Inhibition of the HIF-1α/BNIP3 pathway has a retinal neuroprotective effect

Hiromitsu Kunimi, Deokho Lee, Mari Ibuki, Yusaku Katada, Kazuno Negishi, Kazuo Tsubota, Toshihide Kurihara

Research output: Contribution to journalArticlepeer-review

Abstract

Retinal ischemia is a leading cause of irreversible blindness worldwide. Inner retinal dysfunction including loss of retinal ganglion cells is encountered in a number of retinal ischemic disorders. We previously reported administration of two different hypoxia-inducible factor (HIF) inhibitors exerted neuroprotective effects in a murine model of retinal ischemia/reperfusion (I/R) which mimics these disorders, as inner retinal degeneration could be involved in pathological HIF induction. However, this notion needs further investigation. Therefore, in this study, we attempted to use retina-specific Hif-1α conditional knockout (cKO) mice to uncover this notion more clearly under the same condition. Hif-1α cKO mice showed inner retinal neurodegeneration to a lesser extent than control mice. Hif-1α depletion in a murine 661W retinal cell line reduced cell death under pseudohypoxic and hypoxic conditions. Among hypoxia-related genes, the expression of BCL2 19 kDa protein-interacting protein 3 (Bnip3) was substantially upregulated in the inner retinal layer after retinal I/R. In this regard, we further examined Bnip3 depletion in retinal neurons in vitro and in vivo and found the similar neuroprotective effects. Our results support the notion that the HIF-1α/BNIP3 pathway may have a critical role in inner retinal neurodegeneration, which can be linked with the development of new promising therapeutics for inner retinal ischemic disorders.

Original languageEnglish
Article numbere21829
JournalFASEB Journal
Volume35
Issue number8
DOIs
Publication statusPublished - 2021 Aug

Keywords

  • BNIP3
  • HIF
  • inner retinal degeneration
  • neuroprotection
  • retinal ischemia

ASJC Scopus subject areas

  • Biotechnology
  • Biochemistry
  • Molecular Biology
  • Genetics

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