Klotho enhances FoxO3-mediated manganese superoxide dismutase expression by negatively regulating PI3K/AKT pathway during tacrolimus-induced oxidative stress

被引：101

作者：

Lim, Sun Woo ^{[1
,2
]}

Jin, Long ^{[1
,2
]}

Luo, Kang ^{[1
,2
]}

Jin, Jian ^{[1
,2
]}

Shin, Yoo Jin ^{[1
,2
]}

Hong, Sung Yi ^{[2
]}

Yang, Chul Woo ^{[1
,2
,3
]}

机构：

[1] Catholic Univ Korea, Seoul St Marys Hosp, Coll Med, Transplant Res Ctr, Seoul, South Korea

[2] Catholic Univ Korea, Seoul St Marys Hosp, Inst Convergent Res Consortium Immunol Dis, Coll Med, Seoul, South Korea

[3] Catholic Univ Korea, Seoul St Marys Hosp, Div Nephrol, Dept Internal Med,Coll Med, Seoul, South Korea

来源：

CELL DEATH & DISEASE | 2017年 / 8卷

基金：

新加坡国家研究基金会;

关键词：

CIS-TRANS ISOMERASE; IMMUNOSUPPRESSANT FK506; EXPERIMENTAL-MODEL; BINDING-PROTEIN; ANTIAGING GENE; RENAL INJURY; CYCLOSPORINE; IDENTIFICATION; AMELIORATION; ASSOCIATION;

D O I：

10.1038/cddis.2017.365

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

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.

引用

页码：e2972 / e2972

页数：13

共 37 条

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