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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/).
Background: Recent studies show that preterm birth is associated with hypertension in later life. The renin-angiotensin system (RAS) during pregnancy influences fetal growth and development. In the current study, we investigated the impact of fetal as well as maternal angiotensin (1-7) [Ang (1-7)] and angiotensin II (Ang II) plasma concentrations on the risk of preterm birth.
Methods: Three hundred and nine pregnant women were prospectively included into the study. The pregnant women were divided into two groups, for example, preterm birth of lower than 37 gestational weeks (n = 17) and full-term birth of 37 gestational weeks or more (n = 292). Maternal and neonatal plasma Ang (1-7) and Ang II concentrations were analyzed at birth from maternal venous blood and umbilical cord blood, respectively. Risk factors for premature birth were determined by multiple logistic regression analysis.
Results: Fetal and maternal plasma Ang (1-7) concentrations in the preterm group were lower than those of the term group fetal Ang (1-7) preterm birth: 486.15 +/- 337.34 ng/l and fetal Ang (1-7) term birth: 833.84 +/- 698.12 ng/l and maternal Ang (1-7) preterm birth: 399.86 +/- 218.93 ng/l; maternal Ang (1-7) term birth: 710.34 +/- 598.22 ng/l. Multiple logistic regression analysis considering confounding factors revealed that preeclampsia (P < 0.001), premature rupture of membranes (P = 0.001), lower concentration of maternal Ang (1-7) (P = 0.013) and fetal plasma Ang (1-7) (P = 0.032) were independently associated with preterm birth. We could furthermore demonstrate that the maternal Ang (1-7)/Ang II ratio is independently associated with gestational hypertension or preeclampsia, factors causing preterm birth.
Conclusions: Lower concentrations of maternal and fetal Ang (1-7) are independently associated with preterm birth - a risk factor of hypertension in later life.
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.
Background: The biological properties of oxidized and non-oxidized PTH are substantially different. Oxidized PTH (oxPTH) loses its PTH receptor-stimulating properties, whereas non-oxidized PTH (n-oxPTH) is a full agonist of the receptor. This was described in more than 20 well published studies in the 1970(s) and 80(s). However, PTH oxidation has been ignored during the development of PTH assays for clinical use so far. Even the nowadays used third generation assay systems do not consider oxidation of PTH. We recently developed an assay to differentiate between oxPTH and n-oxPTH. In the current study we established normal values for this assay system. Furthermore, we compare the ratio of oxPTH to n-oxPTH in different population with chronic renal failure: 620 children with renal failure stage 2-4 of the 4C study, 342 adult patients on dialysis, and 602 kidney transplant recipients. In addition, we performed modeling of the interaction of either oxPTH or n-oxPTH with the PTH receptor using biophysical structure approaches. Results: The children had the highest mean as well as maximum n-oxPTH concentrations as compared to adult patients (both patients on dialysis as well as kidney transplant recipients). The relationship between oxPTH and n-oxPTH of individual patients varied substantially in all three populations with renal impairment. The analysis of n-oxPTH in 89 healthy control subjects revealed that n-oxPTH concentrations in patient with renal failure were higher as compared to healthy adult controls (2.25-fold in children with renal failure, 1.53-fold in adult patients on dialysis, and 1.56-fold in kidney transplant recipients, respectively). Computer assisted biophysical structure modeling demonstrated, however, minor sterical- and/or electrostatic changes in oxPTH and n-oxPTH. This indicated that PTH oxidation may induce refolding of PTH and hence alters PTH-PTH receptor interaction via oxidation induced three-dimensional structure alteration of PTH. Conclusion: A huge proportion of circulating PTH measured by current state-of-the-art assay systems is oxidized and thus not biologically active. The relationship between oxPTH and n-oxPTH of individual patients varied substantially. Non-oxidized PTH concentrations are 1.5 - 2.25 fold higher in patients with renal failure as compared to health controls. Measurements of n-oxPTH may reflect the hormone status more precise. The iPTH measures describes most likely oxidative stress in patients with renal failure rather than the PTH hormone status. This, however, needs to be demonstrated in further clinical studies.
Background/Aims: Carbon monoxide (CO) interferes with cytochrome-dependent cellular functions and acts as gaseous transmitter. CO is released from CO-releasing molecules (CORM) including tricarbonyl-dichlororuthenium (II) dimer (CORM-2), molecules considered for the treatment of several disorders including vascular dysfunction, inflammation, tissue ischemia and organ rejection. Cytochrome P450-sensitive function include formation of 1,25-dihydroxyvitamin D-3 (1,25(OH)(2)D-3) by renal 25-hydroxyvitamin D-3 1-alpha-hydroxylase (Cyp27b1). The enzyme is regulated by PTH, FGF23 and klotho. 1,25(OH)(2)D-3 regulates Ca2+ and phosphate transport as well as klotho expression. The present study explored, whether CORM-2 influences 1,25(OH)(2)D-3 formation and klotho expression. Methods: Mice were treated with intravenous CORM-2 (20 mg/kg body weight). Plasma 1,25(OH)(2)D-3 and FGF23 concentrations were determined by ELISA, phosphate, calcium and creatinine concentrations by colorimetric methods, transcript levels by quantitative RT-PCR and protein expression by western blotting. Fgf23 mRNA transcript levels were further determined in rat osteosarcoma UMR106 cells without or with prior treatment for 24 hours with 20 mu M CORM-2. Results: CORM-2 injection within 24 hours significantly increased FGF23 plasma levels and decreased 1,25(OH)(2)D-3 plasma levels, renal Cyp27b1 gene expression as well as renal klotho protein abundance and transcript levels. Moreover, treatment of UMR106 cells with CORM-2 significantly increased Fgf23 transcript levels. Conclusion: CO-releasing molecule CORM-2 enhances FGF23 expression and release and decreases klotho expression and 1,25(OH)(2)D-3 synthesis.
Preclinical work indicates that calcitriol restores vascular function by normalizing the endothelial expression of cyclooxygenase-2 and thromboxane-prostanoid receptors in conditions of estrogen deficiency and thus prevents the thromboxane-prostanoid receptor activation-induced inhibition of nitric oxide synthase. Since endothelial dysfunction is a key factor in the pathogenesis of cardiovascular diseases, this finding may have an important translational impact. It provides a clear rationale to use endothelial function in clinical trials aiming to find the optimal dose of vitamin D for the prevention of cardiovascular events in postmenopausal women.
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.
Nonoxidized, biologically active parathyroid hormone determines mortality in hemodialysis patients
(2013)
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.