Blockade of angiotensin II with losartan attenuates transforming growth factor-β1 inducible gene-h3 (ßig-h3) expression in a model of chronic cyclosporine nephrotoxicity

Background: We recently demonstrated that upregulation of the transforming growth factor (TGF)-β1 inducible gene-h3 (ßig-h3) is associated with tubulointerstitial fibrosis (TIF) in a rat model of chronic cyclosporine A (CsA) nephrotoxicity. This study investigated the association between ßig-h3 expression and TIF during losartan treatment in this model. Methods: 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 ßig-h3 expression was evaluated using in situ hybridization, immunohistochemistry and immunoblotting. Histopathology, expressions of TGF-ß1 and intrarenal angiotensin II were compared across treatment groups. Results: Concurrent administration of losartan significantly attenuated ßig-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-β1 mRNA (336 ± 49 vs. 685 ± 63%, p < 0.01 vs. CsA) and the number of angiotensin II-positive glomeruli (18 ± 5 vs. 38 ± 6, p < 0.05 vs. CsA). Conclusion: Losartan is capable of abrogating the upregulation of TGF-β1 and ßig-h3 expression, and this is associated with attenuated tubulointerstitial fibrosis in chronic CsA nephrotoxicity.