title: Hematological, hepatic, and retinal phenotypes in mice deficient for prolyl hydroxylase domain proteins in the liver.
abstract: Prolyl hydroxylase domain (PHD) proteins catalyze oxygen-dependent prolyl hydroxylation of hypoxia-inducible factor 1α and 2α, 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)hKO) promoted liver erythropoietin (EPO) expression 1246-fold, whereas renal EPO was down-regulated to 6.7% of normal levels. In Phd(1/2/3)hKO 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)hKO), liver EPO increase and renal EPO loss both occurred but were much less dramatic than in Phd(1/2/3)hKO mice. Hematocrit levels, vascular organization, and liver lipid contents all appeared normal in Phd(2/3)hKO mice. In a chronic renal failure model, Phd(2/3)hKO mice maintained normal hematocrit levels throughout the 8-week time course, whereas floxed controls developed severe anemia. Maintenance of normal hematocrit levels in Phd(2/3)hKO mice was accomplished by sensitized induction of liver EPO expression. Consistent with such a mechanism, liver HIF-2α accumulated to higher levels in Phd(2/3)hKO 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)hKO 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.
authors: Center for Vascular Biology, Department of Cell Biology, University of Connecticut Health Center, Farmington, Connecticut.
authors: Li-Juan
authors: LJ
authors: Duan
authors: Center for Vascular Biology, Department of Cell Biology, University of Connecticut Health Center, Farmington, Connecticut.
authors: Kotaro
authors: K
authors: Takeda
authors: Center for Vascular Biology, Department of Cell Biology, University of Connecticut Health Center, Farmington, Connecticut. Electronic address: fong@nso2.uchc.edu.
authors: Guo-Hua
authors: GH
authors: Fong
mesh_terms: D000740:Anemia / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D015153:Blotting, Western; D004195:Disease Models, Animal; D004921:Erythropoietin / Q000378:metabolism*; D007676:Kidney Failure, Chronic / Q000378:metabolism* / Q000473:pathology; D008099:Liver / Q000201:enzymology*; D051379:Mice; D018345:Mice, Knockout; D064828:Prolyl Hydroxylases / Q000172:deficiency*; D060888:Real-Time Polymerase Chain Reaction; D012164:Retinal Diseases / Q000378:metabolism* / Q000473:pathology
chemical_list: D004921:Erythropoietin; D064828:Prolyl Hydroxylases