TY - JOUR A1 - von Websky, Karoline A1 - Reichetzeder, Christoph A1 - Hocher, Berthold T1 - Physiology and pathophysiology of incretins in the kidney JF - Current opinion in nephrology and hypertension : reviews of all advances, evaluations of key references, comprehensive listing of papers N2 - Purpose of reviewIncretin-based therapy with glucagon-like peptide-1 receptor (GLP-1R) agonists and dipeptidyl peptidase-4 (DPP-4) inhibitors is considered a promising therapeutic option for type 2 diabetes mellitus. Cumulative evidence, mainly from preclinical animal studies, reveals that incretin-based therapies also may elicit beneficial effects on kidney function. This review gives an overview of the physiology, pathophysiology, and pharmacology of the renal incretin system.Recent findingsActivation of GLP-1R in the kidney leads to diuretic and natriuretic effects, possibly through direct actions on renal tubular cells and sodium transporters. Moreover, there is evidence that incretin-based therapy reduces albuminuria, glomerulosclerosis, oxidative stress, and fibrosis in the kidney, partially through GLP-1R-independent pathways. Molecular mechanisms by which incretins exert their renal effects are understood incompletely, thus further studies are needed.SummaryThe GLP-1R and DPP-4 are expressed in the kidney in various species. The kidney plays an important role in the excretion of incretin metabolites and most GLP-1R agonists and DPP-4 inhibitors, thus special attention is required when applying incretin-based therapy in renal impairment. Preclinical observations suggest direct renoprotective effects of incretin-based therapies in the setting of hypertension and other disorders of sodium retention, as well as in diabetic and nondiabetic nephropathy. Clinical studies are needed in order to confirm translational relevance from preclinical findings for treatment options of renal diseases. KW - DDP-4 inhibition KW - diabetes KW - diabetic nephropathy KW - GLP-1 receptor KW - hypertension KW - incretins KW - kidney KW - renal impairment Y1 - 2014 U6 - https://doi.org/10.1097/01.mnh.0000437542.77175.a0 SN - 1062-4821 SN - 1473-6543 VL - 23 IS - 1 SP - 54 EP - 60 PB - Lippincott Williams & Wilkins CY - Philadelphia ER - TY - JOUR A1 - Chung, Oliver A1 - Vongpatanasin, Wanpen A1 - Bonaventura, Klaus A1 - Lotan, Yair A1 - Sohns, Christian A1 - Haverkamp, Wilhelm A1 - Dorenkamp, Marc T1 - Potential cost-effectiveness of therapeutic drug monitoring in patients with resistant hypertension JF - Journal of hypertension N2 - Background: Nonadherence to drug therapy poses a significant problem in the treatment of patients with presumed resistant hypertension. It has been shown that therapeutic drug monitoring (TDM) is a useful tool for detecting nonadherence and identifying barriers to treatment adherence, leading to effective blood pressure (BP) control. However, the cost-effectiveness of TDM in the management of resistant hypertension has not been investigated. Results: In the age group of 60-year olds, TDM gained 1.07 QALYs in men and 0.97 QALYs in women at additional costs of (sic)3854 and (sic)3922, respectively. Given a willingness-to-pay threshold of (sic)35 000 per QALY gained, the probability of TDM being cost-effective was 95% or more in all age groups from 30 to 90 years. Results were influenced mostly by the frequency of TDM testing, the rate of nonresponders to TDM, and the magnitude of effect of TDM on BP. Conclusion: Therapeutic drug monitoring presents a potential cost-effective healthcare intervention in patients diagnosed with resistant hypertension. Importantly, this finding is valid for a wide range of patients, independent of sex and age. KW - cardiovascular diseases KW - cost and cost analysis KW - cost-benefit analysis KW - drug monitoring KW - hypertension KW - medication adherence KW - probability KW - risk assessment Y1 - 2014 U6 - https://doi.org/10.1097/HJH.0000000000000346 SN - 0263-6352 SN - 1473-5598 VL - 32 IS - 12 SP - 2411 EP - 2421 PB - Lippincott Williams & Wilkins CY - Philadelphia ER - TY - JOUR A1 - Danquah, Ina A1 - Dobrucky, C. Lydia A1 - Frank, Laura K. A1 - Henze, Andrea A1 - Amoako, Yaw A. A1 - Bedu-Addo, George A1 - Raila, Jens A1 - Schulze, Matthias Bernd A1 - Mockenhaupt, Frank P. A1 - Schweigert, Florian J. T1 - Vitamin A: potential misclassification of vitamin A status among patients with type 2 diabetes and hypertension in urban Ghana JF - The American journal of clinical nutrition : a publication of the American Society for Nutrition, Inc. N2 - Background: Sub-Saharan Africa is facing a double burden of malnutrition: vitamin A deficiency (VAD) prevails, whereas the nutrition-related chronic conditions type 2 diabetes (T2D) and hypertension are emerging. Serum retinol a VAD marker increases in kidney disease and decreases in inflammation, which can partly be attributed to alterations in the vitamin A transport proteins retinol-binding protein 4 (RBP4) and prealbumin. Kidney dysfunction and inflammation commonly accompany T2D and hypertension. Objective: Among urban Ghanaians, we investigated the associations of T2D and hypertension with serum retinol as well as the importance of kidney function and inflammation in this regard. Design: A hospital-based, case-control study in individuals for risk factors of T2D, hypertension, or both was conducted in Kumasi, Ghana (328 controls, 197 with T2D, 354 with hypertension, and 340 with T2D plus hypertension). In 1219 blood samples, serum retinol, RBP4, and prealbumin were measured. Urinary albumin and estimated glomerular filtration rate (eGFR) defined kidney function. C-reactive protein (CRP) >5 mg/L indicated inflammation. We identified associations of T2D and hypertension with retinol by linear regression and calculated the contribution of RBP4, prealbumin, urinary albumin, eGFR, and CRP to these associations as the percentages of the explained variance of retinol. Results: VAD (retinol <1.05 mu mol/L) was present in 10% of this predominantly female, middle-aged, overweight, and deprived population. Hypertension, but not T2D, was positively associated with retinol (beta: 0.12; 95% CI: 0.08, 0,17), adjusted for age, sex, socioeconomic factors, anthropometric measurements, and lifestyle. In addition to RBP4 (72%) and prealbumin (22%), the effect of increased retinol on individuals with hypertension was mainly attributed to impaired kidney function (eGFR: 30%; urinary albumin: 5%) but not to inflammation. Conclusions: In patients with hypertension, VAD might be underestimated because of increased serum retinol in the context of kidney dysfunction. Thus, the interpretation of serum retinol in sub-Saharan Africa should account for hypertension status. KW - hypertension KW - inflammation KW - kidney dysfunction KW - type 2 diabetes KW - vitamin A deficiency Y1 - 2015 U6 - https://doi.org/10.3945/ajcn.114.101345 SN - 0002-9165 SN - 1938-3207 VL - 102 IS - 1 SP - 207 EP - 214 PB - American Society for Nutrition, Inc. CY - Bethesda ER - TY - JOUR A1 - Huber, Matthias A1 - Lezius, Susanne A1 - Reibis, Rona Katharina A1 - Treszl, Andras A1 - Kujawinska, Dorota A1 - Jakob, Stefanie A1 - Wegscheider, Karl A1 - Völler, Heinz A1 - Kreutz, Reinhold T1 - A Single Nucleotide Polymorphism near the CYP17A1 Gene Is Associated with Left Ventricular Mass in Hypertensive Patients under Pharmacotherapy JF - International journal of molecular sciences N2 - Cytochrome P450 17A1 (CYP17A1) catalyses the formation and metabolism of steroid hormones. They are involved in blood pressure (BP) regulation and in the pathogenesis of left ventricular hypertrophy. Therefore, altered function of CYP17A1 due to genetic variants may influence BP and left ventricular mass. Notably, genome wide association studies supported the role of this enzyme in BP control. Against this background, we investigated associations between single nucleotide polymorphisms (SNPs) in or nearby the CYP17A1 gene with BP and left ventricular mass in patients with arterial hypertension and associated cardiovascular organ damage treated according to guidelines. Patients (n = 1007, mean age 58.0 +/- 9.8 years, 83% men) with arterial hypertension and cardiac left ventricular ejection fraction (LVEF) 40% were enrolled in the study. Cardiac parameters of left ventricular mass, geometry and function were determined by echocardiography. The cohort comprised patients with coronary heart disease (n = 823; 81.7%) and myocardial infarction (n = 545; 54.1%) with a mean LVEF of 59.9% +/- 9.3%. The mean left ventricular mass index (LVMI) was 52.1 +/- 21.2 g/m(2.7) and 485 (48.2%) patients had left ventricular hypertrophy. There was no significant association of any investigated SNP (rs619824, rs743572, rs1004467, rs11191548, rs17115100) with mean 24 h systolic or diastolic BP. However, carriers of the rs11191548 C allele demonstrated a 7% increase in LVMI (95% CI: 1%-12%, p = 0.017) compared to non-carriers. The CYP17A1 polymorphism rs11191548 demonstrated a significant association with LVMI in patients with arterial hypertension and preserved LVEF. Thus, CYP17A1 may contribute to cardiac hypertrophy in this clinical condition. KW - clinical study KW - genetics KW - heart KW - hypertension KW - cytochrome P450 17A1 (Cyp17A1) Y1 - 2015 U6 - https://doi.org/10.3390/ijms160817456 SN - 1422-0067 VL - 16 IS - 8 SP - 17456 EP - 17468 PB - MDPI CY - Basel ER - TY - JOUR A1 - Algharably, Engi A. H. A1 - Bolbrinker, Juliane A1 - Lezius, Susanne A1 - Reibis, Rona Katharina A1 - Wegscheider, Karl A1 - Völler, Heinz A1 - Kreutz, Reinhold T1 - Uromodulin associates with cardiorenal function in patients with hypertension and cardiovascular disease JF - Journal of hypertension N2 - Objective:Common genetic variants in the gene encoding uromodulin (UMOD) have been associated with renal function, blood pressure (BP) and hypertension. We investigated the associations between an important single nucleotide polymorphism (SNP) in UMOD, that is rs12917707-G>T, and estimated glomerular filtration rate (eGFR), BP and cardiac organ damage as determined by echocardiography in patients with arterial hypertension.Methods:A cohort of 1218 treated high-risk patients (mean age 58.5 years, 83% men) with documented cardiovascular disease (81% with coronary heart disease) was analysed.Results:The mean values for 24-h SBP and DBP were 124.714.7 and 73.9 +/- 9.4mmHg; mean eGFR was 77.5 +/- 18.3ml/min per 1.73m(2), mean left ventricular ejection fraction was 59.3 +/- 9.9% and mean left ventricular mass index in men and women was 53.9 +/- 23.2 and 54.9 +/- 23.7g/m(2.7) with 50.4% of patients having left ventricular hypertrophy. A significant association between rs12917707 and eGFR was observed with T-allele carriers showing significantly higher eGFR values (+2.6ml/min per 1.73m(2), P=0.006) than noncarriers. This SNP associated also with left atrial diameter (P=0.007); homozygous carriers of the T-allele had smaller left atrial diameter (-1.5mm) than other genotype groups (P=0.040). No significant associations between rs12917707 and other cardiac or BP phenotypes were observed.Conclusions:These findings extend the previously documented role of UMOD for renal function also to treated high-risk patients with arterial hypertension and reveal a novel association with left atrial remodelling and thus a potential cardiorenal link modulated by UMOD. KW - blood pressure KW - cardiovascular complications KW - chronic kidney disease KW - genetics KW - hypertension KW - kidney function KW - organ damage KW - Tamm-Horsfall protein Y1 - 2017 U6 - https://doi.org/10.1097/HJH.0000000000001432 SN - 0263-6352 SN - 1473-5598 VL - 35 SP - 2053 EP - 2058 PB - Lippincott Williams & Wilkins CY - Philadelphia ER - TY - JOUR A1 - Putra, Sulistyo E. Dwi A1 - Reichetzeder, Christoph A1 - Meixner, Martin A1 - Liere, Karsten A1 - Slowinski, Torsten A1 - Hocher, Berthold T1 - DNA methylation of the glucocorticoid receptor gene promoter in the placenta is associated with blood pressure regulation in human pregnancy JF - Journal of hypertension N2 - Background: Blood pressure (BP) regulation during pregnancy is influenced by hormones of placental origin. It was shown that the glucocorticoid system is altered in hypertensive pregnancy disorders such as preeclampsia. Epigenetic mechanism might influence the activity of genes involved in placental hormone/hormone receptor synthesis/action during pregnancy. Method: In the current study, we analyzed the association of 50-C-phosphate-G-30 (CpG) site methylation of different glucocorticoid receptor gene (NR3C1) promoter regions with BP during pregnancy. The study was performed as a nested case-control study (n = 80) out of 1045 mother/ child pairs from the Berlin Birth Cohort. Placental DNA was extracted and bisulfite converted. Nested PCR products from six NR3C1 proximal promoter regions [glucocorticoid receptor gene promotor region B (GR-1B), C (GR-1C), D (GR-1D), E (GR-1E), F (GR-1F), and H (GR-1H)] were analyzed by next generation sequencing. Results: NR3C1 promoter regions GR-1D and GR-1E had a much higher degree of DNA methylation as compared to GR-1B, GR-1F or GR-1H when analyzing the entire study population. Comparison of placental NR3C1 CpG site methylation among hypotensive, normotensive and hypertensive mothers revealed several differently methylated CpG sites in the GR-1F promoter region only. Both hypertension and hypotension were associated with increased DNA methylation of GR-1F CpG sites. These associations were independent of confounding factors, such as family history of hypertension, smoking status before pregnancy and prepregnancy BMI. Assessment of placental glucocorticoid receptor expression by western blot showed that observed DNA methylation differences were not associated with altered levels of placental glucocorticoid receptor expression. However, correlation matrices of all NR3C1 proximal promoter regions demonstrated different correlation patterns of intraregional and interregional DNA methylation in the three BP groups, putatively indicating altered transcriptional control of glucocorticoid receptor isoforms. Conclusion: Our study provides evidence of an independent association between placental NR3C1 proximal promoter methylation and maternal BP. Furthermore, we observed different patterns of NR3C1 promoter methylation in normotensive, hypertensive and hypotensive pregnancy. KW - DNA methylation KW - epigenetics KW - glucocorticoid receptor KW - hypertension KW - hypotension KW - NR3C1 gene KW - placenta KW - pregnancy Y1 - 2017 U6 - https://doi.org/10.1097/HJH.0000000000001450 SN - 0263-6352 SN - 1473-5598 VL - 35 SP - 2276 EP - 2286 PB - Lippincott Williams & Wilkins CY - Philadelphia ER - TY - GEN A1 - Lu, Yong-Ping A1 - Reichetzeder, Christoph A1 - Prehn, Cornelia A1 - Yin, Liang-Hong A1 - Yun, Chen A1 - Zeng, Shufei A1 - Chu, Chang A1 - Adamski, Jerzy A1 - Hocher, Berthold T1 - Cord blood Lysophosphatidylcholine 16:1 is positively associated with birth weight T2 - Postprints der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe N2 - Background/Aims: Impaired birth outcomes, like low birth weight, have consistently been associated with increased disease susceptibility to hypertension in later life. Alterations in the maternal or fetal metabolism might impact on fetal growth and influence birth outcomes. Discerning associations between the maternal and fetal metabolome and surrogate parameters of fetal growth could give new insight into the complex relationship between intrauterine conditions, birth outcomes, and later life disease susceptibility. Methods: Using flow injection tandem mass spectrometry, targeted metabolomics was performed in serum samples obtained from 226 mother/child pairs at delivery. Associations between neonatal birth weight and concentrations of 163 maternal and fetal metabolites were analyzed. Results: After FDR adjustment using the Benjamini-Hochberg procedure lysophosphatidylcholines (LPC) 14:0, 16:1, and 18:1 were strongly positively correlated with birth weight. In a stepwise linear regression model corrected for established confounding factors of birth weight, LPC 16: 1 showed the strongest independent association with birth weight (CI: 93.63 - 168.94; P = 6.94x10(-11)). The association with birth weight was stronger than classical confounding factors such as offspring sex (CI: - 258.81- -61.32; P = 0.002) and maternal smoking during pregnancy (CI: -298.74 - -29.51; P = 0.017). Conclusions: After correction for multiple testing and adjustment for potential confounders, LPC 16:1 showed a very strong and independent association with birth weight. The underlying molecular mechanisms linking fetal LPCs with birth weight need to be addressed in future studies. (c) 2018 The Author(s) Published by S. Karger AG, Basel T3 - Zweitveröffentlichungen der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe - 631 KW - metabolomics KW - Lysophosphatidylcholine KW - birth weight KW - DOHaD KW - hypertension KW - Type 2 Diabetes Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:kobv:517-opus4-424566 SN - 1866-8372 IS - 631 ER - TY - GEN A1 - Huber, Matthias A1 - Lezius, Susanne A1 - Reibis, Rona Katharina A1 - Treszl, Andras A1 - Kujawinska, Dorota A1 - Jakob, Stefanie A1 - Wegscheider, Karl A1 - Völler, Heinz A1 - Kreutz, Reinhold T1 - A single nucleotide polymorphism near the CYP17A1 gene is associated with left ventricular mass in hypertensive patients under pharmacotherapy N2 - Cytochrome P450 17A1 (CYP17A1) catalyses the formation and metabolism of steroid hormones. They are involved in blood pressure (BP) regulation and in the pathogenesis of left ventricular hypertrophy. Therefore, altered function of CYP17A1 due to genetic variants may influence BP and left ventricular mass. Notably, genome wide association studies supported the role of this enzyme in BP control. Against this background, we investigated associations between single nucleotide polymorphisms (SNPs) in or nearby the CYP17A1 gene with BP and left ventricular mass in patients with arterial hypertension and associated cardiovascular organ damage treated according to guidelines. Patients (n = 1007, mean age 58.0 ± 9.8 years, 83% men) with arterial hypertension and cardiac left ventricular ejection fraction (LVEF) ≥40% were enrolled in the study. Cardiac parameters of left ventricular mass, geometry and function were determined by echocardiography. The cohort comprised patients with coronary heart disease (n = 823; 81.7%) and myocardial infarction (n = 545; 54.1%) with a mean LVEF of 59.9% ± 9.3%. The mean left ventricular mass index (LVMI) was 52.1 ± 21.2 g/m2.7 and 485 (48.2%) patients had left ventricular hypertrophy. There was no significant association of any investigated SNP (rs619824, rs743572, rs1004467, rs11191548, rs17115100) with mean 24 h systolic or diastolic BP. However, carriers of the rs11191548 C allele demonstrated a 7% increase in LVMI (95% CI: 1%–12%, p = 0.017) compared to non-carriers. The CYP17A1 polymorphism rs11191548 demonstrated a significant association with LVMI in patients with arterial hypertension and preserved LVEF. Thus, CYP17A1 may contribute to cardiac hypertrophy in this clinical condition. T3 - Zweitveröffentlichungen der Universität Potsdam : Humanwissenschaftliche Reihe - 333 KW - clinical study KW - genetics KW - heart KW - hypertension KW - cytochrome P450 17A1 (Cyp17A1) Y1 - 2017 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:kobv:517-opus4-400074 ER -