Finerenone attenuates glomerular fibrosis via inhibiting mesangial SEMA3C in diabetic mice.

Hyperactivation of the mineralocorticoid receptor (MR) causes pro-inflammatory and pro-fibrotic actions, which play a pivotal role in the pathophysiology of diabetic kidney disease (DKD). Finerenone (FIN), a novel non-steroidal mineralocorticoid receptor antagonist, attenuates glomerular endothelial cell fibrosis in diabetic mice, but the precise mechanism remains unclear. Therefore, This study investigates the mechanisms by which FIN improves glomerular endothelial cell fibrosis in diabetic mice. We used db/db mice to evaluate the effect of FIN on DKD in vivo. SEMA3C knockout mice and inhibition of SEMA3C in mesangial cells were used to evaluate the mechanism of FIN on glomerular fibrosis in vitro. Here we show that FIN treatment protected the kidneys against glomerular fibrosis in db/db mice. This effect was associated with mesangial cell-derived SEMA3C downregulation. Furthermore, knockout SEMA3C in vivo or knockdown of SEMA3C in vitro largely blocked the anti-fibrotic role of FIN. Moreover, we demonstrated that FIN inhibited SEMA3C expression mainly by inhibiting the KRAS/FOXM1 signaling pathway in glomerular mesangial cells of diabetic mice. Our findings elucidate a new molecular mechanism for the anti-fibrotic effect of FIN in DKD through inhibiting mesangial SEMA3C-mediated paracrine signaling, and highlight the pivotal role of FIN in preventing renal fibrosis by targeting SEMA3C.