title: Signals mediating Klotho-induced neuroprotection in hippocampal neuronal cells.
abstract: The erythropoietin (Epo) receptor (EpoR) is expressed in the brain and was shown to have neuroprotective effects against brain damage in animal models. A recent study indicated that EpoR and its activity are the downstream effectors of Klotho for cytoprotection in the kidney. Thus, we propose that Klotho can stimulate the expression of EpoR in neuronal cells to enhance Epo-mediated protection. H19-7 hippocampal neuronal cells were treated with recombinant Klotho. In H19-7 cells, Klotho increased the expression of both the EpoR protein and mRNA. Klotho also enhanced the transcription activity of the EpoR promoter in H19-7 cells. Moreover, Klotho augmented the Epo-triggered phosphorylation of Jak2 and Stat5 and protected H19-7 cells from hydrogen peroxide cytotoxicity. The silencing of EpoR abolished the protective effect of Klotho against peroxide-induced cytotoxicity. Finally, the silencing of GATA1 diminished the Klotho-induced increase in EpoR protein and mRNA expression as well as its promoter activity. In conclusion, Klotho increased EpoR expression in neuronal cells through GATA1, thereby enabling EpoR to function as a cytoprotective protein against oxidative injury.
authors: Division of Nephrology, Department of Internal Medicine College of Medicine, jtcheng5503@yahoo.com.tw.
authors: Meng-Fu
authors: MF
authors: Cheng
authors: Institute of Basic Medical Science, National Cheng Kung University, Tainan City, Taiwan.
authors: Li-Jen
authors: LJ
authors: Chen
authors: Department of Nursing, Tzu Chi College of Technology, Hualien City, Taiwan.
authors: Ho-Shan
authors: HS
authors: Niu
authors: The School of Chinese Medicine for Post-Baccalaureate, I-Shou University, Kaohsiung City, Taiwan.
authors: Ting-Ting
authors: TT
authors: Yang
authors: Department of Neurology, Chi-Mei Medical Center, Yong Kang, Tainan City, Taiwan.
authors: Kao-Chang
authors: KC
authors: Lin
authors: Institute of Medical Sciences, Chang Jung Christian University, Gueiren, Tainan City, Taiwan.
authors: Juei-Tang
authors: JT
authors: Cheng
mesh_terms: D000818:Animals; D002452:Cell Count; D002460:Cell Line; D050982:GATA1 Transcription Factor / Q000378:metabolism; D005966:Glucuronidase / Q000378:metabolism / Q000494:pharmacology*; D006624:Hippocampus / Q000166:cytology*; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D011163:Hydroxymethylbilane Synthase / Q000235:genetics / Q000378:metabolism; D053614:Janus Kinase 2 / Q000235:genetics / Q000378:metabolism; D000090265:Klotho Proteins; D009474:Neurons / Q000187:drug effects*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D034622:RNA Interference / Q000502:physiology; D034741:RNA, Small Interfering / Q000494:pharmacology; D051381:Rats; D017467:Receptors, Erythropoietin / Q000235:genetics / Q000378:metabolism; D050799:STAT5 Transcription Factor / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects* / Q000235:genetics; D014162:Transfection; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D050982:GATA1 Transcription Factor; C494688:GATA1 protein, human; D018696:Neuroprotective Agents; D034741:RNA, Small Interfering; D017467:Receptors, Erythropoietin; D050799:STAT5 Transcription Factor; D006861:Hydrogen Peroxide; D011163:Hydroxymethylbilane Synthase; C507927:Jak2 protein, rat; D053614:Janus Kinase 2; D005966:Glucuronidase; D000090265:Klotho Proteins