellwegeretal.2016,
  author    = {Lu, Yong Ping and Tsuprykov, Oleg and Vignon-Zellweger, Nicolas and Heiden, Susi and Hocher, Berthold},
  title     = {Global Overexpression of ET-1 Decreases Blood Pressure - A Systematic Review and Meta-Analysis of ET-1 Transgenic Mice},
  series = {Naunyn-Schmiedeberg's archives of pharmacology},
  volume    = {41},
  journal   = {Naunyn-Schmiedeberg's archives of pharmacology},
  publisher = {Karger},
  address   = {Basel},
  issn      = {1420-4096},
  doi       = {10.1159/000450567},
  pages     = {770 -- 780},
  year      = {2016},
  abstract  = {Background/Aims: ET-1 has independent effects on blood pressure regulation in vivo, it is involved in tubular water and salt excretion, promotes constriction of smooth muscle cells, modulates sympathetic nerve activity, and activates the liberation of nitric oxide. To determine the net effect of these partially counteracting mechanisms on blood pressure, a systematic meta-analysis was performed. Methods: Based on the principles of Cochrane systematic reviews, we searched in major literature databases - MEDLINE (PubMed), Embase, Google Scholar, and the China Biological Medicine Database (CBM-disc) - for articles relevant to the topic of the blood pressure phenotype of endothelin-1 transgenic (ET-1+/+) mice from January 1, 1988 to March 31, 2016. Review Manager Version 5.0 (Rev-Man 5.0) software was applied for statistical analysis. In total thirteen studies reported blood pressure data. Results: The meta-analysis of blood pressure data showed that homozygous ET-1 transgenic mice (ET-1+/+ mice) had a significantly lower blood pressure as compared to WT mice (mean difference:-2.57 mmHg, 95\% CI: -4.98 similar to -0.16, P = 0.04), with minimal heterogeneity (P = 0.86). A subgroup analysis of mice older than 6 months revealed that the blood pressure difference between ET-1+/+ mice and WT mice was even more pronounced (mean difference: -6.19 mmHg, 95\% CI: -10.76 similar to -1.62, P = 0.008), with minimal heterogeneity (P = 0.91). Conclusion: This meta-analysis provides robust evidence that global ET-1 overexpression in mice lowers blood pressure in an age-dependent manner. Older ET-1+/+ mice have a somewhat more pronounced reduction of blood pressure. (C) 2016 The Author(s) Published by S. Karger AG, Basel},
  language  = {en}
}
@article{TsuprykovChaykovskaKretschmeretal.2015,
  author    = {Tsuprykov, Oleg and Chaykovska, Lyubov and Kretschmer, Axel and Stasch, Johannes-Peter and Pfab, Thiemo and Krause-Relle, Katharina and Reichetzeder, Christoph and Kalk, Philipp and Adamski, Jerzy and Hocher, Berthold},
  title     = {Endothelin-1 overexpression improves renal function in eNOS knockout mice},
  series = {Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry and pharmacology},
  volume    = {37},
  journal   = {Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry and pharmacology},
  number    = {4},
  publisher = {Karger},
  address   = {Basel},
  issn      = {1015-8987},
  doi       = {10.1159/000438516},
  pages     = {1474 -- 1490},
  year      = {2015},
  abstract  = {Background/Aims: To investigate the renal phenotype under conditions of an activated renal ET-1 system in the status of nitric oxide deficiency, we compared kidney function and morphology in wild-type, ET-1 transgenic (ET+/+), endothelial nitric oxide synthase knockout (eNOS-/-) and ET+/+eNOS-/- mice. Methods: We assessed blood pressure, parameters of renal morphology, plasma cystatin C, urinary protein excretion, expression of genes associated with glomerular filtration barrier and tissue remodeling, and plasma metabolites using metabolomics. Results: eNOS-/- and ET+/+eNOS-/- mice developed hypertension. Osteopontin, albumin and protein excretion were increased in eNOS-/- and restored in ET+/+eNOS-/- animals. All genetically modified mice developed renal interstitial fibrosis and glomerulosclerosis. Genes involved in tissue remodeling (serpinel, TIMP1, Collal, CCL2) were up-regulated in eNOS-/-, but not in ET+/+eNOS-/- mice. Plasma levels of free carnitine and acylcarnitines, amino acids, diacyl phosphatidylcholines, lysophosphatidylcholines and hexoses were descreased in eNOS-/- and were in the normal range in ET+/+eNOS-/- mice. Conclusion: eNOS-/- mice developed renal dysfunction, which was partially rescued by ET-1 overexpression in eNOS-/- mice. The metabolomics results suggest that ET-1 overexpression on top of eNOS knockout is associated with a functional recovery of mitochondria (rescue effect in 13-oxidation of fatty acids) and an increase in antioxidative properties (normalization of monounsaturated fatty acids levels). (C) 2015 The Author(s) Published by S. Karger AG, Basel},
  language  = {en}
}
@article{ReichetzedervonWebskyTsuprykovetal.2017,
  author    = {Reichetzeder, Christoph and von Websky, Karoline and Tsuprykov, Oleg and Samarin, Azadeh Mohagheghi and Falke, Luise Gabriele and Putra, Sulistyo Emantoko Dwi and Hasan, Ahmed Abdallah Abdalrahman Mohamed and Antonenko, Viktoriia and Curato, Caterina and Rippmann, Joerg and Klein, Thomas and Hocher, Berthold},
  title     = {Head-to-head comparison of structurally unrelated dipeptidyl peptidase 4 inhibitors in the setting of renal ischemia reperfusion injury},
  series = {British journal of pharmacology : journal of The British Pharmacological Society},
  volume    = {174},
  journal   = {British journal of pharmacology : journal of The British Pharmacological Society},
  publisher = {Wiley},
  address   = {Hoboken},
  issn      = {0007-1188},
  doi       = {10.1111/bph.13822},
  pages     = {2273 -- 2286},
  year      = {2017},
  abstract  = {BACKGROUND AND PURPOSE Results regarding protective effects of dipeptidyl peptidase 4 (DPP4) inhibitors in renal ischaemia-reperfusion injury (IRI) are conflicting. Here we have compared structurally unrelated DPP4 inhibitors in a model of renal IRI. EXPERIMENTAL APPROACH IRI was induced in uninephrectomizedmale rats by renal artery clamping for 30 min. The shamgroup was uninephrectomized but not subjected to IRI. DPP4 inhibitors or vehicle were given p. o. once daily on three consecutive days prior to IRI: linagliptin (1.5 mg.kg(-1).day(-1)), vildagliptin (8mg.kg(-1).day(-1)) and sitagliptin (30 mg.kg(-1).day(-1)). An additional group received sitagliptin until study end (before IRI: 30 mg.kg(-1).day(-1); after IRI: 15mg.kg(-1).day(-1)). KEY RESULTS Plasma-active glucagon-like peptide type 1 (GLP(-1)) increased threefold to fourfold in all DPP4 inhibitor groups 24 h after IRI. Plasma cystatin C, a marker of GFR, peaked 48 h after IRI. Compared with the placebo group, DPP4 inhibition did not reduce increased plasma cystatin C levels. DPP4 inhibitors ameliorated histopathologically assessed tubular damage with varying degrees of drug-specific efficacies. Renal osteopontin expression was uniformly reduced by all DPP4 inhibitors. IRI-related increased renal cytokine expression was not decreased by DPP4 inhibition. Renal DPP4 activity at study end was significantly inhibited in the linagliptin group, but only numerically reduced in the prolonged/dose-adjusted sitagliptin group. Active GLP(-1) plasma levels at study end were increased only in the prolonged/dose-adjusted sitagliptin treatment group. CONCLUSIONS AND IMPLICATIONS In rats with renal IRI, DPP4 inhibition did not alter plasma cystatin C, a marker of glomerular function, but may protect against tubular damage.},
  language  = {en}
}
@article{ChaykovskaHeunischvonEinemetal.2018,
  author    = {Chaykovska, Lyubov and Heunisch, Fabian and von Einem, Gina and Hocher, Carl-Friedrich and Tsuprykov, Oleg and Pavkovic, Mira and Sandner, Peter and Kretschmer, Axel and Chu, Chang and Elitok, Saban and Stasch, Johannes-Peter and Hocher, Berthold},
  title     = {Urinary cGMP predicts major adverse renal events in patients with mild renal impairment and/or diabetes mellitus before exposure to contrast medium},
  series = {PLoS one},
  volume    = {13},
  journal   = {PLoS one},
  number    = {4},
  publisher = {PLoS},
  address   = {San Fransisco},
  issn      = {1932-6203},
  doi       = {10.1371/journal.pone.0195828},
  pages     = {13},
  year      = {2018},
  abstract  = {Background The use of iodine-based contrast agents entails the risk of contrast induced nephropathy (CIN). Radiocontrast agents elicit the third most common cause of nephropathy among hospitalized patients, accounting for 11-12\% of cases. CIN is connected with clinically significant consequences, including increased morbidity, prolonged hospitalization, increased risk of complications, potential need for dialysis, and increased mortality rate. The number of in hospital examinations using iodine-based contrast media has been significantly increasing over the last decade. In order to protect patients from possible complications of such examinations, new biomarkers are needed that are able to predict a risk of contrast-induced nephropathy. Urinary and plasma cyclic guanosine monophosphate (cGMP) concentrations are influenced by renal function. Urinary cGMP is primarily of renal cellular origin. Therefore, we assessed if urinary cGMP concentration may predict major adverse renal events (MARE) after contrast media exposure during coronary angiography. Methods Urine samples were prospectively collected from non-randomized consecutive patients with either diabetes or preexisting impaired kidney function receiving intra-arterial contrast medium (CM) for emergent or elective coronary angiography at the Charite Campus Mitte, University Hospital Berlin. Urinary cGMP concentration in spot urine was analyzed 24 hours after CM exposure. Patients were followed up over 90 days for occurrence of death, initiation of dialysis, doubling of plasma creatinine concentration or MARE. Results In total, 289 consecutive patients were included into the study. Urine cGMP/creatinine ratio 24 hours before CM exposure expressed as mean +/- SD was predictive for the need of dialysis (no dialysis: 89.77 +/- 92.85 mu M/mM, n = 277; need for dialysis: 140.3 +/- 82.90 mu M/mM, n = 12, p = 0.008), death (no death during follow-up: 90.60 +/- 92.50 mu M/mM, n = 280; death during follow-up: 169.88 +/- 81.52 mu M/mM, n = 9; p = 0.002), and the composite endpoint MARE (no MARE: 86.02 +/- 93.17 mu M/mM, n = 271; MARE: 146.64 +/- 74.68 mu M/mM, n = 18, p<0.001) during the follow-up of 90 days after contrast media application. cGMP/creatinine ratio stayed significantly increased at values exceeding 120 pM/mM in patients who developed MARE, required dialysis or died. Conclusions Urinary cGMP/creatinine ratio >= 120 mu M/mM before CM exposure is a promising biomarker for the need of dialysis and all-cause mortality 90 days after CM exposure in patients with preexisting renal impairment or diabetes.},
  language  = {en}
}