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

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.

Retinal degeneration induced in a mouse model of ischemia–reperfusion injury and its management by pemafibrate treatment

“…With regard to improvements in retinal damage, we found that oral administration of pemafibrate ameliorated the reduction in the amplitudes of the a-wave and b-wave 5 days after retinal I/R injury (Figure 1C,D). Loss of mid-peripheral retinal ganglion cells (observed in our and other previous reports 4,26,47,48 ) was substantially suppressed by the oral administration of pemafibrate 5 days after retinal I/R injury, as analyzed by NeuN staining (Figure 1E,F). We further confirmed that retinal I/R injury-induced retinal cell loss was related to retinal cell death, as analyzed by the TUNEL assay under our current conditions (Figure S2).…”

“…An early response transcription factor c-Jun, a heat shock stress response factor Hsp25, and antioxidant factors (Nrf2 and Hmox-1) were screened based on several previous studies and the public GEO database (Figure S1, and Table S1 and S2). 26,[57][58][59][60][61][62][63] While the expression of c-Jun was remarkably decreased by oral administration of pemafibrate (Figure 3C), the expression levels of Hsp25, Nrf2, and Hmox-1 were considerably increased by oral administration of pemafibrate (Figure 3D,E).…”

“…Retinal I/R injury was induced in mice, as previously described. 26,29,30 A combination of midazolam (40 μg/100 μl; Sandoz, Tokyo, Japan), medetomidine (7.5 μg/100 μl; Orion, Espoo, Finland), and butorphanol tartrate (50 μg/100 μl; Meiji Seika Pharma, Tokyo, Japan), termed 'MMB', 31 was used for mouse anesthesia. Cannulation of the anterior chamber was conducted using a 5 mm 35gauge needle.…”

Retinal Diseases Regulated by Hypoxia—Basic and Clinical Perspectives: A Comprehensive Review

“…Lee et al, demonstrated that 2-azahypoxanthine (AHX), a fairy chemical from the fungus Lepista sordida [ 44 , 45 ], had an inhibitory effect on HIF activation in retinal cells and suppressed Vegf mRNA upregulation under CoCl 2 -induced pseudo hypoxic conditions [ 46 ]. Moreover, Kunimi et al, reported inhibition of the Hif-1α/Bnip3 pathway has a retinal neuroprotective effect [ 47 , 48 , 49 ]. Although the clinical study using HIF-inhibitors has not been started, a HIF inhibitor becomes available in the future, it would have the advantage of inhibiting VEGF in addition to retinal protection.…”

Starburst amacrine cells amplify optogenetic visual restoration through gap junctions

“…The retinas then were flat-mounted, and the sections were mounted on slide glass. The TUNEL assay was performed based on our previous reports 49,50 .…”