title: The erythropoietin receptor is a downstream effector of Klotho-induced cytoprotection.
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.
authors: Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, Texas, 75390-8885, USA. ming-chang.hu@utsouthwestern.edu
authors: Ming-Chang
authors: MC
authors: Hu
authors: Mingjun
authors: M
authors: Shi
authors: Han J
authors: HJ
authors: Cho
authors: Jianning
authors: J
authors: Zhang
authors: Alevtina
authors: A
authors: Pavlenco
authors: Shuzhen
authors: S
authors: Liu
authors: Sachdev
authors: S
authors: Sidhu
authors: Lily J-S
authors: LJ
authors: Huang
authors: Orson W
authors: OW
authors: Moe
mesh_terms: D058186:Acute Kidney Injury / Q000139:chemically induced* / Q000503:physiopathology*; D000818:Animals; D002460:Cell Line; D019610:Cytoprotection / Q000502:physiology*; D004195:Disease Models, Animal; D005966:Glucuronidase / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D006801:Humans; D006861:Hydrogen Peroxide / Q000009:adverse effects; D066298:In Vitro Techniques; D053614:Janus Kinase 2 / Q000378:metabolism; D007668:Kidney / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D000090265:Klotho Proteins; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D010766:Phosphorylation / Q000187:drug effects; D034741:RNA, Small Interfering / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017467:Receptors, Erythropoietin / Q000502:physiology*; D050799:STAT5 Transcription Factor / Q000378:metabolism
chemical_list: D034741:RNA, Small Interfering; D017467:Receptors, Erythropoietin; D050799:STAT5 Transcription Factor; D006861:Hydrogen Peroxide; D053614:Janus Kinase 2; D005966:Glucuronidase; D000090265:Klotho Proteins
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