Abstract 9102: Superoxide-Dependent Cathepsin Activation is Associated with Hypertensive Renal Remodeling and Dysfunction and Represents a Target for Angiotensin Type 1 Receptor Blocker
Background: Cathepsin activation by angiotensin II has been implicated in cardiovascular disease pathogenesis. Angiotensin II receptor blockers (ARBs) improve clinical outcomes in proteinuric kidney disease. We examined the actions of ARBs in hypertensive renal insufficiency in Dahl salt-sensitive (DS) rats.
Methods and Results: DS rats on a high-salt diet were randomly assigned to four groups (n = 15 per group) treated with vehicle (0.5% carboxymethyl cellulose), olmesartan (3 mg/kg daily), the cysteine protease inhibitor E64d (5 mg/kg daily), or NADPH oxidase inhibitor apocynin (0.5 mmol/kg daily) from age 12 to 19 weeks. Rats fed a low-salt diet served as controls. High-salt rats developed massive proteinuria and glomerulosclerosis, which were attenuated by olmesartan. Angiotensin II levels, macrophage infiltration, and expression of NADPH subunits (gp91phox, p22phox, Rac1) were significantly higher (P < 0.01) in the failing kidneys of vehicle-treated rats than in control-rat kidneys; olmesartan significantly attenuated these changes. Olmesartan-treated rats had less fibrosis, lower collagen type I and III mRNA expression, and lower cathepsin S activity than vehicle-treated rats. E64d and apocynin mimicked these beneficial effects. Both olmesartan and siRNA targeted against the angiotensin II type 1 receptor and gp91phox reduced angiotensin II-induced cathepsin S protein production in cultured rat podocytes. Olmesartan had no effects on renin and aldosterone activity of kidney tissues.
Conclusions: This is the first report showing that, in DS rats, cathepsins can trigger and promote kidney remodeling, and that olmesartan suppresses cathepsin activation by inhibiting the NADPH oxidase-dependent superoxide anion production, thus attenuating hypertensive kidney remodeling.
- © 2010 by American Heart Association, Inc.