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

Ming C Hu, Mingjun Shi, Han J. Cho, Jianning Zhang, Alevtina Pavlenco, Shuzhen Liu, Sachdev Sidhu, Jun-Shen Huang, Orson W Moe

Research output: Contribution to journalArticle

40 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)468-481
Number of pages14
JournalKidney International
Volume84
Issue number3
DOIs
StatePublished - Sep 2013

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Erythropoietin Receptors
Cytoprotection
Kidney
Peroxides
Phosphorylation
Antigen Receptors
Proteins
Erythropoiesis
Reperfusion Injury
Hydrogen Peroxide
Small Interfering RNA
Epithelial Cells
Cell Line
Wounds and Injuries

Keywords

  • cytotoxicity
  • erythropoietin
  • erythropoietin receptor
  • Klotho
  • NRK cell
  • oxidative stress

ASJC Scopus subject areas

  • Nephrology

Cite this

The erythropoietin receptor is a downstream effector of Klotho-induced cytoprotection. / Hu, Ming C; Shi, Mingjun; Cho, Han J.; Zhang, Jianning; Pavlenco, Alevtina; Liu, Shuzhen; Sidhu, Sachdev; Huang, Jun-Shen; Moe, Orson W.

In: Kidney International, Vol. 84, No. 3, 09.2013, p. 468-481.

Research output: Contribution to journalArticle

Hu, Ming C ; Shi, Mingjun ; Cho, Han J. ; Zhang, Jianning ; Pavlenco, Alevtina ; Liu, Shuzhen ; Sidhu, Sachdev ; Huang, Jun-Shen ; Moe, Orson W. / The erythropoietin receptor is a downstream effector of Klotho-induced cytoprotection. In: Kidney International. 2013 ; Vol. 84, No. 3. pp. 468-481.
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