Tribbles Homolog 3 Mediates the Development and Progression of Diabetic Retinopathy.
Priyamvada M PitaleIrina V SaltykovaYvonne Adu-AgyeiwaahSergio Li CalziTakashi SatohShizuo AkiraOleg GorbatyukMichael E BoultonMachelle T PardueW Timothy GarveyMohammad AtharMaria B GrantMarina S GorbatyukPublished in: Diabetes (2021)
The current understanding of the molecular pathogenesis of diabetic retinopathy does not provide a mechanistic link between early molecular changes and the subsequent progression of the disease. In this study, we found that human diabetic retinas overexpressed TRIB3 and investigated the role of TRIB3 in diabetic retinal pathobiology in mice. We discovered that TRIB3 controlled major molecular events in early diabetic retinas via HIF1α-mediated regulation of retinal glucose flux, reprogramming cellular metabolism, and governing of inflammatory gene expression. These early molecular events further defined the development of neurovascular deficit observed in mice with diabetic retinopathy. TRIB3 ablation in the streptozotocin-induced mouse model led to significant retinal ganglion cell survival and functional restoration accompanied by a dramatic reduction in pericyte loss and acellular capillary formation. Under hypoxic conditions, TRIB3 contributed to advanced proliferative stages by significant upregulation of GFAP and VEGF expression, thus controlling gliosis and aberrant vascularization in oxygen-induced retinopathy mouse retinas. Overall, our data reveal that TRIB3 is a master regulator of diabetic retinal pathophysiology that may accelerate the onset and progression of diabetic retinopathy to proliferative stages in humans and present TRIB3 as a potentially novel therapeutic target for diabetic retinopathy.
Keyphrases
- diabetic retinopathy
- optical coherence tomography
- gene expression
- endothelial cells
- type diabetes
- diabetic rats
- wound healing
- high glucose
- mouse model
- poor prognosis
- oxidative stress
- single molecule
- dna methylation
- signaling pathway
- vascular endothelial growth factor
- adipose tissue
- machine learning
- drug induced
- mass spectrometry
- high resolution
- genome wide
- artificial intelligence
- atomic force microscopy
- wild type
- radiofrequency ablation