Yoon Hye Eun, Lim Sun Woo, Piao Shang Guo, Song Ji-Hyun, Kim Jin, Yang Chul Woo
Division of Nephrology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea.
Nephron Exp Nephrol. 2012;120(4):e123-33. doi: 10.1159/000342117. Epub 2012 Sep 13.
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.
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.
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.
Statin-mediated upregulation of klotho expression and differential regulation of FoxO expression promote resistance to CsA-induced oxidative stress.
我们最近报道，长期使用环孢素（CsA）诱导的氧化应激与抗衰老基因klotho表达降低有关。本研究评估他汀类药物的抗氧化作用是否可能上调CsA诱导的肾损伤中klotho的表达。
进行了两项独立实验。首先，在正常小鼠肾脏中评估他汀类药物对klotho表达的剂量依赖性作用。其次，在小鼠实验性慢性CsA肾病中评估他汀类药物对klotho表达的作用。我们对klotho、叉头框O转录因子[FoxOs；磷酸化的FoxO1（p-FoxO1）和FoxO3a（p-FoxO3a）]及其靶分子、锰超氧化物歧化酶（MnSOD）、Bim和血红素加氧酶-1进行了免疫组织化学和免疫印迹分析。
他汀类药物治疗在正常小鼠肾脏中以剂量依赖性方式上调klotho表达，并减轻了CsA肾病小鼠肾脏中klotho表达的降低。给予CsA可增加p-FoxO1表达并降低p-FoxO3a表达，而同时给予他汀类药物治疗可逆转这些变化，增加抗氧化酶MnSOD和血红素加氧酶-1的表达，并降低促凋亡蛋白Bim的表达。
他汀类药物介导的klotho表达上调和FoxO表达的差异调节促进了对CsA诱导的氧化应激的抵抗。
