MicroRNA ‐mediated Ets1 repression in retinal endothelial cells: A novel anti‐angiogenic mechanism in nonproliferative diabetic retinopathy

Abstract Aims This study aimed to discover the regulatory mechanisms contributing to angiogenesis in nonproliferative diabetic retinopathy (NPDR). Materials and Methods This study employed a case–control design involving type 2 diabetes patients with and without NPDR. We utilised microRNA sequencing to analyse plasma and retina samples from T2D patients, to identify both existing and novel microRNAs relevant to retinal health. An integrative approach combining single‐cell sequencing data from mouse and rat models was used to explore the molecular mechanism in retinal cells under diabetes condition. Results We identified a specific set of circulating microRNAs with strong predictive potential for distinguishing NPDR patients. In addition, a novel microRNA targeting the ETS proto‐oncogene 1 (Ets1), a key regulator of microvascular angiogenesis, was found to be upregulated in the plasma of NPDR patients. Analysis of single‐cell sequencing data suggested that Ets1 expression was downregulated in diabetic endothelial cells and was associated with the repression of Angiopoietin‐1 and phosphoinositide 3‐kinase‐Akt (PI3K‐Akt) signalling pathways, indicating an anti‐angiogenic mechanism in NPDR. Conclusions The identification of a novel microRNA involved in the anti‐angiogenic mechanism in NPDR provides new insights into the molecular underpinnings of endothelial dysfunction in diabetic retinopathy. Our retina‐specific circulating microRNA panel has potential utility in risk assessment and early detection of NPDR.