Mammalian members of the forkhead box protein O (FoxO) class of transcription factors are implicated in the regulation of oxidative stress, and FoxO proteins are negatively regulated by the phosphatidylinositol 3-kinase (PI3K)–AKT signaling pathway. We examined the effect of Klotho on the PI3K/AKT pathway and manganese superoxide dismutase (MnSOD) during tacrolimus (Tac)-induced oxidative stress. Klotho-treated mice showed decreased Tac-induced oxidative stress accompanied by functional and histological improvements. Klotho inhibited the PI3K/AKT-mediated phosphorylation of FoxO3a and enhanced FoxO3a binding to the MnSOD promoter. Klotho increased MnSOD mRNA and protein expression in mitochondria. In addition, Klotho reduced Tac-induced mitochondrial dysfunction and decreased mitochondrial reactive oxygen species production, and these effects were enhanced by blocking PI3K activity with LY294002. Collectively, our data showed that Klotho protects Tac-induced oxidative stress by negatively regulating the PI3K/AKT pathway and subsequently enhancing FoxO3a-mediated MnSOD expression.

CITATION INFORMATION: Lim S., Luo K., Il J., Shin Y., Ko E., Chung B., Yang C. Klotho Enhances FoxO3-Mediated Manganese Superoxide Dismutase Expression by Negatively Regulating PI3K/AKT Pathway during Tacrolimus-Induced Oxidative Stress Am J Transplant. 2017;17 (suppl 3).

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