Hypoxia-Inducible Factor-1 alpha in Rods Is Neuroprotective Following Retinal Detachment

PURPOSE. Following retinal detachment (RD) photoreceptors (PRs) sustain hypoxic stress and eventually die. Hypoxia-inducible factor-1 alpha (HIF-1 alpha) plays a central role in cellular adaptation to hypoxia. The purpose of this study is to determine the necessity of HIF-1a on PR cell survival after RD. METHODS. Experimental RD was created in mice by injection of hyaluronic acid (1%) into the subretinal space. Mice with conditional HIF-1 alpha knockout in rods (denoted as HIF-1 alpha(Delta rod)) were used. HIF-1 alpha expression in retinas was measured real-time polymerase chain reaction (RT-PCR) and Western blotting. PR cell death after RD was evaluated using TUNEL assay. Optical coherence tomography (OCT) and histology were used to evaluate retinal layer thicknesses and PR cell densities. A hypoxia signaling pathway PCR array was used to examine the expression of HIF-1a target genes after RD. RESULTS. HIF-1 alpha protein levels were significantly increased after RD, and depletion of HIF-1a in rods blunted this increase. A compensatory increase of HIF-2a protein was observed in HIF-1 alpha(Delta rod) mice. Conditional knockout (cKO) of HIF-1a in rods did not lead to any morphologic change in attached retinas but resulted in significantly increased PR cell loss after RD. HIF-1a cKO in rods altered the responses to retinal detachment for 25 out of 83 HIF-1 alpha target genes that were highly enriched for genes involved in glycolysis. CONCLUSIONS. Rod-derived HIF-1 alpha plays a key role in the PR response to RD, mediating the transcriptional activity of a battery of genes to promote PR cell survival.