The mineralocorticoid receptor antagonist eplerenone reduces renal interstitial fibrosis after long-term cyclosporine treatment in rat: antagonizing cyclosporine nephrotoxicity

Nielsen, Finn Årup; Jensen, Boye L.; Hansen, Pernille; Marcussen, Niels; Bie, Peter

doi:10.1186/1471-2369-14-42

Cited by 24 publications

(21 citation statements)

References 22 publications

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“…Nielsen et al [25] studied the effect of eplerenone (∼100 mg PO daily) on renal interstitial fibrosis after prolonged cyclosporine (CsA) treatment in rats. In contrast to our results, their results indicated that eplerenone significantly lowered blood pressure.…”

Section: Discussionmentioning

confidence: 99%

Eplerenone-Mediated Aldosterone Blockade Prevents Renal Fibrosis by Reducing Renal Inflammation, Interstitial Cell Proliferation and Oxidative Stress

Chen¹,

Sun

Zhong³

et al. 2013

Kidney Blood Press Res

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Background/Aims: Prolonged elevation of serum aldosterone leads to renal fibrosis. Inflammation also plays a role in the pathogenesis of renal disease. We used a rat model of interstitial renal fibrosis to test the hypothesis that eplerenone-mediated aldosterone blockade prevents renal fibrosis due to its anti-inflammatory and anti-proliferative effects. Methods: Eplerenone (a selective aldosterone blocker) or vehicle (control), was given to male Wistar rats (50 mg/kg, twice daily) for 7 days before unilateral ureteral obstruction (UUO) and for an additional 28 days after surgery. Body weight, blood pressure, renal histo-morphology, immune-staining for macrophages, monocyte chemotactic protein-1, proliferating cell nuclear antigen, α-smooth muscle actin, and serum and urine markers of renal function and oxidative stress were determined for both groups on 7, 14, and 28 days after surgery. Results: Epleronone had no effect on body weight or blood pressure. However, eplerenone inhibited the development of renal fibrosis, inflammation (macrophage and monocyte infiltration), interstitial cell proliferation, and activation of interstitial cells (α-SMA expression). Epleronone also reduced oxidative stress. Conclusion: The anti-fibrotic effect of eplerenone appears to be unrelated to its effect on blood pressure. Eplerenone inhibits renal inflammation, interstitial cell proliferation, phenotypic changes of interstitial cells, and reduces oxidative stress.

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Section: Discussionmentioning

confidence: 99%

Eplerenone-Mediated Aldosterone Blockade Prevents Renal Fibrosis by Reducing Renal Inflammation, Interstitial Cell Proliferation and Oxidative Stress

Chen¹,

Sun

Zhong³

et al. 2013

Kidney Blood Press Res

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“…However, prolonged use of cyclosporine A can induce renal fibrosis. Thus, its clinical use is in part limited by its nephrotoxicity effect (3,59). The cyclosporine A model is good for studying interstitial fibrosis (23).…”

Section: Mercuric Chloride (Hgcl 2 )mentioning

confidence: 99%

Pathophysiological Mechanisms of Renal Fibrosis: A Review of Animal Models and Therapeutic Strategies

2017

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Abstract. Chronic kidney disease (CKD) is a long-term condition in which theChronic kidney disease (CKD) represents a serious hazard to human health, and has a high prevalence. In developed countries, it is estimated that more than 10% of adults present some degree of CKD (1). Despite a varied initial evolution, which is related to the diversity of its aetiologies -namely genetics, autoimmune-related infections, environmental factors, diet, and drugs -progressive renal disease frequently results in renal fibrosis and finally in renal failure. The mechanisms implicated in renal fibrosis are still poorly understood, and existing therapies are ineffective or only slightly successful, hence it is essential to understand the pathophysiological mechanisms underlying the usual development of CKD, and to discover and better understand new strategies for treating this disease. In order to study the biopathology of this disease and to evaluate new treatments, animal models are required. The perfect animal model for renal disease research should have human-like renal anatomy, haemodynamics and physiology, as well as enabling the determination of relevant renal, biochemical and haemodynamic parameters. In all probability, no species can consistently meet all these requirements, and the experimental plan and other constraints often determine the choice of animal models for particular research applications. With this in mind, this review aims to describe and analyze animal models of renal fibrosis and suggest new areas of research. Renal Fibrosis: Aetiology and PathophysiologyDiabetes and hypertension are currently the two principal causes of CKD (2), among other causes such as infectious glomerulonephritis, renal vasculitis, ureteral obstruction, genetic alterations, autoimmune diseases (1) and drugs (3, 4). In general, diabetes causes glomerular hypertension by reducing the afferent arteriolar resistance while stimulating the efferent arterioles (2). Thus, elevated glomerular capillary pressure is one of the major factors in progressive renal sclerosis (5). Diabetes and hypertension gradually lead to glomerular expansion, which causes endothelial dysfunction and haemodynamic changes: loss of the glomerular basement membrane electric charge and its thickening, a decreased number of podocytes, foot-process effacement and mesangial distension have been shown to 1

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“…These data allow considering MR as a novel potential therapeutic target for IR and NAFLD. Moreover, MR blockade has been shown to ameliorate experimental organ fibrosis in the heart , lung and kidney . If that beneficial effects also occurs in the liver then MR blockade would provide action on both metabolic and fibrogenic phenomena rendering this class of drugs potentially useful agents for NASH.…”

Section: Discussionmentioning

confidence: 99%

Beneficial effects of mineralocorticoid receptor blockade in experimental non‐alcoholic steatohepatitis

Pizarro

Solı́s

Quintero

et al. 2015

Liver International

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Background Therapeutic options to treat Non-alcoholic steatohepatitis (NASH) are limited. Mineralocorticoid receptor (MR) activation could play a role in hepatic fibrogenesis and its modulation could be beneficial for NASH. Aim To investigate whether eplerenone, a specific MR antagonist, ameliorates liver damage in experimental NASH. Methods C57bl6 mice were fed a choline-deficient-amino-acid–defined (CDAA) diet for 22 weeks with or without eplerenone supplementation. Serum levels of aminotransferases and aldosterone were measured and hepatic steatosis, inflammation, and fibrosis scored histologically. Hepatic triglyceride content (HTC) and hepatic mRNA levels of pro-inflammatory pro-fibrotic, oxidative stress-associated genes and of MR were also assessed. Results CDAA diet effectively induced fibrotic NASH, and increased the hepatic expression of pro-inflammatory, pro-fibrotic and oxidative stress-associated genes. Hepatic MR mRNA levels significantly correlated with the expression of pro-inflammatory and pro-fibrotic genes and were significantly increased in hepatic stellate cells obtained from CDAA-fed animals. Eplerenone administration was associated to a reduction in histological steatosis and attenuation of liver fibrosis development, which was associated to a significant decrease in the expression of collagen-α1, collagen type III, alpha 1 and Matrix metalloproteinase-2. Conclusion The expression of MR correlates with inflammation and fibrosis development in experimental NASH. Specific MR blockade with eplerenone has hepatic anti-steatotic and anti-fibrotic effects. These data identifies eplerenone as a potential novel therapy for NASH. Considering its safety and FDA-approved status, human studies are warranted

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The mineralocorticoid receptor antagonist eplerenone reduces renal interstitial fibrosis after long-term cyclosporine treatment in rat: antagonizing cyclosporine nephrotoxicity

Cited by 24 publications

References 22 publications

Eplerenone-Mediated Aldosterone Blockade Prevents Renal Fibrosis by Reducing Renal Inflammation, Interstitial Cell Proliferation and Oxidative Stress

Eplerenone-Mediated Aldosterone Blockade Prevents Renal Fibrosis by Reducing Renal Inflammation, Interstitial Cell Proliferation and Oxidative Stress

Pathophysiological Mechanisms of Renal Fibrosis: A Review of Animal Models and Therapeutic Strategies

Beneficial effects of mineralocorticoid receptor blockade in experimental non‐alcoholic steatohepatitis

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