Wang Yu, Wu Yandi, Xiang Li, Xu Chunhua, Lau Chi-Wai, Zhang Chenglin, Deng Dan, Liu Junli, Xia Yin, Ma Ronald, Huang Yu, Wang Li
Department of Biomedical Sciences, City University of Hong Kong, Hong Kong, 999077, China.
Department of Endocrinology and Metabolism, Shenzhen University General Hospital, Shenzhen University, Shenzhen, 518055, China.
Sci China Life Sci. 2025 Sep 10. doi: 10.1007/s11427-024-2880-1.
Fibroblast activation plays a critical role in renal fibrosis, the final common pathway of chronic kidney disease (CKD). Previously, we and others reported that yes-associated protein (YAP) is activated in the renal tubular cells of fibrotic kidneys in human patients. However, the mechanisms by which YAP activation in tubular cells contributes to the activities of renal fibroblasts remain unclear. Here, we demonstrate that activation of YAP specifically in renal tubular cells induces E2F transcription factor 2 (E2F2) binding and promotes fibroblast activation through the secretion of fibroblast growth factor 2 (FGF2). FGF2 stimulated the activation of renal interstitial fibroblasts, which exhibited two key characteristics: enhanced synthesis of collagens and fibronectins, which are hallmarks of the fibrotic process, and increased secretion of chemoattractant cytokines that promoted the migration and activation of macrophages. The recruitment and activation of macrophages further exacerbated renal inflammation, thereby accelerating the progression of fibrogenesis. As confirmed by the clinical data, the serum levels of FGF2 were significantly higher in patients with diabetic kidney disease (DKD) and inversely correlated with the estimated glomerular filtration rate. In addition, inhibition of either YAP, E2F2, or FGF2 significantly ameliorated renal fibrosis and improved kidney function in mouse models of chronic kidney disease and renal fibrosis. Our results revealed that YAP complexed with E2F2 and promoted FGF2 expression and secretion in renal tubular cells, which in turn activated fibroblasts, followed by increased macrophage infiltration and activation. The YAP-E2F2-FGF2 axis represents a potential therapeutic target for renal fibrosis.
成纤维细胞激活在肾纤维化中起关键作用，肾纤维化是慢性肾脏病（CKD）的最终共同通路。此前，我们和其他人报道，Yes相关蛋白（YAP）在人类患者纤维化肾脏的肾小管细胞中被激活。然而，肾小管细胞中YAP激活促进肾成纤维细胞活性的机制仍不清楚。在这里，我们证明，特异性地在肾小管细胞中激活YAP可诱导E2F转录因子2（E2F2）结合，并通过分泌成纤维细胞生长因子2（FGF2）促进成纤维细胞激活。FGF2刺激肾间质成纤维细胞的激活，其表现出两个关键特征：胶原蛋白和纤连蛋白合成增加，这是纤维化过程的标志，以及趋化因子细胞因子分泌增加，促进巨噬细胞的迁移和激活。巨噬细胞的募集和激活进一步加剧了肾脏炎症，从而加速了纤维化的进展。临床数据证实，糖尿病肾病（DKD）患者血清FGF2水平显著升高，且与估计肾小球滤过率呈负相关。此外，在慢性肾脏病和肾纤维化小鼠模型中，抑制YAP、E2F2或FGF2均可显著改善肾纤维化并改善肾功能。我们的结果表明，YAP与E2F2结合并促进肾小管细胞中FGF2的表达和分泌，进而激活成纤维细胞，随后巨噬细胞浸润和激活增加。YAP-E2F2-FGF2轴代表了肾纤维化的一个潜在治疗靶点。
