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Hypertension-induced renal fibrosis and spironolactone response vary by rat strain and mineralocorticoid receptor gene expression

Department of Pharmacy Practice, College of Pharmacy, University of Illinois at Chicago, Chicago, IL 60612, USA, humma{at}uic.edu

Lucy A. Fashingbauer

Department of Pharmacy Practice, College of Pharmacy, University of Illinois at Chicago, Chicago, IL 60612, USA

Joseph R. Camp

Department of Pharmacy Practice, College of Pharmacy, University of Illinois at Chicago, Chicago, IL 60612, USA

Stephen T. King

Research Resources Center, University of Illinois at Chicago, Chicago, IL 60612, USA

David L. Geenen

Department of Medicine, Section of Cardiology and Center for Cardiovascular Research, University of Illinois at Chicago, Chicago, IL 60612, USA

Introduction. Aldosterone promotes renal fibrosis via the mineralocorticoid receptor (MR), thus contributing to hypertension-induced nephropathy. We investigated whether MR gene expression influences renal fibrosis and MR antagonist response in a two-kidney, one-clip hypertensive rat model.

Materials and methods. Brown Norway (BN), Lewis, and ACI rats were randomised to spironolactone 20 mg/kg/day or water by gavage, starting four weeks after left renal artery clipping. Blood pressure was measured bi-weekly by tail cuff. After eight weeks of treatment, right kidneys were removed and examined for fibrosis and gene expression. Rats of each strain undergoing no intervention served as controls.

Results. Blood pressure increased similarly among strains after clipping and was unaffected by spironolactone. Hypertension caused the greatest renal fibrosis in BN rats (p < 0.001 by ANOVA compared to other strains). Real-time PCR analysis showed greater renal collagen type I and MR gene expression in untreated, hypertensive BN rats (both p < 0.05 compared to other strains). Spironolactone attenuated fibrosis, with similar fibrosis among strains of spironolactone-treated rats.

Conclusion. Hypertension-induced renal fibrosis was greatest in rats with the highest MR gene expression. Spironolactone abolished inter-strain differences in fibrosis. Our data suggest that MR genotype may influence aldosterone-induced renal damage, and consequently, renal response to aldosterone antagonism.

Key Words: aldosterone • collagen • fibrosis • gene • hypertension • kidney • mineralocorticoid • pharmacogenetics • spironolactone

Journal of Renin-Angiotensin-Aldosterone System, Vol. 9, No. 3, 146-153 (2008)
DOI: 10.1177/1470320308096367


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