The erythropoietin receptor is a downstream effector of Klotho-induced cytoprotection

被引:71
作者
Hu, Ming-Chang [1 ,2 ]
Shi, Mingjun [2 ]
Cho, Han J. [2 ]
Zhang, Jianning [1 ]
Pavlenco, Alevtina [3 ]
Liu, Shuzhen [4 ]
Sidhu, Sachdev [3 ]
Huang, Lily J-S [4 ]
Moe, Orson W. [1 ,2 ,5 ]
机构
[1] Univ Texas SW Med Ctr Dallas, Dept Internal Med, Dallas, TX 75390 USA
[2] Univ Texas SW Med Ctr Dallas, Charles & Jane Pak Ctr Mineral Metab & Clin Res, Dallas, TX 75390 USA
[3] Univ Toronto, Terrence Donelly Ctr Biomed Res, Toronto, ON, Canada
[4] Univ Texas SW Med Ctr Dallas, Dept Cell Biol, Dallas, TX 75390 USA
[5] Univ Texas SW Med Ctr Dallas, Dept Physiol, Dallas, TX 75390 USA
基金
美国国家卫生研究院;
关键词
cytotoxicity; erythropoietin; erythropoietin receptor; Klotho; NRK cell; oxidative stress; RECOMBINANT-HUMAN-ERYTHROPOIETIN; ISCHEMIA-REPERFUSION INJURY; TISSUE PROTECTION; MESSENGER-RNA; SURFACE EXPRESSION; INDUCED APOPTOSIS; UP-REGULATION; CELL; CARCINOMA; CANCER;
D O I
10.1038/ki.2013.149
中图分类号
R5 [内科学]; R69 [泌尿科学(泌尿生殖系疾病)];
学科分类号
100201 [内科学]; 100221 [泌尿外科学];
摘要
Although the role of the erythropoietin (EPO) receptor (EpoR) in erythropoiesis has been known for decades, its role in nonhematopoietic tissues is still not well defined. Klotho has been shown and EPo has been suggested to protect against acute ischemia-reperfusion injury in the kidney. Here we found in rat kidney and in a rat renal tubular epithelial cell line (NRK cells) EpoR transcript and antigen, and EpoR activity signified as EPo-induced phosphorylation of Jak2, ErK, Akt, and Stat5 indicating the presence of functional EpoR. Transgenic overexpression of Klotho or addition of exogenous recombinant Klotho increased kidney EpoR protein and transcript. In NRK cells, Klotho increased EpoR protein, enhanced EPo-triggered phosphorylation of Jak2 and Stat5, the nuclear translocation of phospho-Stat5, and protected NRK cells from hydrogen peroxide cytotoxicity. Knockdown of endogenous EpoR rendered NRK cells more vulnerable, and overexpression of EpoR more resistant to peroxide-induced cytotoxicity, indicating that EpoR mitigates oxidative damage. Knockdown of EpoR by siRNA abolished Epo-induced Jak2, and Stat5 phosphorylation, and blunted the protective effect of Klotho against peroxide-induced cytotoxicity. Thus in the kidney, EpoR and its activity are downstream effectors of Klotho enabling it to function as a cytoprotective protein against oxidative injury.
引用
收藏
页码:468 / 481
页数:14
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