| Objective:To explore the anti-fibrotic mechanism of pravastatin and losartan co-treatment in a rat model of chronic cyclosporine A (CsA) nephrotoxicity.Methods:Five subgroups of Sprague-Dawley rats were given vehicle, CsA (15mg/kg s.c), CsA and losartan (10mg/kg in drinking water), CsA and pravastatin (20mg/kg in drinking water), or a combination of CsA, losartan, and pravastatin for 4 weeks. Renal function, systolic blood pressure, and lipid profiles were measured. In addition, renal histopathology (tubulointerstitial fibrosis, TIF) and expressions of transforming growth factorβ1 (TGF-β1) and TGF-βinducible gene-h3 (βig-h3) were evaluated with Northern blot, in situ hybridization, and immunoblotting.Results:Compared with the CsA-treated rats, the pravastatin or losartan-treated rats significantly decreased TIF [losartan:(26±10)%; pravastatin:(31±8)%, P<0.01 vs. (45±6)%] in parallel with down-regulating TGF-β1 [losartan:(230±20)%; pravastatin:(240±15)%, P<0.05] andβig-h3 [losartan:(178±21)%; pravastatin:(167±10)%, P<0.05] expression, and that combined treatment with losartan and pravastatin further decreased these parameters compared with giving each drug alone [TIF:(11±5)%; TGF-(31: (150±28)%;βig-h3:(126±9)%, P<0.05]. Correlation analysis revealed thatβig-h3 expression closely associated with TGF-β1 expression (r=0.787, P<0.001) and TIF (r=0.688, P<0.001). However, there were no significant differences in systolic blood pressure or serum lipid parameters between groups.Conclusion:Combined treatment with pravastatin and losartan provided synergistic effect on fibrotic processes by inhibitingβig-h3 expression in a rat model of chronic CsA-induced nephrotoxicity, and this effect was independent of their hypotensive and hypolipidemic actions. |
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