Inhibition of the HIF-1α/BNIP3 pathway has a retinal neuroprotective effect
Inhibition of the HIF-1α/BNIP3 pathway has a retinal neuroprotective effect
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DOI：
10.1096/fj.202100572r
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发表时间：
2021-08-01
期刊：
影响因子：
4.8
通讯作者：
Kurihara, Toshihide
中科院分区：
文献类型：
--
作者：
Kunimi, Hiromitsu;Lee, Deokho;Kurihara, Toshihide
视网膜缺血是世界范围内不可逆性失明的主要原因。视网膜内功能障碍，包括视网膜神经节细胞的丢失，在许多视网膜缺血性疾病中都会遇到。我们先前报道了两种不同的缺氧诱导因子(HIF)抑制剂在模拟这些障碍的小鼠视网膜缺血/再灌注(I/R)模型中发挥神经保护作用，因为视网膜内变性可能参与病理性HIF的诱导。然而，这一观点还需要进一步调查。因此，在这项研究中，我们试图使用视网膜特异性Hif-1α条件性基因敲除(CKO)小鼠在相同条件下更清楚地揭示这一概念。HIF-1αCKO小鼠视网膜内神经变性程度较对照小鼠轻。小鼠视网膜细胞系661W中HIF-1α的缺失减少了假低氧和低氧条件下的细胞死亡。在低氧相关基因中，BCL2 19 kDa蛋白相互作用蛋白3(Bnip3)在视网膜I/R后表达显著上调。在这方面，我们进一步研究了Bnip3在体外和体内视网膜神经元中的缺失，发现了相似的神经保护作用。我们的结果支持HIF-1α/BNIP3通路可能在视网膜内神经退行性变中起关键作用的观点，这可能与开发治疗视网膜内缺血性疾病的新疗法有关。
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-1 alpha conditional knockout (cKO) mice to uncover this notion more clearly under the same condition. Hif-1 alpha cKO mice showed inner retinal neurodegeneration to a lesser extent than control mice. Hif-1 alpha 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-1 alpha/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.