Kidney tubulointerstitial disease culminates in renal fibrosis, which is a key determinant of subsequent end-stage renal disease. Kr & uuml;ppel-like factor 4 (KLF4), one of the Yamanaka transcription factors, controls various essential cellular functions, and has been implicated in kidney diseases. However, evidence regarding the role of KLF4 in renal fibrosis specifically within tubular epithelial cells and fibroblasts remains limited. In our study, we observed significant induction of KLF4 protein in tubular and interstitial myofibroblasts from mouse and human fibrotic kidneys. Mice with epithelium or fibroblast-specific deletion of KLF4 showed reduced extracellular matrix (ECM) deposition and downregulation of Hippo signaling components in both fibrotic models. Gain-and loss-of-function experiments supported that KLF4 signaling was responsible for TGF-beta 1-induced ECM production in both tubular cells and fibroblasts. Mechanistically, KLF4 protein can interact with YAP protein, promote YAP activation and drive the expression of downstream signaling proteins, whereas inhibition of the Hippo signaling suppresses KLF4-mediated ECM deposition in both epithelial cells and fibroblasts. Interestingly, KLF4's action in tubular cells may play a more significant role in fibrogenesis compared to its role in fibroblasts. Finally, inhibition of KLF4 signaling with Kenpaullone dramatically improved ECM deposition in fibrotic nephropathy models. Inhibiting KLF4/YAP signaling dramatically improve kidney fibrogenesis, suggesting that targeting this signaling pathway may shine light on therapeutic strategies to mitigate kidney fibrosis in patients with chronic kidney diseases.
[1]Nanjing Med Univ, Affiliated Hosp 1, Dept Nephrol, Nanjing, Peoples R China.
[2]Nanjing Med Univ, Geriatr Hosp, Jiangsu Prov Official Hosp, Jiangsu Prov Geriatr Hosp, Nanjing, Peoples R China.
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