Fan Chunmeng, Liu Yu, Chang Jing, Huang Mingcong, Gao Zihao, Wang Huade, Zheng Xiang, Li Menghe, Xu Jialiang, Yin Jiming, Zeng Xiangjun
Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Capital Medical University, Beijing, People's Republic of China.
Diabetic Cardiac and Renal Complications, Laboratory for Clinical Medicine, Capital Medical University, Beijing, People's Republic of China.
FASEB J. 2025 Jun 30;39(12):e70747. doi: 10.1096/fj.202500489R.
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.
内皮-间充质转化（EndMT）是纤维化过程中的一个关键病理生理过程，与大电导钙激活钾（BKCa）通道相关。Apelin是一种脂肪因子，据报道它可减轻糖尿病肾病（DN）中主要由高血糖引起的肾小球EndMT，且与BKCa有关。因此，推测Apelin通过增加肾小球内皮细胞（GECs）中的BKCa来减少肾小球EndMT。结果表明，Apelin在体内和体外均能抑制糖尿病肾小球纤维化和EndMT，如增加内皮标志物CD31、血管内皮钙黏蛋白，减少间充质标志物α-平滑肌肌动蛋白（α-SMA）、结蛋白，在内皮细胞中特异性敲除APJ后这些作用被逆转。同时，Apelin增加BKCa，在高糖条件下，GECs中BKCa被iberiotoxin（IBTX）抑制后，Apelin对Wnt/β-连环蛋白信号通路的抑制作用被消除。此外，在高糖条件下，IBTX还抑制了SP1向细胞核的转位，随后增加了Apelin处理的GECs中DKK1的表达。总之，Apelin/APJ通过抑制Wnt/β-连环蛋白通路减轻糖尿病肾小球纤维化中的EndMT，该通路由BKCa激活的SP1介导，导致GECs中DKK1表达增加。
