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

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

  • Sci China Life Sci. 2025 Sep 10. doi: 10.1007/s11427-024-2880-1.
Yu Wang 1 2,  Yandi Wu 1,  Li Xiang 3,  Chunhua Xu 4,  Chi-Wai Lau 4,  Chenglin Zhang 5,  Dan Deng 6,  Junli Liu 7,  Yin Xia 4,  Ronald Ma 8,  Yu Huang 1 9,  Li Wang 10 11
Affiliations

Affiliations

  • 1 Department of Biomedical Sciences, City University of Hong Kong, Hong Kong, 999077, China.
  • 2 Department of Endocrinology and Metabolism, Shenzhen University General Hospital, Shenzhen University, Shenzhen, 518055, China.
  • 3 State Key Laboratory of Environmental and Biological Analysis and Department of Chemistry, Hong Kong Baptist University, Hong Kong, 999077, China.
  • 4 School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong, 999077, China.
  • 5 Department of Pathophysiology, School of Basic Medical Sciences, Shenzhen University Medical School, Shenzhen, 518060, China.
  • 6 Department of Applied Science, Hong Kong Metropolitan University, Hong Kong, 999077, China.
  • 7 Shanghai Diabetes Institute, Department of Endocrinology and Metabolism, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai Jiao Tong University, Shanghai, 201306, China.
  • 8 Department of Medicine and Therapeutics, Chinese University of Hong Kong, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, 999077, China.
  • 9 Tung Biomedical Sciences Centre, City University of Hong Kong, Hong Kong, 999077, China.
  • 10 Department of Biomedical Sciences, City University of Hong Kong, Hong Kong, 999077, China. li.wang@cityu.edu.hk.
  • 11 Tung Biomedical Sciences Centre, City University of Hong Kong, Hong Kong, 999077, China. li.wang@cityu.edu.hk.
PMID: 40947460 DOI: 10.1007/s11427-024-2880-1
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.

Keywords

E2F2; FGF2; YAP; chronic kidney disease; fibroblast activation; renal fibrosis; tubular injury.

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