Protective Effects of Selective Mineralocorticoid Receptor Antagonist in Alport Syndrome on Top of Renin-Angiotensin-System/ Sodium-Glucose Transporter 2 Blockade.
Ontology highlight
ABSTRACT:
SUBMITTER: Song ZR
PROVIDER: S-EPMC10927468 | biostudies-literature | 2024 Mar
REPOSITORIES: biostudies-literature
Publications
Protective Effects of Selective Mineralocorticoid Receptor Antagonist in Alport Syndrome on Top of Renin-Angiotensin-System/ Sodium-Glucose Transporter 2 Blockade.
Song Zhuo-Ran ZR Li Yang Y Zhang Hong H Zhou Xu-Jie XJ
Kidney international reports 20231223 3
Similar Datasets
Project description:Background: Several studies suggest that dietary beta hydroxybutyrate supplementation delays the progression of chronic kidney disease (CKD) by suppressing inflammation and fibrosis. We hypothesized that the oral supplementation with the beta-hydroxybutyrate (BHB) precursor 1,3-butanediol in addition to inhibitors of the renin-angiotensin system (RAS) and sodium-glucose transporter (SGLT)2 would be superior to dual RAS/SGLT2 blockade alone in attenuating the loss of glomerular filtration rate in Col4a3-deficient mice with Alport nephropathy, a spontaneous model of progressive CKD. Methods: We performed a placebo-controlled study in Col4a3-deficient mice with Alport nephropathy. Treatment was initiated at a late stage of the disease at the age of six weeks. Mice were fed food admixes of 10 μg/g ramipril plus 30 μg/g empagliflozin with or without addition of 0,04g/g 1,3-butanediol (concentration per gram of bodyweight). The mice were monitored daily and sacrificed upon reaching renal failure. The glomerular filtration rate (GFR) was measured at the start of the treatment and after one and four weeks. Results: The addition of beta hydroxybutyrate significantly attenuated the loss of glomerular filtration rate beyond the effect of dual RAS/SGLT2 blockade. The mean glomerular filtration rate after four weeks of treatment was 1.4±5.0 μl/min (vehicle), 61.3±51.1 μl/min (RASi + SGLT2i), and 138.9±68.5 μl/min (RASi + SGLT2i + 1,3-butanediol). No additional effects on lifespan could be observed. Kidney RNA sequencing revealed significant protective effects on inflammation when adding the beta hydroxybutyrate precursor 1,3-butanediol to RAS/SGLT2 inhibition. In histopathology, antifibrotic effects were seen upon beta hydroxybutyrate addition. Conclusion: The results in mice suggest that beta hydroxybutyrate supplementation improves the GFR in Alport syndrome by suppressing inflammation and fibrosis. However, the effects did not lead to a significant increase in lifespan. Furthermore, the observed effects stay behind the effects of finerenone as a combination partner, which was tested earlier in the same mouse model.
2025-03-24 | GSE287708 | GEO
Project description:In the early months of the coronavirus disease 2019 (COVID-19) pandemic, a hypothesis emerged suggesting that pharmacologic inhibitors of the renin-angiotensin system (RAS) may increase COVID-19 severity. This hypothesis was based on the role of angiotensin-converting enzyme 2 (ACE2), a counterregulatory component of the RAS, as the binding site for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), allowing viral entry into host cells. Extrapolations from prior evidence led to speculation that upregulation of ACE2 by RAS blockade may increase the risk of adverse outcomes from COVID-19. However, counterarguments pointed to evidence of potential protective effects of ACE2 and RAS blockade with regard to acute lung injury, as well as substantial risks from discontinuing these commonly used and important medications. Here we provide an overview of classic RAS physiology and the crucial role of ACE2 in systemic pathways affected by COVID-19. Additionally, we critically review the physiologic and epidemiologic evidence surrounding the interactions between RAS blockade and COVID-19. We review recently published trial evidence and propose important future directions to improve upon our understanding of these relationships.
| S-EPMC7929063 | biostudies-literature
Project description:Diabetic kidney disease is the most frequent cause of end-stage renal disease. This implies failure of current therapeutic approaches based on renin-angiotensin system (RAS) blockade. Recent phase 3 clinical trials of paricalcitol in early diabetic kidney disease and bardoxolone methyl in advanced diabetic kidney disease failed to meet the primary endpoint or terminated on safety concerns, respectively. However, various novel strategies are undergoing phase 2 and 3 randomized controlled trials targeting inflammation, fibrosis and signaling pathways. Among agents currently undergoing trials that may modify the clinical practice on top of RAS blockade in a 5-year horizon, anti-inflammatory agents currently hold the most promise while anti-fibrotic agents have so far disappointed. Pentoxifylline, an anti-inflammatory agent already in clinical use, was recently reported to delay estimated glomerular filtration rate (eGFR) loss in chronic kidney disease (CKD) stage 3-4 diabetic kidney disease when associated with RAS blockade and promising phase 2 data are available for the pentoxifylline derivative CTP-499. Among agents targeting chemokines or chemokine receptors, the oral small molecule C-C chemokine receptor type 2 (CCR2) inhibitor CCX140 decreased albuminuria and eGFR loss in phase 2 trials. A dose-finding trial of the anti-IL-1β antibody gevokizumab in diabetic kidney disease will start in 2015. However, clinical development is most advanced for the endothelin receptor A blocker atrasentan, which is undergoing a phase 3 trial with a primary outcome of preserving eGFR. The potential for success of these approaches and other pipeline agents is discussed in detail.
| S-EPMC4485003 | biostudies-literature
Project description:Aims/hypothesisThis meta-analysis aimed to compare the renal outcomes between ACE inhibitor (ACEI)/angiotensin II receptor blocker (ARB) and other antihypertensive drugs or placebo in type 2 diabetes.MethodsPublications were identified from Medline and Embase up to July 2011. Only randomised controlled trials comparing ACEI/ARB monotherapy with other active drugs or placebo were eligible. The outcome of end-stage renal disease, doubling of serum creatinine, microvascular complications, microalbuminuria, macroalbuminuria and albuminuria regression were extracted. Risk ratios were pooled using a random-effects model if heterogeneity was present; a fixed-effects model was used in the absence of heterogeneity.ResultsOf 673 studies identified, 28 were eligible (n = 13-4,912). In direct meta-analysis, ACEI/ARB had significantly lower risk of serum creatinine doubling (pooled RR = 0.66 [95% CI 0.52, 0.83]), macroalbuminuria (pooled RR = 0.70 [95% CI 0.50, 1.00]) and albuminuria regression (pooled RR 1.16 [95% CI 1.00, 1.39]) than other antihypertensive drugs, mainly calcium channel blockers (CCBs). Although the risks of end-stage renal disease and microalbuminuria were lower in the ACEI/ARB group (pooled RR 0.82 [95% CI 0.64, 1.05] and 0.84 [95% CI 0.61, 1.15], respectively), the differences were not statistically significant. The ACEI/ARB benefit over placebo was significant for all outcomes except microalbuminuria. A network meta-analysis detected significant treatment effects across all outcomes for both active drugs and placebo comparisons.Conclusions/interpretationOur review suggests a consistent reno-protective effect of ACEI/ARB over other antihypertensive drugs, mainly CCBs, and placebo in type 2 diabetes. The lack of any differences in BP decrease between ACEI/ARB and active comparators suggest this benefit is not due simply to the antihypertensive effect.
| S-EPMC3268972 | biostudies-literature
Project description:Dietary fats and sodium are both palatable and are hypothesized to synergistically contribute to ingestive behavior and thereby obesity. Contrary to this hypothesis, C57BL/6J mice fed a 45% high fat diet exhibited weight gain that was inhibited by increased dietary sodium content. This suppressive effect of dietary sodium upon weight gain was mediated specifically through a reduction in digestive efficiency, with no effects on food intake behavior, physical activity, or resting metabolism. Replacement of circulating angiotensin II levels reversed the effects of high dietary sodium to suppress digestive efficiency. While the AT1 receptor antagonist losartan had no effect in mice fed low sodium, the AT2 receptor antagonist PD-123,319 suppressed digestive efficiency. Correspondingly, genetic deletion of the AT2 receptor in FVB/NCrl mice resulted in suppressed digestive efficiency even on a standard chow diet. Together these data underscore the importance of digestive efficiency in the pathogenesis of obesity, and implicate dietary sodium, the renin-angiotensin system, and the AT2 receptor in the control of digestive efficiency regardless of mouse strain or macronutrient composition of the diet. These findings highlight the need for greater understanding of nutrient absorption control physiology, and prompt more uniform assessment of digestive efficiency in animal studies of energy balance.
| S-EPMC4464075 | biostudies-literature
Project description:Methamphetamine (METH) abuse has become a major public health concern worldwide without approved pharmacotherapies. The brain renin-angiotensin system (RAS) is involved in the regulation of neuronal function as well as neurological disorders. Angiotensin II (Ang II), which interacts with Ang II type 1 receptor (AT1-R) in the brain, plays an important role as a neuromodulator in dopaminergic transmission. However, the role of brain RAS in METH-induced behavior is largely unknown. Here, we revealed that repeated METH administration significantly upregulated the expression of AT1-R in the striatum of mice, but downregulated dopamine D3 receptor (D3R) expression. A specific AT1-R blocker telmisartan, which can penetrate the brain-blood barrier (BBB), or genetic deletion of AT1-R was sufficient to attenuate METH-triggered hyperlocomotion in mice. However, intraperitoneal injection of AT1-R blocker losartan, which cannot penetrate BBB, failed to attenuate METH-induced behavior. Moreover, intra-striatum re-expression of AT1 with lentiviral virus expressing AT1 reversed the weakened locomotor activity of AT1-/- mice treated with METH. Losartan alleviated METH-induced cytotoxicity in SH-SY5Y cells in vitro, which was accompanied by upregulated expressions of D3R and dopamine transporter. In addition, intraperitoneal injection of perindopril, which is a specific ACE inhibitor and can penetrate BBB, significantly attenuated METH-induced hyperlocomotor activity. Collectively, our results show that blockade of brain RAS attenuates METH-induced hyperlocomotion and neurotoxicity possibly through modulation of D3R expression. Our findings reveal a novel role of Ang II-AT1-R in METH-induced hyperlocomotion.
| S-EPMC5935642 | biostudies-literature
Project description:Blockade of the renin-angiotensin system is renoprotective in a variety of chronic nephropathies, but the direct effect of such treatment in active, immune complex-mediated glomerulonephritis is unknown. This study investigated the short- and long-term effects of an angiotensin-converting enzyme inhibitor (enalapril) and an angiotensin II type 1 receptor blocker (losartan) in thymic stromal lymphopoietin transgenic (TSLPtg) mice, which develop mixed cryoglobulinemia and severe cryoglobulinemia-associated membranoproliferative glomerulonephritis. Enalapril and losartan each reduced hypertension, proteinuria, glomerular extracellular matrix deposition, and mesangial cell activation in TSLPtg mice. These renoprotective effects were not observed with hydralazine treatment, despite a similar antihypertensive effect. Treatment with enalapril or losartan also decreased renal plasminogen activator inhibitor-1 in TSLPtg mice, assessed by immunohistochemistry and quantitative real-time reverse transcriptase-PCR. None of the treatments affected immune complex deposition or macrophage infiltration. Overall, enalapril- and losartan-treated TSLPtg mice survived significantly longer than untreated TSLPtg mice. These studies demonstrate that angiotensin blockade may provide renoprotective benefits, independent of its BP-lowering effect, in the treatment of active immune complex-mediated glomerulonephritis.
| S-EPMC2396930 | biostudies-literature
Project description:Aldosterone promotes glomerular and tubular sclerosis independent of angiotensin II in animal models of diabetic nephropathy. Most human studies testing the renoprotective benefit of adding an angiotensin receptor blocker or a mineralocorticoid receptor antagonist to a regimen based on inhibition of angiotensin-converting enzyme (ACE) used relatively low doses of ACE inhibitors. Furthermore, these studies did not determine whether antiproteinuric effects were independent of BP lowering. We conducted a double-blind, placebo-controlled trial in 81 patients with diabetes, hypertension, and albuminuria (urine albumin-to-creatinine ratio > or =300 mg/g) who all received lisinopril (80 mg once daily). We randomly assigned the patients to placebo, losartan (100 mg daily), or spironolactone (25 mg daily) for 48 wk. We obtained blood and urine albumin, urea, creatinine, electrolytes, A1c, and ambulatory BP at baseline, 24, and 48 wk. Compared with placebo, the urine albumin-to-creatinine ratio decreased by 34.0% (95% CI, -51.0%, -11.2%, P = 0.007) in the group assigned to spironolactone and by 16.8% (95% CI, -37.3%, +10.5%, P = 0.20) in the group assigned to losartan. Clinic and ambulatory BP, creatinine clearance, sodium and protein intake, and glycemic control did not differ between groups. Serum potassium level was significantly higher with the addition of either spironolactone or losartan. In conclusion, the addition of spironolactone, but not losartan, to a regimen including maximal ACE inhibition affords greater renoprotection in diabetic nephropathy despite a similar effect on BP. These results support the need to conduct a long-term, large-scale, renal failure outcomes trial.
| S-EPMC2794224 | biostudies-literature
Project description:IntroductionVERTIS CV was a placebo-controlled cardiovascular (CV) outcome trial evaluating the sodium-glucose cotransporter 2 inhibitor ertugliflozin in patients with type 2 diabetes and established atherosclerotic CV disease. The aim of the current analyses was to evaluate VERTIS CV cardiorenal outcomes according to baseline use of renin-angiotensin-aldosterone system (RAAS) inhibitors or diuretics, including mineralocorticoid receptor antagonists (MRAs).MethodsParticipants received ertugliflozin 5 mg, ertugliflozin 15 mg, or placebo once daily and were followed for a mean of 3.5 years. Prespecified CV and kidney outcomes were analyzed by Cox proportional hazard modeling in participant subgroups defined by baseline use of RAAS inhibitors (angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers) or diuretics (loop diuretics, non-loop diuretics, MRAs), with interaction testing to assess for treatment effect modification.ResultsA total of 8,246 patients were randomized in VERTIS CV. At baseline, 6,686 (81%) participants were being treated with RAAS inhibitors, 3,542 (43%) with diuretics, 1,252 (15%) with loop diuretics, and 674 (8%) with MRAs. No significant interactions were observed for cardiorenal outcomes by baseline use of RAAS inhibitors or MRAs (p interaction > 0.05 for all). Statistically significant interactions for a first event of hospitalization for heart failure (HHF) or CV death, and of HHF (alone), were observed with baseline use of diuretics, including loop diuretics, with an increased benefit of ertugliflozin treatment versus placebo.ConclusionIn VERTIS CV, baseline use of diuretics, particularly loop diuretics, identified a subgroup that demonstrated greater benefit with ertugliflozin on first HHF/CV death and HHF outcomes, with no modification of treatment effect observed with baseline use of RAAS inhibitors or MRAs. There was no evidence of treatment effect on the kidney composite outcomes by baseline use of RAAS inhibitors, diuretics, loop diuretics, or MRAs.
| S-EPMC11870670 | biostudies-literature
Project description: Not available
| S-EPMC8071656 | biostudies-literature