Purchase this article with an account.
Jonathan Sears, Tamara J Lee, George Hoppe, Suzy Yoon, John Au, M Julieta Zutel; Stabilizing Hepatic HIF-1α Prevents Oxygen-induced Retinopathy. Invest. Ophthalmol. Vis. Sci. 2014;55(13):5386.
Download citation file:
© ARVO (1962-2015); The Authors (2016-present)
Activation of hypoxia inducible factor (HIF) by intraperitoneal (IP) dimethyloxaloylglycine (DMOG), a competitive inhibitor of HIF prolyl hydroxylase (HIF PHi), can prevent oxygen induced retinopathy (OIR) in mice and rats. The purpose of this study was to prove that DMOG induced retinovascular protection is dependent on hepatic HIF-1.
Liver-specific HIF-1α KO mice were generated by crossing a HIF1α 2-lox strain with an albumin-cre strain, both on C57BL/6J (WT) backgrounds. HIF-mediated genes were measured by qPCR (n=5) and ELISA (n=5) and circulating progenitor cells enumerated by flow cytometry (n=6). In vivo localization of HIF PHi was assessed in the luciferase-oxygen dependent degradation domain mouse (luc-ODD). OIR was induced by rearing newborn mice from P7 to P12 in 75% oxygen, their retinas were dissected at P17 and vasculature stained by lectin GS-IB4 (n=10).
Ablation of hepatic HIF1α reduced liver erythropoietin (EPO) mRNA by 50% and serum Epo by 70% in response to IP DMOG compared to the WT. There was no difference in the EPO transcript levels between the WT and KO kidney or retina. Consequently, DMOG produced no increase in the circulating bone marrow-derived angiogenic progenitor cells in KO whereas the WT were doubled (p = 0.0003). Both intraperitoneal and subcutaneous DMOG injection resulted in hepatic luminescence in the luc-ODD mouse. Finally, unlike WT, KO was not protected by DMOG injection in the OIR model measured by the reduction of the avascular retina (p < 0.0001).
We demonstrate that DMOG induced retinovascular protection is dependent on hepatic HIF-1 because mice deficient in liver specific HIF-1α have hyperoxia induced damage even with DMOG treatment. The localization of DMOG action to the liver is further supported by evidence that 1) mRNA and protein erythropoietin levels within liver and serum increase in wild type animals but are reduced in liver specific HIF-1α knockout mice, 2) liver HIF-1α KO mice have decreased levels of endothelial angiogenic precursor cell levels compared to wild type animals in response to DMOG, and 3) hepatic luminescence in the luciferase-oxygen dependent degradation domain (luc-ODD) mouse is created by subcutaneous and intraperitoneal DMOG. These findings uncover a novel endocrine mechanism for retinovascular protection. Activating HIF in visceral organs such as the liver may be a simple strategy to protect peripheral capillary beds.
This PDF is available to Subscribers Only