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M. Zutel, G. Hoppe, J. E. Sears; Tissue-Specific Expression of Fetal HIF Prolyl Hydroxylases. Invest. Ophthalmol. Vis. Sci. 2010;51(13):4476.
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Hypoxia inducible factor prolyl hydroxylase (HIF PHD) is the rate limiting enzyme that controls the catabolism of the α subunit of HIF-1 protein. Our previous studies have demonstrated that systemic PHD inhibition prevents hyperoxia induced retinovascular obliteration by targeting hepatic PHD. The purpose of this investigation is to compare the tissue-specific, developmental expression of HIF-1α and PHD in the oxygen-induced retinopathy (OIR) model.
Total RNA from OIR and control mice was isolated from liver, kidney, brain, and retina followed by oligo(dT)-primed reverse transcription. Expression of PHD1, PHD2, PHD3, and HIF-1α from postnatal days 6, 12, and 18 was compared using qPCR and normalized to hypoxanthine-guanine phosphoribosyltransferase expression.
The developmental expression patterns of all isoforms of PHD are nearly identical for retina, brain and kidney, demonstrating a gradual decline after P6. In contrast, hepatic PHD 1, 2, and 3 expression progressively increases from P6 through P18. HIF-1α subunit transcript follows a similar pattern for retina, brain, liver, and kidney, peaking at P12. However, retinal HIF-1α demonstrates 4-fold greater expression in retina than in the other organs (p < 3•10-6). The OIR cycle reverses the normal developmental patterns of PHD expression, causing a decline in all hepatic isoforms of PHD expression and a significant increase in retinal PHD 2, and 3 at P18 (p = 4•10-6 and 3•10-4, respectively).
Our data demonstrate that mRNA levels of PHDs are selectively affected by hyperoxia/hypoxia in the liver and retina. The expression patterns within the OIR cycle are opposite to the normal developmental pattern of PHDs. Hepatic and retinal PHD expression have an inverse relationship both during development and within the OIR cycle. Exploiting the reciprocal activities of hepatic and retinal PHD may offer a systemic approach to preventing oxygen-induced retinopathy.
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