PUBLICATION
Progressively Decreased HCN1 Channels Results in Cone Morphological Defects in Diabetic Retinopathy
- Authors
- Han, R., Jin, M., Xu, G., He, J.
- ID
- ZDB-PUB-220921-20
- Date
- 2022
- Source
- The Journal of neuroscience : the official journal of the Society for Neuroscience 42(43): 8200-8212 (Journal)
- Registered Authors
- He, Jie, Jin, Mengmeng
- Keywords
- none
- MeSH Terms
-
- Animals
- Blood Glucose/metabolism
- Diabetes Mellitus*/metabolism
- Diabetic Retinopathy*/genetics
- Diabetic Retinopathy*/metabolism
- Female
- Male
- Retina/metabolism
- Retinal Cone Photoreceptor Cells/metabolism
- Zebrafish
- PubMed
- 36123121 Full text @ J. Neurosci.
Citation
Han, R., Jin, M., Xu, G., He, J. (2022) Progressively Decreased HCN1 Channels Results in Cone Morphological Defects in Diabetic Retinopathy. The Journal of neuroscience : the official journal of the Society for Neuroscience. 42(43):8200-8212.
Abstract
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping