Combined Effects of Losartan and Pravastatin on Interstitial Inflammation and Fibrosis in Chronic Cyclosporine-Induced Nephropathy

Abstract

Statins and angiotensin II type I receptor blockers have synergistic effects on vascular smooth-muscle-cell proliferation and the progression of renal diseases. We evaluated whether combined treatment with losartan (LSRT) and pravastatin (PRVT) affords superior protection compared with their respective monotherapies in treating chronic cyclosporine (CsA)-induced nephropathy in rats. Rats maintained on a low salt diet were given vehicle, CsA (15 mg/kg), CsA and LSRT (10 mg/kg), CsA and PRVT (5 mg/kg), or a combination of CsA, LSRT, and PRVT for 28 days. Basic parameters (renal function, systolic blood pressure, serum high-sensitivity C-reactive protein [hs-CRP], and lipid profiles), histopathology (arteriolopathy, tubulointerstitial fibrosis, and inflammatory cell infiltration), and inflammatory and fibrotic factors (intrarenal CRP, angiotensin II, osteopontin, and transforming growth factor [TGF]-beta1) were studied. LSRT or PRVT treatment significantly attenuated the histopathologic changes induced by CsA, and combined treatment with LSRT and PRVT further decreased these parameters compared with giving each drug alone. Increased levels of angiotensin II, intrarenal CRP, osteopontin, and TGF-beta1 in CsA-treated rat kidney were reduced by treatment with either LSRT or PRVT and were further decreased by the combination of the two drugs. There were no significant differences in systolic blood pressure or serum lipid parameters between groups. Combined treatment with LSRT and PRVT provided synergistic effects in attenuating inflammatory and fibrotic processes in a rat model of chronic CsA-induced nephropathy, and this effect was independent of their hypolipidemic and hypotensive actions.