Abstract 5155: Superoxide-Dependent Cathepsin Activation System is Associated with Hypertensive Renal Remodeling and Represents a Target for Statin

Abstract

Objective: Cathepsins are members of the cysteine protease family that participate in various types of tissue remodeling. Given that NADPH oxidase is implicated in protease activation, we examined the possible role of NADPH oxidase-dependent cathepsin activation in hypertensive renal remodeling with heart failure (HF) in Dahl salt-sensitive (DS) rats. Methods and Results: DS rats maintained 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; CMC), low-dose pitavastatin (1 mg/kg/d; Pitava-L), high-dose pitavastatin (3 mg/kg/d; Pitava-H), E64d (a cysteine protease inhibitor), or pitavastatin from 12 to 19 weeks of age. Rats fed a low-salt diet served as controls. Marked cortical mesangial matrix expansion and the levels of collagen type I and III, angiotensin II type receptor 1 (AT 1 R), and mineralocorticoid receptor (MR) mRNAs and the activity of cathepsin S and its protein in the kidney were increased in the CMC group with HF at 19 weeks compared with control rats. Immunostaining showed strong signaling for cathepsin S in the glomerular cells in the kidney of HF rats. Treatment with either dose of pitavastatin reduced the extent of fibrosis, the collagen type I and III mRNAs, and cathepsin S activity and its protein expression compared with those in CMC rats. The decrease in the ratio of reduced to oxidized glutathione and the increase in macrophage infiltration and NADPH oxidase activity as well as its subunits (including p22phox and gp91phox) and superoxide production apparent in the kidney of CMC rats were also inhibited by pitavastatin in a dose-dependent manner. These benefic effects of pitavastatin were partially mimicked by E64d and accompanied by amelioration of kidney fibrosis. Furthermore, both doses of pitavastatin reduced the levels of AT1R and MR mRNAs but not plasma angiotensin II levels. Conclusions: This is the first report showing that cathepsins are likely to trigger and promote kidney remodeling, and that pitavastatin suppresses the cathepsin activation system by the inhibiting NADPH oxidase-dependent superoxide anion production, leading to the prevention of kidney remodeling in hypertensive HF rats.