93-OR: Muller Glial-Derived Zfp36 Expression Protects the Retina from Diabetes-Induced Damages in the Early Stage of Diabetic Retinopathy

Diabetic retinopathy (DR), one of the most common complications of diabetes, is the leading cause of blindness among working-age populations in the US. The molecular mechanisms responsible for the initiation and early progression of DR have not been fully elucidated. This represents a significant barrier to the development of effective therapies to prevent or slow down the initiation of DR. Retinal Muller glial cells have been shown to play important roles in the initiation and early progression of DR. However, the underlying molecular mechanisms remain unclear. To address this question, we profiled the transcriptomic alterations induced by diabetes specifically in Muller glial cells by RNA-seq in the early stage of DR using diabetic rat models. Zinc finger protein 36 homolog (Zfp36), which is a RNA binding protein and functions via destabilizing the mRNAs of pro-inflammatory genes, was found to be upregulated in Muller glia by diabetes at one and two months after the induction of diabetes. As the disease progresses, the level of Zfp36 decreased to below its normal level starting from three months after diabetes. In addition, depleting Zfp36 enhanced gliosis, retinal ganglion cell degeneration, and vascular lesions in diabetic rats. Over-expression of Zfp36 slowed down the occurrence of DR-related retinopathy phenotypes. More importantly, Zfp36 can modulate inflammatory responses induced by diabetes in Muller glial cells. Based on these results, we concluded that Muller glial cells can exert protective roles via Zfp36, and failure of maintaining Zfp36 levels contributes the development of DR. Disclosure S. Wang: None. Funding American Diabetes Association/Pathway to Stop Diabetes (1-16-INI-16)