Prevention of experimental cyclosporin-induced interstitial fibrosis by losartan and enalapril

Abstract

The pathogenesis of renal scarring in chronic cyclosporin nephropathy is unknown. In this study, we evaluated the effects of renin-angiotensin system blockade by enalapril and losartan in a salt-dependent model of cyclosporin-associated chronic tubulointerstitial fibrosis (TIF). Rats kept on normal or low-salt diet were given cyclosporin, cyclosporin+enalapril, cyclosporin+losartan, cyclosporin+enalapril#losartan, or vehicle for 14 and 28 days. Cyclosporin reduced glomerular filtration rate (GFR) in rats fed either diet, but only salt-depleted animals developed significant TIF. Cyclosporin also impaired renal concentrating ability and caused tubular enzymuria. Renin-angiotensin system blockade decreased blood pressure (BP) and promoted afferent arteriolar vasodilatation. Losartan reduced plasma renin activity and prevented cyclosporin-induced increment of cortical alpha 1(I) procollagen mRNA. Renin-angiotensin blockade did not improve GFR and tubular function; however, it strikingly prevented TIF development, even in presence of very low BP. Rats treated with cyclosporin, hydralazine, and furosemide achieved BP values similar to losartan or enalapril groups, but there was no protection against interstitial fibrosis development. These results suggest that cyclosporin-related chronic interstitial injury is mediated by angiotensin II and that the mechanisms promoting the interstitial scarring can be dissociated from glomerular and tubular dysfunction in cyclosporin nephropathy.

Inhibition of Prolyl-4-Hydroxylase Ameliorates Chronic Rejection of Mouse Kidney Allografts

“…Inflammatory cell infiltrates are a constant feature in several renal diseases that progress to interstitial fibrosis. For example, inflammatory infiltrates and interstitial fibrosis were attenuated by the use of angiotensinconverting enzyme inhibitors and renal function was improved by treatment in cyclosporine nephrotoxicity in the rat (39). Unlike our study, the reduction in inflammatory infiltrates and scarring were associated with lower TGFb expression in kidneys.…”

Hyperuricemia induces a primary renal arteriolopathy in rats by a blood pressure-independent mechanism

“…Rats administered oxonic acid and cyclosporin showed higher serum uric acid levels in association with worse afferent arteriolar lesions and more severe tubulointerstitial disease (15). Like the uric acid model, the arteriolopathy in experimental cyclosporin nephropathy can also be prevented by enalapril or losartan (2).…”

Expression of Apoptosis-related Genes in Chronic Cyclosporine Nephrotoxicity in Mice

“…In this model, blockade of renin-angiotensin system improved chronic CsA nephrotoxicity (40) and decreased TGFb1 (41). There is enough evidence to suggest that both angiotensin II (42) and TGF-b1 (43), acting either independently or in concert, can induce apoptosis.…”