title: Ischaemia-induced retinal neovascularisation and diabetic retinopathy in mice with conditional knockout of hypoxia-inducible factor-1 in retinal Müller cells.
abstract: OBJECTIVE
  Retinal Müller cells are known to produce inflammatory and angiogenic cytokines, which play important roles in diabetic retinopathy. Hypoxia-inducible factor (HIF)-1 has been shown to play a crucial role in retinal inflammation and neovascularisation. We sought to determine the role of Müller cell-derived HIF-1 in oxygen-induced retinopathy (OIR) and diabetic retinopathy using conditional Hif-1α (also known as Hif1a) knockout (KO) mice.
  
  
  METHODS
  Conditional Hif-1α KO mice were generated by crossing mice expressing cyclisation recombinase (cre, also known as P1_gp003) in Müller cells with floxed Hif-1α mice and used for OIR and streptozotocin-induced diabetes to induce retinal neovascularisation and inflammation, respectively. Abundance of HIF-1α and pro-angiogenic and pro-inflammatory factors was measured by immunoblotting and immunohistochemistry. Retinal neovascularisation was visualised by angiography and quantified by counting pre-retinal nuclei. Retinal inflammation was evaluated by leucostasis and vascular leakage.
  
  
  RESULTS
  While the Hif-1α KO mice showed significantly decreased HIF-1α levels in the retina, they exhibited no apparent histological or visual functional abnormalities under normal conditions. Compared with wild-type counterparts, Hif-1α KO mice with OIR demonstrated attenuated overproduction of vascular endothelial growth factor (VEGF) and intercellular adhesion molecule (ICAM)-1, reduced vascular leakage and alleviated neovascularisation in the retina. Under diabetes conditions, disruption of Hif-1α in Müller cells attenuated the increases of retinal vascular leakage and adherent leucocytes, as well as the overproduction of VEGF and ICAM-1.
  
  
  CONCLUSIONS
  Müller cell-derived HIF-1α is a key mediator of retinal neovascularisation, vascular leakage and inflammation, the major pathological changes in diabetic retinopathy. Müller cell-derived HIF-1α is therefore a promising therapeutic target for diabetic retinopathy.
authors.affiliation: Department of Physiology, The University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.
authors.forename: M
authors.initials: M
authors.lastname: Lin
authors.forename: Y
authors.initials: Y
authors.lastname: Chen
authors.forename: J
authors.initials: J
authors.lastname: Jin
authors.forename: Y
authors.initials: Y
authors.lastname: Hu
authors.forename: K K
authors.initials: KK
authors.lastname: Zhou
authors.forename: M
authors.initials: M
authors.lastname: Zhu
authors.forename: Y-Z
authors.initials: YZ
authors.lastname: Le
authors.forename: J
authors.initials: J
authors.lastname: Ge
authors.forename: R S
authors.initials: RS
authors.lastname: Johnson
authors.forename: J-X
authors.initials: JX
authors.lastname: Ma
mesh_terms: D000792:Angiography; D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000139:chemically induced / Q000150:complications / Q000378:metabolism*; D003930:Diabetic Retinopathy / Q000209:etiology* / Q000378:metabolism / Q000503:physiopathology; D004195:Disease Models, Animal; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D019426:Integrases / Q000378:metabolism; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D007511:Ischemia / Q000150:complications* / Q000378:metabolism / Q000503:physiopathology; D018921:Leukostasis / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D012160:Retina / Q000378:metabolism* / Q000473:pathology; D015861:Retinal Neovascularization / Q000209:etiology* / Q000378:metabolism / Q000503:physiopathology; D012171:Retinal Vessels / Q000000981:diagnostic imaging / Q000378:metabolism / Q000503:physiopathology*; D013311:Streptozocin / Q000009:adverse effects; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D042461:Vascular Endothelial Growth Factor A; D018799:Intercellular Adhesion Molecule-1; D013311:Streptozocin; C045073:Cre recombinase; D019426:Integrases