LncRNA MEG3 inhibits renal fibrinoid necrosis of diabetic nephropathy via the MEG3/miR-21/ORAI1 axis.

Abstract

Diabetic nephropathy (DN) is one of the most common and lethal diabetic complications worldwide and is associated with a high risk of mortality. However, the exact mechanism behind its development is unknown. The mesangial cells (MCs) and non-coding RNAs are critical for DN, but it is unknown whether a MEG3/miR-21/ORAI1 regulatory axis exists in MCs. Hence, in this study, we aimed to understand whether the MEG3/miR-21/ORAI1 regulatory axis has a role in the pathophysiology of DN. We demonstrated that high-glucose stimuli downregulated MEG3 and ORAI1 expression while enhancing miR-21 expression. Exogenous miR-21 mimics inhibited ORAI1 expression, which was partially salvaged or reversed by MEG3 overexpression. Furthermore, RIP assay demonstrated that the beads labeled with AGO2 antibody could enrich more miR-21 and MEG3 than those labeled with control IgG antibody; both of them formed the RNA-induced silencing complex. Further, the biochemical indicators of db/db mice significantly improved, and renal fibrinoid necrosis was ameliorated using a miR-21 inhibitor. The MEG3/miR-21/ORAI1 axis regulates the manifestation of DN in diabetic mice and MCs, and the miR-21 inhibitor can be a potential therapeutic strategy to alleviate DN, once the presence of such an axis is found in humans.