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Am J Physiol Renal Physiol 291: F1308-F1314, 2006. First published June 20, 2006; doi:10.1152/ajprenal.00167.2006
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Oxidative stress and glomerular filtration barrier injury: role of the renin-angiotensin system in the Ren2 transgenic rat

Adam T. Whaley-Connell,1,3 Nazif A. Chowdhury,1 Melvin R. Hayden,1 Craig S. Stump,1,2,4,5 Javad Habibi,1,5 Charles E. Wiedmeyer,6 Patricia E. Gallagher,7 E. Ann Tallant,7 Shawna A. Cooper,1 C. Daniel Link,1 Carlos Ferrario,7 and James R. Sowers1,2,4,5

Departments of 1Internal Medicine and 2Medical Pharmacology and Physiology, Divisions of 3Nephrology and 4Endocrinology, and 5Harry S. Truman Veterans Affairs Medical Center, University of Missouri-Columbia School of Medicine, and 6College of Veterinary Medicine, University of Missouri-Columbia, Columbia, Missouri; and 7Hypertension and Vascular Disease Unit, Bowman Gray School of Medicine, Wake Forest University, Winston-Salem, North Carolina

Submitted 15 May 2006 ; accepted in final form 15 June 2006

TG(mRen2)27 (Ren2) transgenic rats overexpress the mouse renin gene, manifest hypertension, and exhibit increased tissue ANG II levels and oxidative stress. Evidence indicates that elevated tissue ANG II contributes to oxidative stress, increases in glomerular macromolecular permeability, and consequent albuminuria. Furthermore, angiotensin type 1 receptor (AT1R) blockers reduce albuminuria and slow progression of renal disease. However, it is not known whether improvements in glomerular filtration barrier integrity and albuminuria during treatment are related to reductions in oxidative stress and/or kidney renin-angiotensin system (RAS) activity. To investigate the renal protective effects of AT1R blockade, we treated young (6–7 wk old) male Ren2 rats with valsartan (Ren2-V; 30 mg/kg) for 3 wk and measured urine albumin, kidney malondialdehyde (MDA), RAS component mRNAs, and NADPH oxidase subunits (gp91phox and Rac1) compared with age-matched untreated Ren2 and Sprague-Dawley (S-D) rats. Basement membrane thickness, slit pore diameter and number, and foot process base width were measured by transmission electron microscopy (TEM). Results indicate that AT1R blockade lowered systolic blood pressure (30%), albuminuria (91%), and kidney MDA (80%) in Ren2-V compared with untreated Ren2 rats. Increased slit pore number and diameter and reductions in basement membrane thickness and podocyte foot process base width were strongly associated with albuminuria and significantly improved following AT1R blockade. AT1R blockade was also associated with increased angiotensin-converting enzyme-2 and neprilysin expression, demonstrating a beneficial shift in balance of renal RAS. Thus reductions in blood pressure, albuminuria, and tissue oxidative stress with AT1R blockade were associated with improved indexes of glomerular filtration barrier integrity and renal RAS in Ren2 rats.

TG(mRen2)27 rat; malondialdehyde; NADPH oxidase; angiotensin receptor blocker


Address for reprint requests and other correspondence: J. R. Sowers, Univ. of Missouri School of Medicine, 1 Hospital Dr., MA410 Medical Science Bldg., Columbia, MO 65212 (e-mail: sowersj{at}health.missouri.edu)




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