Abstract 8273: Statins Enhance the Beneficial Effects of Olmesartan on Renal Injury in Salt-Sensitive Hypertensive Rats via the Reduction of an Angiotensin-Mineralocorticoid Receptor Signaling Interaction
Objective. The renin-angiotensin-aldosterone system (RAAS) has been implicated in the pathogenesis of chronic cardiorenal diseases. Statins and angiotensin type 1 receptor (AT1R) antagonist improve hypertensive renal remodeling and dysfunction in patients with proteinuric kidney disease. The present study investigated the comparative effects of a combination of statin and AT1R antagonist and AT1R antagonist monotherapy on renal injury.
Methods and Results. Dahl salt-sensitive (DS) rats on a high-salt diet were randomly assigned to four groups (n = 10 for each group) that were treated with either vehicle (0.5% carboxymethyl cellulose), a low or high dosage of olmesartan (1 or 3 mg/kg/d), or pitavastatin (1 mg/kg/d) plus olmesartan (1 mg/kg/d) from 12 to 19 weeks of age. Rats fed a low-salt diet served as age-matched controls. Rats on the high-salt diet developed massive proteinuria and glomerulosclerosis, and these changes were attenuated by olmesartan in a dose-dependent manner. The amounts of mRNAs for AT1R, mineralocorticoid receptor (MR), osteopontin, monocyte chemoattractant protein-1 and collagen type I, and the activities for matrix metalloproteinase-9 and cathepsin S were significantly higher in the failing kidneys of vehicle-treated rats than in the age-matched control rats; Olmesartan significantly attenuated these changes. Olmesartan attenuated both the decrease in the ratio of reduced to oxidized form glutathione and the increase in nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity apparent in the kidney cortex of vehicle-treated rats. Furthermore, olmesartan inhibited kidney cortex vascular inflammation and renal fibrosis. The addition of pitavastatin significantly enhanced these beneficial effects of AT1R antagonism via anti-inflammation and anti-proteolysis.
Conclusions: The beneficial renal effects of AT1R antagonism are likely attributable, at least in part, to the attenuation of renal oxidative stress and renal vascular inflammation induced by the AT1R-MR signaling interaction. The combination of statin with angiotensin receptor blocker (ARB) may be a potential therapeutic strategy for renal injury with proteinuria.
- © 2011 by American Heart Association, Inc.