The circRNA MKLN1 regulates autophagy in the development of diabetic retinopathy

Abstract

Diabetic retinopathy (DR) is a common complication in patients with diabetes and has become an important cause of blindness in working-age people. However, the mechanisms involved have not been fully elucidated. Circular RNAs (circRNAs) can play an important role in DR, and they can accurately regulate the expression of target genes through a new regulatory model: the competing endogenous RNA (ceRNA) model. We isolated total RNA from extracellular vesicles in the serum of healthy individuals (Con) and individuals with diabetes mellitus without DR (DM), nonproliferative DR (NPDR), or proliferative DR (PDR) and subjected them to deep sequencing. We found aberrantly high expression of circMKLN1. In a streptozotocin (STZ)-induced mice model of diabetes, the inhibition of circMKLN1 with AAV2 transduction markedly ameliorated retinal acellular vessels and vascular leakage, which was reversed by intravitreal injection of rapamycin, a potent autophagy inducer. In addition, circMKLN1 adsorbs miR-26a-5p as a molecular sponge and mediates high glucose (HG)/methylglyoxal (MG)-induced autophagy in hRMECs. CircMKLN1-silencing treatment reduces HG/MG-related reactive autophagy and inflammation. In addition, miR-26a-5p targeting by circMKLN1 plays an important role in the regulation of Rab11a expression. Thus, either new biomarkers or new therapeutic targets may be identified with the translation of these findings.