Inhibition of the YAP-E2F2-FGF2 axis in renal tubular cells ameliorates renal fibrosis in chronic kidney disease.

Abstract

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.