Neuroprotective role of erythropoietin by antiapoptosis in the retina.
Erythropoietin (EPO) stimulates red blood cell production, in part by inhibiting apoptosis of the red blood cell precursors. The erythropoietic effects of EPO are circadian stage dependent. Retinal injury due to light occurs through oxidative mechanisms and is manifest by retinal and retinal pigment epithelium (RPE) cells apoptosis. The visual cycle might be circadian coordinated as a means of effectively protecting the retina from the detrimental effects of light-induced, oxygen-dependent, free radical-mediated damage, especially at the times of day when light is more intense. We show that the retinal expression of EPO and its receptor (EPOR), as well as subsequent Janus kinase 2 (Jak2) phosphorylations, are each tightly linked to a specific time after oxidative stress and in anticipation of daily light onset. This is consistent with physiological protection against daily light-induced, oxidatively mediated retinal apoptosis. In vitro, we verify that EPO protects RPE cells from light, hyperoxia, and hydrogen peroxide-induced retinal cell apoptosis, and that these stimuli increase EPO and EPOR expression in cultured RPE cells. Together, these data support the premise that EPO and its EPOR interactions represent an important retinal shield from physiologic and pathologic light-induced oxidative injury.
Chung
Hyewon
H
Department of Ophthalmology, Asan Medical Center, Seoul, Korea.
Lee
Hyunju
H
Lamoke
Folami
F
Hrushesky
William J M
WJ
Wood
Patricia A
PA
Jahng
Wan Jin
WJ
D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3 / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004921:Erythropoietin / Q000378:metabolism / Q000494:pharmacology*; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D051547:Heme Oxygenase-1 / Q000378:metabolism; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D053614:Janus Kinase 2 / Q000378:metabolism; D008027:Light / Q000009:adverse effects; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000187:drug effects; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D017467:Receptors, Erythropoietin / Q000378:metabolism; D012164:Retinal Diseases / Q000209:etiology / Q000473:pathology*; D055213:Retinal Pigment Epithelium / Q000187:drug effects; D012243:Rhodopsin / Q000378:metabolism; D013879:Thioredoxins / Q000378:metabolism; D051020:bcl-X Protein / Q000378:metabolism
C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D016760:Proto-Oncogene Proteins c-fos; D017467:Receptors, Erythropoietin; D051020:bcl-X Protein; D004921:Erythropoietin; D013879:Thioredoxins; D012243:Rhodopsin; D051547:Heme Oxygenase-1; C507926:Jak2 protein, mouse; D053614:Janus Kinase 2; D053148:Caspase 3