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1 Internal Medicine, Division of Nephrology, University of Missouri-Columbia School of Medicine, Columbia, Missouri, United States
2 Internal Medicine, University of Missouri-Columbia School of Medicine, Columbia, Missouri, United States
3 Internal Medicine, Division of Endocrinology, University of Missouri-Columbia School of Medicine, United States; Harry S Truman Veterans Affairs Medical Center, United States
4 Internal Medicine, University of Missouri-Columbia School of Medicine, Columbia, Missouri, United States; Harry S Truman Veterans Affairs Medical Center, United States
5 College of Veterinary Medicine, University of Missouri, Columbia, Missouri, United States
6 Hypertension & Vascular Disease Center, Wake Forest University School of Medicine, Winston-Salem, North Carolina, United States
7 Hypertension Research Center, Bowman-Gray School of Medicine, Winston-Salem, North Carolina, United States
8 Hypertension Center, Wake Forest University School of Medicine, Winston-Salem, North Carolina, United States
9 Department of Internal Medicine, University of Missouri, Columbia, Missouri, United States
* To whom correspondence should be addressed. E-mail: sowersj{at}health.missouri.edu.
TG(mRen2)27 (Ren2) transgenic rats overexpress the mouse renin gene, manifest hypertension (HTN) and exhibit increased tissue angiotensin-II (Ang-II) levels and oxidative stress. Evidence indicates elevated tissue Ang-II contributes to oxidative stress, increases in glomerular macromolecular permeability and consequent albuminuria. Further, 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 week old) male Ren2 rats with valsartan (Ren2-V; 30mg/kg) for three weeks and measured urine albumin, kidney malondialdehyde (MDA), RAS component mRNAs, and NADPH oxidase subunits (gp91phox and Rac1) compared to age-matched untreated Ren2 and Sprague-Dawley (SD) rats. Basement membrane thickness, slit-pore diameter and number, and foot process base-width were measured by transmission electron microscopy. Results indicate that AT1R blockade lowered systolic blood pressure (30%), albuminuria (91%), and kidney MDA (80%) in the Ren2-V compared to untreated Ren2 rats. Increased slit-pore number and diameter, 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 ACE2 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 indices of glomerular filtration barrier integrity and renal RAS in Ren2 rats.
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