| Objective:To observe whether anti-fibrotic effect of losartan (LSRT) and pravastatin (PRVT) isassociated with preservation of Klotho gene expression and inhibition of oxidative stress in an animal model of chronic cyclosporine (CsA) nephropathy.Methods:Total of 40 male ICR mice maintained on a low-sodium diet were given vehicle (olive oil, 1mL.kg-1.day-1), CsA (30 mg.kg-l.day-1), CsA and PRVT (20mg.kg-1.day-1), CsA and LSRT (10 mg.kg-1.day-1), or a combination of CsA, PRVT and LSRT for 28 days. The protective effect of PRVT and LSRT on CsA-induced renal injury were evaluated with basic parameters (body weight, systolic blood pressure, renal function, blood lipid) histopathology, oxidative stress [8-hydroxy-2’-deoxyguanosine (8-OHdG) excretion and manganese superoxide dismutase (MnSOD) expression]. In addition, Klotho protein expression were examined by immunohistochemistry and immunoblotting.Results:Compared with the Vehicle group, CsA group showed renal dysfunction and striped tubulointerstitial fibrosis. LSRT or PRVT treatment improved renal function and tubulointerstitial fibrosis, and combined treatment with LSRT and PRVT further improved above paramers compared with giving each drug alone. In the molecular level, decreased Klotho gene expression induced by CsA was significantly increased by LSRT or PRVT treatment, and further increased when LSRT and PRVT were combimed. Pearson correlation coeffect analysis revealed that Klotho protein expression was correlated with the degree of tubulointerstitial fibrosis (r=-0.819, P<0.001) and oxidative stress (MnSOD:r= 0.763; 8-OHdG:r=-0.827 P<0.001, respectively). There was no significant difference in blood pressure and blood lipid levels between treatment groups.Conclusion:Combined treatment with LSRT and PRVT has a renoprotective effect against CsA-induced nephropathy through upregulation of Klotho protein expression, and these effects were independent on their hypolipidemic and hypotensive actions. |
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