Journal
AMERICAN JOURNAL OF PATHOLOGY
Volume 184, Issue 4, Pages 1240-1250Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.ajpath.2013.12.014
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Funding
- NIH [5R01-EY019721]
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Prolyl hydroxylase domain (PHD) proteins catalyze oxygen-dependent prolyl hydroxylation of hypoxia-inducible factor 1 alpha and 2 alpha, tagging them for pVHL-dependent polyubiquitination and proteasomal degradation. In this study, albumin Cre (Alb(cre)) mediated, hepatocyte-specific triple disruption of Phd1, Phd2, and Phd3 (Phd(1/2/3)hK0) promoted Liver erythropoietin (EP0) expression 1246-fold, whereas renal EPO was down-regulated to 6.7% of normal levels. In Phd(1/2/3)hK0 mice, hematocrit levels reached 82.4%, accompanied by severe vascular malformation and steatosis in the Liver. In mice double-deficient for hepatic PHD2 and PHD3 (Phd(2/3)hK0), liver EPO increase and renal EPO loss both occurred but were much less dramatic than in Phd(1/2/3)hK0 mice. Hematocrit levels, vascular organization, and liver lipid contents all appeared normal in Phd(2/3)hK0 mice. In a chronic renal failure model, Phd(2/3)hK0 mice maintained normal hematocrit levels throughout the 8-week time course, whereas foxed controls developed severe anemia. Maintenance of normal hematocrit levels in Phd(2/3) hK0 mice was accomplished by sensitized induction of liver EPO expression. Consistent with such a mechanism, liver HIF-2 alpha accumulated to higher levels in Phd(2/3)hK0 mice in response to conditions causing modest systemic hypoxia. Besides promoting erythropoiesis, EPO is also known to modulate retinal vascular integrity and neovascularization. In Phd(1/2/3)hK0 mice, however, neonatal retinas remained sensitive to oxygen-induced retinopathy, suggesting that local EPO may be more important than hepatic and/or renal EPO in mediating protective effects in the retina.
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