miR-214 and its primary transcript Dnm3os regulate fibrosis and inflammation through RAGE signalling in diabetic kidney disease

Pathological signaling via the receptor for advanced glycation end-products (RAGE) is critical in diabetic kidney disease (DKD) development, while RAGE deletion is reno-protective. Non-coding RNAs (ncRNAs), including microRNAs (miRs), also play key roles in DKD, including renal fibrosis. However, the involvement of ncRNAs in RAGE signaling remains unclear. This study investigated the regulation of ncRNAs by RAGE and assessed renal expression of ncRNAs, miRs, fibrotic/inflammatory markers in diabetic RAGE knockout (KO) and wild-type (WT) mice, as well as in mesangial cells (MCs) obtained from these mice. Diabetes induction in both RAGE^-/- and WT mice exhibited elevated renal expression of miR-214 and its host ncRNA, Dnm3os. miR-214 and Dnm3os levels were remarkably higher in RAGE^-/- MCs compared to WT MCs. Overexpression of miR-214 in WT MCs reduced fibrotic/inflammatory gene expression, while its inhibition increased these markers. Human DKD tissue demonstrated higher DNM3os expression compared to controls. Notably, miR-214 targeted the RAGE signaling mediator diaphanous1 (DIAPH1), while Dnm3os had an opposing effect, enhancing fibrosis and inflammation. miR-214 administration in a DKD mouse model significantly reduced renal fibrosis. These findings propose a novel mechanism where miR-214 and Dnm3os act as negative and positive regulators of fibrosis via the RAGE-DIAPH1 axis.