oxalylglycine and Retinal-Diseases

Activation of hypoxia-inducible factor (HIF) can prevent oxygen-induced retinopathy in rodents. Here we demonstrate that dimethyloxaloylglycine (DMOG)-induced retinovascular protection is dependent on hepatic HIF-1 because mice deficient in liver-specific HIF-1α experience hyperoxia-induced damage even with DMOG treatment, whereas DMOG-treated wild-type mice have 50% less avascular retina (P < 0.0001). Hepatic HIF stabilization protects retinal function because DMOG normalizes the b-wave on electroretinography in wild-type mice. The localization of DMOG action to the liver is further supported by evidence that i) mRNA and protein erythropoietin levels within liver and serum increased in DMOG-treated wild-type animals but are reduced by 60% in liver-specific HIF-1α knockout mice treated with DMOG, ii) triple-positive (Sca1/cKit/VEGFR2), bone-marrow-derived endothelial precursor cells increased twofold in DMOG-treated wild-type mice (P < 0.001) but are unchanged in hepatic HIF-1α knockout mice in response to DMOG, and iii) hepatic luminescence in the luciferase oxygen-dependent degradation domain mouse was induced 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 capillary beds in the retina and in other peripheral tissues.

Topics: Amino Acids, Dicarboxylic; Animals; Erythropoietin; Hyperoxia; Hypoxia-Inducible Factor 1, alpha Subunit; Liver; Mice; Mice, Knockout; Oxygen; Retinal Diseases

To study the effect of systemic hypoxia-inducible factor prolyl hydroxylase inhibition (HIF PHDi) in the rat 50/10 oxygen-induced retinopathy (OIR) model.. Oxygen-induced retinopathy was created with the rat 50/10 OIR model. OIR animals received intraperitoneal injections of dimethyloxalylglycine (DMOG, 200 μg/g), an antagonist of α-ketoglutarate cofactor and inhibitor for HIF PHD, on postnatal day (P)3, P5, and P7. Control animals received intraperitoneal injections of PBS. On P14 and P21, animals were humanely killed and the effect on vascular obliteration, tortuosity, and neovascularization quantified. To analyze HIF and erythropoietin, rats at P5 were injected with DMOG (200 μg/g). Western blot or ELISA measured the levels of HIF-1 and Epo protein. Epo mRNA was measured by quantitative PCR.. Alternating hyperoxia and hypoxia in untreated rats led to peripheral vascular obliteration on day P14 and P21. Rats that were treated with systemic DMOG by intraperitoneal injections had 3 times less ischemia and greater peripheral vascularity (P = 0.001) than control animals treated with PBS injections. Neovascularization similarly decreased by a factor of 3 (P = 0.0002). Intraperitoneal DMOG administration increased the levels of HIF and Epo in the liver and brain. Serum Epo also increased 6-fold (P = 0.0016). Systemic DMOG had no adverse effect on growth of rats treated with oxygen.. One of the many controversies in the study of retinopathy of prematurity is whether hyperoxia or alternating hyperoxia and hypoxia creates the disease phenotype in humans. We have previously demonstrated that PHDi prevents OIR in mice exposed to 5 days of sustained 75% oxygen followed by 5 days of 21% oxygen. The 50/10 rat experiments demonstrate that PHDi is also effective in a 24-hour alternating hyperoxia-hypoxia model. The rat OIR model further validates the therapeutic value of HIF PHDi to prevent retinopathy of prematurity because it reduces oxygen-induced vascular obliteration and retinovascular growth attenuation in prolonged and/or alternating hyperoxia.

Topics: Amino Acids, Dicarboxylic; Animals; Animals, Newborn; Blotting, Western; Disease Models, Animal; Enzyme-Linked Immunosorbent Assay; Erythropoietin; Hyperoxia; Hypoxia-Inducible Factor 1; Injections, Intraperitoneal; Neovascularization, Pathologic; Oxygen; Procollagen-Proline Dioxygenase; Rats; Retinal Diseases; Retinal Vessels