Angiotensin II blockade decreases TGF-beta1 and matrix proteins in cyclosporine nephropathy.
Angiotensin II (Ang II) is implicated in fibrosis but the precise mechanism of this effect remains unclear. In a model of chronic cyclosporine (CsA) nephropathy, we previously showed that TGF-beta1 plays a role in CsA-induced tubulointerstitial fibrosis and arteriolopathy by stimulating extracellular matrix (ECM) protein synthesis and inhibiting ECM degradation through increasing the synthesis of plasminogen activator inhibitor (PAI)-1. We hypothesized that Ang II contributes to fibrosis by inducing TGF-beta1. Salt-depleted rats were given placebo, CsA alone, CsA + nilvadipine, CsA + hydralazine/hydrochlorthiazide, CsA + losartan (AT1 receptor antagonist) or CsA + enalapril (Ang converting enzyme inhibitor) and were sacrificed at 7 and 28 days. All treated groups achieved similar blood pressures and glomerular filtration rates. The lesion of chronic CsA nephropathy was ameliorated by concomitant therapy with losartan or enalapril at 28 days, a phenomenon not observed in the other treatment groups. Similarly, Ang II blockade resulted in decreased expression of TGF-beta1 and PAI-1 by Northern and ELISA. Similarly, the expression of ECM proteins directly influenced by TGF-beta decreased with Ang II blockade. These results suggest that CsA-induced fibrosis in this model is independent of renal hemodynamics and is mediated, at least partly, through Ang II induction of TGF-beta1 expression.
Shihab
F S
FS
Division of Nephrology, University of Utah and Department of Veterans Affairs Medical Center, Salt Lake City 84132, USA. fshihab@msscc.med.utah.edu
Bennett
W M
WM
Tanner
A M
AM
Andoh
T F
TF
D000804:Angiotensin II / Q000037:antagonists & inhibitors*; D000818:Animals; D015152:Blotting, Northern; D016572:Cyclosporine; D016326:Extracellular Matrix Proteins / Q000378:metabolism*; D007150:Immunohistochemistry; D007166:Immunosuppressive Agents; D007668:Kidney / Q000378:metabolism; D007674:Kidney Diseases / Q000139:chemically induced* / Q000378:metabolism* / Q000473:pathology; D008297:Male; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*
D016326:Extracellular Matrix Proteins; D007166:Immunosuppressive Agents; D017395:Plasminogen Activator Inhibitor 1; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta; D000804:Angiotensin II; D016572:Cyclosporine