LEF1 influences diabetic retinopathy and retinal pigment epithelial cell ferroptosis via the miR-495-3p/GRP78 axis through lnc-MGC.

BACKGROUND: Diabetic retinopathy (DR) is one of the major eye diseases contributing to blindness worldwide. Endoplasmic reticulum (ER) stress in retinal cells is a key factor leading to retinal inflammation and vascular leakage in DR, but its mechanism is still unclear. AIM: To investigate the potential mechanism of LEF1 and related RNAs in DR. METHODS: ARPE-19 cells were exposed to high levels of glucose for 24 hours to simulate a diabetic environment. Intraperitoneally injected streptozotocin was used to induce the rat model of DR. The expression levels of genes and related proteins were measured by RT-qPCR and Western blotting; lnc-MGC and miR-495-3p were detected by fluorescent in situ hybridization; CCK-8 and TUNEL assays were used to detect cell viability and apoptosis; enzyme-linked immunosorbent assay was used to detect inflammatory factors; dual-luciferase gene assays were used to verify the targeting relationship; and the retina was observed by HE staining. RESULTS: LEF1 and lnc-MGC have binding sites, and lnc-MGC can regulate the miR-495-3p/GRP78 molecular axis. In high glucose-treated cells, inflammation was aggravated, the intracellular reactive oxygen species concentration was increased, cell viability was reduced, apoptosis was increased, the ER response was intensified, and ferroptosis was increased. As an ER molecular chaperone, GRP78 regulates the ER and ferroptosis under the targeting of miR-495-3p, whereas inhibiting LEF1 can further downregulate the expression of lnc-MGC, increase the level of miR-495-3p, and sequentially regulate the level of GRP78 to alleviate the occurrence and development of DR. Animal experiments indicated that the knockdown of LEF1 can affect the lnc-MGC/miR-495-3p/GRP78 signaling axis to restrain the progression of DR. CONCLUSION: LEF1 knockdown can regulate the miR-495-3p/GRP78 molecular axis through lnc-MGC, which affects ER stress and restrains the progression of DR and ferroptosis in retinal pigment epithelial cells.