Regression of Existing Glomerulosclerosis by Inhibition of Aldosterone

Aldigier, Jean-Claude; Kanjanbuch, Talerngsak; Ma, Lijun; Brown, Nancy J.; Fogo, Agnes B.

doi:10.1681/asn.2004090804

Cited by 161 publications

(133 citation statements)

References 56 publications

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“…24 We also demonstrated the modulation of adrenomedullin expression in response to various injurious stimuli in cultured podocytes. 27 Furthermore, a recent article by Aldigier et al 44 indicates the role of aldosterone in podocyte injury seen in a rat model of renal ablation. Thus, podocytes in DSHs might be injured by mechanical stress, oxidative stress, and/or vasoactive substances.…”

Section: Discussionmentioning

confidence: 99%

Podocyte Injury Underlies the Glomerulopathy of Dahl Salt-Hypertensive Rats and Is Reversed by Aldosterone Blocker

et al. 2006

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Abstract-Recent clinical studies implicate proteinuria as a key prognostic factor for renal and cardiovascular complications in hypertensives. The pathogenesis of proteinuria in hypertension is, however, poorly elucidated. Podocytes constitute the final filtration barrier in the glomerulus, and their dysfunction may play a pivotal role in proteinuria. In the present study, we examined the involvement of podocyte injury in Dahl salt-hypertensive rats, an animal model prone to hypertensive glomerulosclerosis, and explored the effects of inhibition of aldosterone. Four-week-old Dahl salt-resistant and salt-sensitive rats were fed a 0.3% or 8.0% NaCl diet. Some salt-loaded Dahl salt-sensitive rats were treated with a selective aldosterone blocker eplerenone (1.25 mg/g diet) or hydralazine (0.5 mmol/L). After 6 weeks, salt-loaded Dahl salt-sensitive rats developed severe hypertension, proteinuria, and glomerulosclerosis. Immunostaining for nephrin, a constituent of slit diaphragm, was attenuated, whereas expressions of damaged podocyte markers desmin and B7-1 were upregulated in the glomeruli of salt-loaded Dahl salt-sensitive rats. Electron microscopic analysis revealed podocyte foot process effacement. Podocytes were already impaired at as early as 2 weeks of salt loading in Dahl salt-sensitive rats, when proteinuria was modestly increased. Both eplerenone and hydralazine partially reduced systemic blood pressure as measured by indirect and direct methods in salt-loaded Dahl salt-sensitive rats, but only eplerenone dramatically improved podocyte damage and retarded the progression of proteinuria and glomerulosclerosis. Our findings suggest that podocyte injury underlies the glomerulopathy of Dahl salt-hypertensive rats and that inhibition of aldosterone by eplerenone is protective against podocyte damage, proteinuria, and glomerulosclerosis in this hypertensive model.

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Section: Discussionmentioning

confidence: 99%

Podocyte Injury Underlies the Glomerulopathy of Dahl Salt-Hypertensive Rats and Is Reversed by Aldosterone Blocker

et al. 2006

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“…In rats, MR antagonists markedly ameliorated glomerular and/or tubulointerstitial injury in several models of nephropathy, including spontaneously hypertensive strokeprone rats (50,51), angiotensin II and NO synthase inhibitortreated rats (52), aldosterone-treated rats (25), and in a ureteral obstruction model (66). Moreover, Aldigier et al (2) reported that MR blockade not only reduced the development of glomerulosclerosis but also induced regression of existing glomerulosclerosis in rats after 5/6 nephrectomy. In humans, pilot studies showed that the addition of spironolactone to angiotensin-converting enzyme inhibitors had no hemodynamic effects but markedly reduced proteinuria in patients with renal failure (8) and in patients with type 2 diabetes (53).…”

Section: Invited Reviewmentioning

confidence: 99%

New insights into the pathophysiology of cyclosporine nephrotoxicity: a role of aldosterone

Bobadilla¹,

Gamba²

2007

American Journal of Physiology-Renal Physiology

116

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Cyclosporine A (CsA), a calcineurin inhibitor, has improved allograft survival in solid organ transplantation and has been increasingly applied in the management of autoimmune diseases. While marked progress has been made in patient and allograft survival rates, clinical use of CsA is often limited by its nephrotoxic effect, which can be presented as two distinct and well-characterized forms: acute and chronic nephrotoxicity. The acute form is characterized by renal vasoconstriction, induced by an imbalance of vasoactive substances release, which leads to renal dysfunction. This form is reversible. The chronic toxicity, in contrast, is characterized by the vasoconstriction plus the development of structural damage that includes arteriolopathy and tubulointerstitial fibrosis that are often not reversible. The exact mechanisms of these deleterious effects are not fully understood, but major advances have occurred over the last few years. Here we review the current literature regarding the pathogenesis and strategies that have been used to ameliorate renal injury in chronic CsA nephrotoxicity. Recent observations suggest that aldosterone plays a central role in the pathogenesis of CsA nephrotoxicity and that spironolactone could be a useful agent to prevent it. These studies and the use of mineralocorticoid receptor blockade are discussed.

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“…Animal studies have shown that aldosterone has an independent role in the development of hypertensive nephropathy and vascular injury resulting in myocardial and renal fibrosis, and its blockade reduces proteinuria (12)(13)(14)(15)(16). In humans, RAS blockade with ACEi or ARB results in an incomplete suppression of serum aldosterone levels, a phenomenon known as "aldosterone escape" (17).…”

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confidence: 99%

Aldosterone Antagonists for Preventing the Progression of Chronic Kidney Disease

Navaneethan

Nigwekar

Sehgal³

et al. 2009

Clinical Journal of the American Society of Nephrology

229

133

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Background and objectives: Addition of aldosterone antagonists (AA) might provide renal benefits to proteinuric chronic kidney disease (CKD) patients over and above the inhibition of renin-angiotensin system blockers (RAS). We evaluated the benefits and harms of adding selective and nonselective AA in CKD patients already on RAS.Design, setting, participants, & measurements: MEDLINE, EMBASE, and Renal Health Library were searched for relevant randomized clinical trials in adult CKD patients. Results were summarized using the random-effects model.Results: Eleven trials (991 patients) were included. In comparison to angiotensin-converting enzyme inhibitors (ACEi) and/or angiotensin receptor blockers (ARB) plus placebo, nonselective AA along with ACEi and/or ARB significantly reduced 24 h proteinuria (seven trials, 372 patients, weighted mean difference [WMD] ؊0.80 g, 95% CI ؊1.27, ؊0.33) and BP. This did not translate into an improvement in GFR (WMD ؊0.70 ml/min/1.73m 2 , 95% CI ؊4.73, 3.34). There was a significant increase in the risk of hyperkalemia with the addition of nonselective AA to ACEi and/or ARB (relative risk 3.06, 95% CI 1.26, 7.41). In two trials, addition of selective AA to ACEi resulted in an additional reduction in 24 h proteinuria, without any impact on BP and renal function. Data on cardiovascular outcomes, long-term renal outcomes and mortality were not available in any of the trials.Conclusions: Aldosterone antagonists reduce proteinuria in CKD patients already on ACEis and ARBs but increase the risk of hyperkalemia. Long-term effects of these agents on renal outcomes, mortality, and safety need to be established. Clin J Am Soc Nephrol 4: 542-551, 2009. doi: 10.2215 C hronic kidney disease (CKD) affects 25 to 30 million Americans and several million people across the globe in both developed and developing nations (1,2). A number of treatment options have been shown to delay the progression of kidney damage (3,4). To date, the major impact on delaying the progression of CKD and the risk of end-stage kidney disease (ESKD) has been provided by the use of renin-angiotensin system (RAS) blockers such as angiotensin-converting enzyme inhibitors (ACEi) and angiotensin receptor-blocking agents (ARB). These agents have become standard of care in proteinuric CKD patients (5-8). Both ACEi and ARB significantly reduce proteinuria and the risk of ESKD by about 20 to 30% (9). But this is suboptimal given the higher costs and burden of ESKD (10). Thus, studies exploring interventions for traditional and nontraditional risk factors for CKD are advocated (11).Animal studies have shown that aldosterone has an independent role in the development of hypertensive nephropathy and vascular injury resulting in myocardial and renal fibrosis, and its blockade reduces proteinuria (12-16). In humans, RAS blockade with ACEi or ARB results in an incomplete suppression of serum aldosterone levels, a phenomenon known as "aldosterone escape" (17). When patients are treated with ACEi or ARB, aldosterone levels decrease during...

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Regression of Existing Glomerulosclerosis by Inhibition of Aldosterone

Cited by 161 publications

References 56 publications

Podocyte Injury Underlies the Glomerulopathy of Dahl Salt-Hypertensive Rats and Is Reversed by Aldosterone Blocker

Podocyte Injury Underlies the Glomerulopathy of Dahl Salt-Hypertensive Rats and Is Reversed by Aldosterone Blocker

New insights into the pathophysiology of cyclosporine nephrotoxicity: a role of aldosterone

Aldosterone Antagonists for Preventing the Progression of Chronic Kidney Disease

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