Prevention of experimental cyclosporine-induced interstitial fibrosis by losartan and enalapril. Burdmann, Emmanuel A., Takeshi F. Andoh, Cynthia C. Nast, Andrew Evan, Bret A. Connors, Thomas M. Coffman, Jessie Lindsley, William M. Bennett. Division of Nephrology, Hypertension and Clinical Pharmacology, PP 262, Oregon Health Sciences University, Portland, OR, 97201, Department of Anatomic Pathology, Cedars-Sinai Medical Center, Los Angeles, CA, 90048, Department of Anatomy, University of Indiana Medical Center, Indianapolis, IN, 46202-5120, Division of Nephrology, Duke University, Durham, NC, 27705, Dr. Emmanuel A. Burdmann's present address is Faculdade de Medicina da Universidade de Sao Paulo, Laborat[acute]orio de Fisiopatologia Renal (LIM 16), Av. Dr. Arnaldo 455, 3/s.67, 01246, Sao Paulo, SP, Brasil
APStracts 2:0082F, 1995.
The pathogenesis of renal scarring in chronic cyclosporine 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 cyclosporine-associated chronic tubulointerstitial fibrosis(TIF). Rats kept on normal or low salt diet were given cyclosporine, cyclosporine+enalapril, cyclosporine+losartan, cyclosporine+enalapril+losartan or vehicle for 14 and 28 days. Cyclosporine reduced GFR in rats fed either diet, but only salt -depleted animals developed significant TIF. Cyclosporine 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 cyclosporine-induced increment of cortical [alpha]1 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 cyclosporine, 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 cyclosporine-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 cyclosporine nephropathy. 

Received 25 August 1994; accepted in final form 10 April 1995.
APS Manuscript Number F303-4.
Article publication pending Am. J. Physiol. (Renal Fluid Electrolyte
Physiology).
ISSN 1080-4757 Copyright 1995 The American Physiological Society.
Published in APStracts on 26 May 1995.