miR-214 and Its Primary Transcript Dnm3os Regulate Fibrosis and Inflammation Through RAGE Signaling in Diabetic...

Pathologic signaling via the receptor for advanced glycation end products (RAGE) is critical to diabetic kidney disease (DKD) development, whereas RAGE deletion is renoprotective. Noncoding RNAs (ncRNAs), including miRNAs, also play key roles in DKD, including in 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, miRNAs, and fibrotic/inflammatory markers in diabetic RAGE-knockout and wild-type (WT) mice as well as in mesangial cells (MCs) obtained from these mice. Diabetes induction in both RAGE-/- and WT mice was associated with elevated renal expression of miR-214 and its host ncRNA, Dnm3os. miR-214 and Dnm3os levels were remarkably higher in RAGE-/- MCs compared with WT MCs. Overexpression of miR-214 in WT MCs reduced fibrotic/inflammatory gene expression, whereas its inhibition increased these markers. Human DKD tissue demonstrated higher DNM3os expression compared with controls. Notably, miR-214 targeted the RAGE signaling mediator protein diaphanous homolog 1 (DIAPH1), whereas Dnm3os had an opposite effect, enhancing fibrosis and inflammation. miR-214 administration in a DKD mouse model significantly reduced renal fibrosis. These findings suggest a novel mechanism by which miR-214 and Dnm3os act as negative and positive regulators of fibrosis via the RAGE-DIAPH1 axis.

The mechanism of renoprotection as a result of receptor for advanced glycation end products (RAGE) deletion is unclear but seems to involve noncoding (ncRNAs). We investigated the regulation of ncRNAs by RAGE in the context of diabetic kidney disease (DKD), exploring the renal expression of ncRNAs, microRNAs, and fibrotic and inflammatory markers in diabetic RAGE-knockout (KO) and wild-type mice, as well as in mesangial cells (MCs) obtained ex vivo from these mice. Elevated miR-214 levels in diabetic RAGE-KO mice had antifibrotic effects by targeting protein diaphanous homolog 1 (DIAPH1). In contrast, the coexpressed host ncRNA, Dnm3os, had an opposite effect, enhancing fibrosis and inflammation in MCs. We propose a novel regulatory mechanism in DKD involving miR-214 and Dnm3os as negative and positive regulators of fibrosis, respectively, through the RAGE-DIAPH1 axis. Targeting DIAPH1 through miR-214 may represent a novel therapeutic strategy for DKD.