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Abstract
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.
Highlights
Klotho, an anti-aging protein, is predominantly expressed in the brain and kidneys,[1] it extends the mouse lifespan by 20–30%,2 and Klotho-deficient mice show multiple agerelated phenotypes and experience premature death.[1,3]
Immunoreactivity against 8-OHdG and 4-HHE, and the urine 8-OHdG concentration markedly increased in the Tac group, which was reversed by recombinant Klotho (rKlotho) treatment
The number of terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL)-positive cells in tissue sections was significantly higher in the Tac group versus the vehicle (VH) group, and this was reduced by the addition of rKlotho (Figures 2i–l, p)
Summary
An anti-aging protein, is predominantly expressed in the brain and kidneys,[1] it extends the mouse lifespan by 20–30%,2 and Klotho-deficient mice show multiple agerelated phenotypes and experience premature death.[1,3]. Recent data showed an association between human longevity and a functional variant of Klotho.[4] A recent report showed that Klotho overexpression in mice extended the lifespan by repressing of insulin or insulin-like growth factor-1 signaling, an evolutionarily conserved mechanism for lifespan extension.[2] Yamamoto et al.[5] reported that Klothoinduced expression of the manganese superoxide dismutase (MnSOD) protein, a mitochondrial antioxidant enzyme that detoxifies superoxides, in COS, HELA, and CHO cells and that the anti-oxidative effect of Klotho potentially contributes to its anti-aging properties. The AKT-mediated phosphorylation of FoxO inhibits FoxO activity by promoting its interaction with 14-3-3 proteins and nuclear exportation, and by inducing its proteasomal degradation.[10] FoxO3a can upregulate MnSOD expression.[2,5,11] FoxO3a functions as a negative regulator of mitochondrial ROS production,[12] and thereby closely associates with resistance to oxidative stress.
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