The Potential Regulatory Roles of Hsa_Circ_0002629/Hsa-miR-532-3p axis for the Retina Neovascularization in Diabetic Retinopathy In Vitro and In Vivo

Diabetic retinopathy (DR), a major microvascular complication of diabetes, can lead to blindness, and its incidence is increasing. CircRNAs have been associated with a variety of tumors and vascular diseases, including DR. Here, we investigated the potential regulatory roles of hsa_circ_0002629/hsa-miR-532-3p in retinal neovascularization in DR. Human retinal microvascular epithelial cells (hRECs) were exposed to three different conditions: low glucose (LG), LG plus mannitol, and high glucose (HG). Then, cells cultured under HG conditions were transfected with short interfering RNAs (siRNAs) targeting hsa_circ_0002629, hsa-miR-532-3p mimics and inhibitors, and a hsa_circ_0002629 overexpression (OE) plasmid to assess hREC viability in hyperglycemia. Streptozotocin (STZ)-induced DR model rats were injected with rno-miR-532-3p agomir or antagomir every 2 weeks. Dual-luciferase reporter assays and FISH were used to investigate the direct binding relationship among hsa_circ_0002629, hsa-miR-532-3p, and HMGA2. QPCR analysis revealed that the expression levels of hsa_circ_0002629 were markedly elevated, while those of hsa-miR-532-3p were decreased in aqueous humor samples of DR patients and HG-exposed hRECs. Hsa_circ_0002629 overexpression improved hREC viability in hyperglycemia, reflected in augmented DNA synthesis, proliferation, migration, and tube formation; however, these effects were partially rescued by hsa-miR-532-3p mimics. In STZ-induced DR model rats, vitreous microinjection of rno-miR-532-3p agomir alleviated the pathologic features DR, including retinal vascular leakage, capillary decellularization, pericyte loss, fibrosis, and gliosis. Moreover, dual-luciferase reporter and FISH assays indicated that hsa-miR-532-3p directly targets both hsa_circ_0002629 and HMGA2. These results indicated that the hsa_circ_0002629/hsa-miR-532-3p axis regulates the development of DR via HMGA2 within the DR microenvironment. The hsa_circ_0002629/hsa-miR-532-3p/HMGA2 signaling pathway plays an essential role in the progression of DR and may represent a promising target for the clinical diagnosis and treatment of this condition.