Progressively Decreased HCN1 Channels Results in Cone Morphological Defects in Diabetic Retinopathy

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.