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John Au, George Hoppe, Maria J. Zutel, Jonathan E. Sears; Prevention of Oxygen Induced Retinopathy by Systemic PHD Inhibition is Associated with Hepatic but not Retinal Erythropoietin Transcription. Invest. Ophthalmol. Vis. Sci. 2011;52(14):3983.
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© ARVO (1962-2015); The Authors (2016-present)
Hyperoxia is hypothesized to cause retinovascular growth attenuation and vascular obliteration by stimulating the catabolism of hypoxia inducible factor (HIF). Systemic blockade of HIF degradation through HIF prolyl hydroxylase inhibition (HIF PHDi) prevents oxygen-induced retinopathy (OIR). In order to understand whether this protective response is initiated in the liver or locally in the eye, we compared retinal and hepatic erythropoietin (Epo), PHD 1,2,3, and HIF-1a mRNA after systemic HIF PHDi.
Dimethyloxalylglycine (DMOG) was injected intraperitoneally (200 µg/g) at P7 and mice exposed to hyperoxia for 12 hours. Control injections were comprised of intraperitoneal phosphate buffered solution (PBS). A standard mouse OIR model was also used to compare effects of hyperoxia and DMOG. Total RNA isolated from liver, kidney, brain, and retina was analyzed for the levels of Epo, PHD1,2,3, and HIF-1 mRNA using quantitative PCR.
By P12 in OIR model, hyperoxia drastically downregulated expression of Epo in all tested tissues (by 60 to 90%). Return to normoxia resulted in an expected 10-fold induction of retinal Epo mRNA, whereas hepatic Epo transcription remained significantly repressed (40% of control). In contrast, a single intraperitoneal injection of DMOG produced a 12-fold increase in Epo mRNA from liver yet barely discernable increases in Epo mRNA in kidney, brain, and retina at P8. The liver expresses more PHD 1 and 3 than retina. PHD 2 is the major retinal isoform. HIF-1a transcription in all tissues was unaffected by hyperoxia/normoxia treatment, but curiously, HIF-1a mRNA was increased by DMOG especially in the liver. While retinal HIF-1a mRNA only doubled, its hepatic levels rose 7 times after DMOG treatment.
Hepatic Epo transcription fails to be activated by changes in oxygen but is exquisitely sensitive to systemic HIF PHDi. These findings reaffirm the concept that the liver could be efficiently induced to protect multiple end organs during hyperoxia. Transcriptional upregulation of HIF-1α by DMOG may suggest a retinal rescue pathway that is independent of the canonical HIF posttranslational stabilization.
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