Long-term mineralocorticoid receptor blockade ameliorates progression of experimental diabetic renal disease

Abstract

The final end point of diabetic renal disease is the accumulation of excess collagen. A number of studies have shown that aldosterone antagonism ameliorates progression of renal fibrosis. This study was designed to examine the effect of the mineralocorticoid receptor blocker eplerenone (EPL) on progression in streptozotocin (STZ)-treated spontaneously hypertensive rats (SHR), an accelerated model of Type I diabetes. STZ-treated SHRs with a blood glucose >18 mmol/L were randomly divided into treatment (100 mg/kg/day EPL) and non-treatment groups. Sham-injected SHR animals were used as a control. Functional parameters were monitored for 16 weeks, with structural parameters assessed at completion. Both hyperglycaemic groups developed progressive albuminuria, but the increase was ameliorated by EPL from Week 12. STZ-SHRs had elevated kidney weight/body weight ratio, glomerular size, glomerular macrophages (ED-1-positive cells), tissue transforming growth factor beta 1 (TGFβ1) concentrations and glomerular collagen IV staining (all P < 0.05 versus control animals). EPL reduced glomerular volume, TGFβ1 expression and glomerular collagen IV without changing glomerular macrophage infiltration. The ability of EPL to ameliorate these functional and structural changes in hyperglycaemic SHRs suggest that EPL has a renoprotective role in diabetic renal disease.

Mineralocorticoid Receptor Activation and Mineralocorticoid Receptor Antagonist Treatment in Cardiac and Renal Diseases

“…25,30 In the rat kidney, aldosterone increases the expression of intercellular adhesion molecule-1. 31 These effects may be mediated by serum-and glucocorticoid-induced protein kinase-1 and transcription factors nuclear factor-κB and activator protein-1, the expression and activity of which, respectively, are stimulated by aldosterone/salt or angiotensin II/salt in animal heart and kidneys. [29][30][31][32][33] Kidney biopsies from patients with high albuminuria show significant increases in the expression of serum-and glucocorticoid-induced protein kinase-1 and the inflammatory mediators macrophage chemoattractant protein-1, TGF-β, and The direct deleterious effects of aldosterone/MR activation in the heart and kidneys and the common pathophysiological mechanisms involved.…”

“…30,[34][35][36] Renal fibrosis occurs in hypertensive transgenic rats with elevated serum aldosterone and proteinuria, and aldosterone is known to increase the renal expression of the fibrotic proteins osteopontin, fibrinogen, collagen type 1, plasminogen activator inhibitor-1, and connective tissue growth factor. 26,31,37 Oxidative stress is a well-recognized trigger for inflammation and contributes to the development of fibrosis. In several animal models, increases in angiotensin II and aldosterone enhance oxidative stress in the heart, as is evident from increased nicotinamide adenine dinucleotide phosphate oxidase activity, expression of nicotinamide adenine dinucleotide phosphate oxidase components, and reactive oxygen species formation.…”

Combination therapy with spironolactone and candesartan protects against streptozotocin-induced diabetic nephropathy in rats

“…Aldosterone is detrimental to patients with hypertension (Park and Schiffrin, 2002) and it can lead to progressive tissue damage in the heart, vasculature, and kidneys (Park and Schiffrin, 2002). Accumulating evidence suggests that the mineralocorticoid receptor antagonist, spironolactone, has been shown to prevent diabetic renal injury (Lian et al, 2012;Toyonaga et al, 2012). Moreover, the beneficial effects of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker in preventing diabetic nephropathy are widely accepted in current medical science (Abuissa and O'Keefe, 2008).…”

Myeloid Mineralocorticoid Receptor Activation Contributes to Progressive Kidney Disease

“…1 They can also suppress kidney damage in animal models of GN and diabetic nephropathy without affecting BP. [2][3][4][5][6] In addition, MR antagonists provide added protection against proteinuria and loss of renal function when used with standard antihypertensive therapies in patients with diabetic and nondiabetic CKD. [7][8][9] The clinical use of MR antagonists is limited by the development of hyperkalemia due to the importance of the MR in tubular regulation of salt balance.…”