BACKGROUND: We recently reported that long-term cyclosporine (CsA)-induced 
oxidative stress is associated with decreased expression of klotho, an 
anti-aging gene. This study evaluated whether the antioxidant effect of statin 
might upregulate klotho expression in CsA-induced renal injury.
METHODS: Two separate experiments were performed. First, the dose-dependent 
effect of statin on klotho expression was evaluated in normal mouse kidneys. 
Second, the effect of statin on klotho expression was evaluated in experimental 
chronic CsA nephropathy in mice. We performed immunohistochemistry and 
immunoblotting for klotho, Forkhead box O transcription factors [FoxOs; 
phosphorylated FoxO1 (p-FoxO1) and FoxO3a (p-FoxO3a)] and their target 
molecules, manganese superoxide dismutase (MnSOD), Bim and hemeoxygenase-1.
RESULTS: Statin treatment upregulated klotho expression in a dose-dependent 
manner in the normal mouse kidney and alleviated the decrease in klotho 
expression in kidneys exhibiting CsA nephropathy. CsA administration increased 
p-FoxO1 expression and decreased p-FoxO3a expression, whereas concurrent statin 
treatment reversed these changes, increased the expression of the antioxidant 
enzymes MnSOD and hemeoxygenase-1 and decreased the expression of the 
pro-apoptotic protein Bim.
CONCLUSION: Statin-mediated upregulation of klotho expression and differential 
regulation of FoxO expression promote resistance to CsA-induced oxidative 
stress.