26rg59 10.3205/26rg59 urn:nbn:de:0183-26rg591 Meeting Abstract Henning Henning Yoshiyuki Y

Institute of Physiology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany

author Schubert Schubert A. A

Institute of Physiology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany

author Sunny Sunny S. S

Department of Physiological Genomics, Biomedical Center, Ludwig-Maximilians-Universität München, Germany

author Hausherr Hausherr J. J

Department of Thoracic and Cardiovascular Surgery, West German Heart and Vascular Center, University of Duisburg-Essen, Essen, Germany

author Padberg Padberg C. C

Institute of Physiology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany

author Grosche Grosche A. A

Department of Physiological Genomics, Biomedical Center, Ludwig-Maximilians-Universität München, Germany

author Fandrey Fandrey J. J

Institute of Physiology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany

author Krishnacoumar Krishnacoumar B. B

Institute of Physiology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany

author Leu Leu T. T

Institute of Physiology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany

author German Medical Science GMS Publishing House

Düsseldorf

610 20260910 engl This is an Open Access article distributed under the terms of the Creative Commons Attribution 4.0 License. Dieser Artikel ist ein Open-Access-Artikel und steht unter den Lizenzbedingungen der Creative Commons Attribution 4.0 License (Namensnennung). M0658 59 Retinologische Gesellschaft 38. Jahrestagung der Retinologischen Gesellschaft Grundlagen-Session Badenweiler 20260703 20260704 26rg59 TextPurpose: Dysregulated metabolic homeostasis in the retina is increasingly recognized as an early pathophysiological driver of retinal degenerative diseases. Hypoxia is at the center of many retinal diseases and causes the stabilization of hypoxia-inducible factors (HIFs), dimeric transcription factors with an oxygen-labile α-subunit and a constitutively expressed β-subunit. The two major isoforms HIF-1 and HIF-2 orchestrate a cascade of adaptations to ensure the survival of hypoxic cells. HIF-2α, the α-subunit of HIF-2, is predominantly expressed in Müller glia and astrocytes. Ist selective localization to Müller glia strongly suggests a role in retinal energy metabolism, although this function has not yet been investigated.Methods: We have characterized the role of HIF-2 in the retina of aged transgenic mice (Hif2afl/fl x Nes-Cre) that lack Hif2a in retinal cells with emphasis on energy metabolism. For this purpose, we have conducted high resolution fluorescence microscopy, as well as immunohistochemical and gene expression analyses. For functional assessment, we have performed Metabolic Flux Analyses of the retina using retinal punches in a Seahorse XFe24 Bioanalyzer. In addition, we have treated porcine retinal organotypic cultures with Belzutifan, an EMA-approved HIF-2 inhibitor, to evaluate the translational potential of HIF-2 inhibition.Results: We found that HIF-2α is predominantly expressed in Müller glia and ganglion cells of the retina. In Hif2a-/- mice, we observed elevated glutamine synthetase (GS) levels in Müller glia, while glial fibrillary acidic protein (GFAP) was decreased. Furthermore, mitochondrial localization of pyruvate dehydrogenase (PDH) was increased in Hif2a-/- mice suggesting better pyruvate utilization. In line with this, functional assessment of the metabolic phenotype revealed that Hif2a-/- mice had an improved metabolic phenotype in terms of mitochondrial respiration and glycolytic flux. Consistent with these findings, the inhibition of HIF-2 signaling by Belzutifan treatment enhanced the metabolic phenotype of the porcine retina. Detailed investigation of retinal neurons and Müller glia isolated via magnetic-activated cell sorting (MACS) revealed that the enhanced metabolic phenotype was driven by retinal neurons rather than Müller glia.Conclusion: Our findings suggest that targeting HIF-2 in the retina is a promising strategy to counteract hypoxia-associated metabolic impairment with a promising translational perspective.Author contributions: The authors Krishnacoumar and Leu contributed equally. 0 0 0 0