糖尿病性视网膜病变
视网膜病变
斑马鱼
视网膜
PDX1型
内科学
生物
视网膜
内分泌学
微血管病
糖尿病
医学
眼科
神经科学
遗传学
基因
小岛
作者
Ruyi Han,Mengmeng Jin,Gezhi Xu,Jie He
标识
DOI:10.1523/jneurosci.2550-21.2022
摘要
Historically, diabetic retinopathy has been recognized as a vascular disease. Recent clinical evidence suggests the initiation of diabetic retinopathy with neuropathy rather than microangiopathy. However, the molecular mechanism that drives diabetic retinopathy-associated neuropathy remains mostly unexplored. Here, we reported progressive diabetic retinopathy defects in blood glucose levels, shortening of cone segments and uncoupled appearance of retinal vascular abnormalities from pdx1+/− mutants zebrafish to glucose-treated pdx1+/− mutants zebrafish of both sexes. Further single-cell transcriptomic analysis revealed cones as the most vulnerable retinal neuron type that underwent three developmentally progressive cell states (States 1-3), predominantly present in WT animals, pdx1+/− mutants, and glucose-treated pdx1+/− mutants, respectively. Mechanistically, the expression of hcn1 was progressively decreased in cones during its transition from State 1 to State 3. Furthermore, genetic hcn1 disruption resulted in similar cone segment defects found in the diabetic retinopathy model, suggesting the involvement of progressive hcn1 reduction in diabetic retinopathy-associated cone defects. Thus, our study provided a vertebrate retina model representing progressive diabetic retinopathy defects and further gained new mechanistic insights into the cone morphologic defects as an early neuropathy in diabetic retinopathy. Significance Statement: We create a vertebrate retina model representing the progressive diabetic retinopathy-associated defects using zebrafish. Further systematic single-cell transcriptome analysis reveals two novel cell states of cones in response to different levels of higher glucose and the progressive decrease of HCN1 channels as a mechanism underlying cone defects in diabetic retinopathy.
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