Blockade of Angiotensin II with Losartan Attenuates Transforming Growth Factor beta1 Inducible Gene-h3 (betaig-h3) Expression in a Model of Chronic Cyclosporine Nephrotoxicity

摘要

Background: We recently demonstrated that upregula-tion of the transforming growth factor (TGF)-(31 inducible gene-h3 ((3ig-h3) is associated with tubulointerstitial fibrosis (TIF) in a rat model of chronic cyclosporine A (CsA) nephrotoxicity. This study investigated the association between (3ig-h3 expression and TIF during losartan treatment in this model. Adult Sprague-Dawley rats kept on a salt-depleted diet (0.05% sodium) were treated daily for 4 weeks with vehicle (olive oil, 1 ml/kg), CsA (15 mg/kg) or both CsA and losartan (10 mg/kg in drinking water). The effect of losartan on betaig-h3 expression was evaluated using in situ hybridization, immunohisto-chemistry and immunoblotting. Histopathology, expressions of TGF-beta1 and intrarenal angiotensin II were compared across treatment groups. Results: Concurrent administration of losartan significantly attenuated (3ig-h3 mRNA and protein expression within the tubulointerstitium of CsA-treated kidneys. This was accompanied by the retardation of TIF (18+-5 vs. 39+-5%, p < 0.01 vs. CsA) and the expression of TGF-beta1 mRNA (336+-49 vs. 685+-63%, p < 0.01 vs. CsA) and the number of angiotensin ll-positive glomeruli (18+-5 vs. 38+-6, p < 0.05 vs. CsA). Conclusion: Losartan is capable of abrogating the upregulation of TGF-beta1 and betaig-h3 expression, and this is associated with attenuated tubulointerstitial fibrosis in chronic CsA nephrotoxicity.