Apelin Alleviated Endothelial‐To‐Mesenchymal Transition via Increasing <scp>BKCa</scp> in Diabetic Nephropathy

Endothelial-to-mesenchymal transition (EndMT) is a critical pathophysiological process in fibrosis which is associated with large conductance calcium-activated potassium (BKCa) channels. Apelin, an adipokine, was reported to alleviate glomerular EndMT mainly caused by hyperglycemia in diabetic nephropathy (DN) and related to BKCa. Therefore, it is supposed that apelin reduced glomerular EndMT by increasing BKCa in glomerular endothelial cells (GECs). The results showed that apelin inhibited diabetic glomerular fibrosis and EndMT in vivo and in vitro, such as increasing endothelial markers CD31, VE-Cadherin and decreasing mesenchymal α-SMA, Desmin, which were reversed after specific APJ knockout in endothelial cells. Meanwhile, apelin increased BKCa, and the suppressed effect of apelin on Wnt/β-Catenin signaling pathway was canceled after BKCa was inhibited by Iberiotoxin (IBTX) in GECs under high glucose condition. Furthermore, IBTX also inhibited SP1 translocation into nuclei, followed by increased expression of DKK1 in apelin treated GECs under high glucose condition. In conclusion, apelin/APJ alleviated EndMT in diabetic glomerular fibrosis by inhibiting the Wnt/β-Catenin pathway, which was mediated by BKCa activated SP1, leading to an increased expression of DKK1 in GECs.