Abstract 11534: HMG-CoA Reductase Inhibition Enhances Renoprotective Effects of Angiotensin Receptor1 Antagonism in Salt-Sensitive Hypertensive Rats
Introduction: The mineralocorticoid receptor has been implicated in the pathogenesis of chronic cardiorenal disease. 3-hydroxy-3methylgutaryl coenzyme A (HMG-CoA) reductase inhibitors, statins, improved renal dysfunction in patients with proteinuric kidney disease.
Objective: We aimed to clarify the potential effect of a statin to enhance the inhibitory effect of an angiotensin type1 receptor blocker (ARB) on renal injury and the cellular mechanism of the effect of ARB on renal remodeling and proteinuria.
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 glutathione to oxidized 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 by 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 ARB may be a potential therapeutic strategy for renal injury with proteinuria.
Author Disclosures: L. Hu: None. X. Cheng: None. Z. Huang: None. T. Sasaki: None. A. Inoue: None. H. Wu: None. E. Zhu: None. M. Kuzuya: None. T. Murohara: None. K. Okumura: None.
- © 2014 by American Heart Association, Inc.