HuD and Alpha-crystallin A Axis Protects Neuro-Retinal Cells in Early Diabetes

Diabetic retinopathy (DR) is a prevalent microvascular complication of diabetes; however, neuro-retinal degeneration is also observed in patients with diabetes without signs of DR. The mechanisms leading to neuro-retinal cell loss before vascular complications manifest in diabetes remain poorly understood. In this study, we investigated the neuronal RNA-binding protein HuD as a novel regulator of neuro-retinal degeneration in the early stage of diabetes. We determined the expression of HuD and alpha-crystallin A (CRYAA) in the retinal ganglion cell layer. HuD and CRYAA were down-regulated in the retinas of streptozotocin-induced diabetic rats and in neuro-retinal cells (R-28) treated with high glucose. Cryaa mRNA was identified as a novel target transcript of HuD, and we demonstrated that HuD post-transcriptionally regulates the expression of Cryaa mRNA by binding to its 3′-untranslated region. Silencing and overexpression of HuD positively regulated the expressions of Cryaa mRNA and protein. We demonstrated that the increase in inflammatory cytokines such as TNFα, IL-1β, and IL-6 in R-28 cells under hyperglycemic conditions was a result of both CRYAA and HuD levels. Silencing HuD and CRYAA enhanced high glucose-induced R-28 cell death, whereas their overexpression alleviated this effect. HuD post-transcriptionally regulates CRYAA expression, influencing the function and viability of neuro-retinal cells under diabetic conditions. Our results suggest that the HuD/CRYAA axis plays a crucial role in neuro-retinal cells and has the potential to serve as a prognostic factor and therapeutic target for diabetic neuro-retinal degeneration.