Sp1-like protein KLF13 acts as a negative feedback regulator of TGF-β signaling and fibrosis

Transforming growth factor β (TGF-β) is the primary factor that drives fibrosis in most forms of chronic kidney disease. The aim of this study was to identify endogenous regulators of TGF-β signaling and fibrosis. Here, we show that tubulointerstitial fibrosis is aggravated by global deletion of KLF13 and attenuated by adeno-associated virus-mediated KLF13 overexpression in renal tubular epithelial cells. KLF13 recruits a repressor complex comprising SIN3A and histone deacetylase 1 (HDAC1) to the TGF-β target genes, limiting the profibrotic effects of TGF-β. Temporary upregulation of TGF-β induces KLF13 expression, creating a negative feedback loop that triggers the anti-fibrotic effect of KLF13. However, persistent activation of TGF-β signaling reduces KLF13 levels through FBXW7-mediated ubiquitination degradation and HDAC-dependent mechanisms to inhibit KLF13 transcription and offset the anti-fibrotic effect of KLF13. Collectively, our data demonstrate a role of KLF13 in regulating TGF-β signaling and fibrosis. [Display omitted] •KLF13 recruits a repressor complex comprising SIN3A and HDAC1 to TGF-β target genes•TGF-β induces KLF13 expression, forming a negative feedback loop of TGF-β signaling pathway•Persistent TGF-β activation reduces KLF13 levels through FBXW7-mediated degradation•Persistent TGF-β activation reduces KLF13 transcription levels through HDAC Yang et al. show that KLF13, a transcription factor, recruits a repressor complex comprising SIN3A and HDAC1 to TGF-β target genes, limiting the profibrotic effects of TGF-β. TGF-β induces KLF13 expression, creating a negative feedback loop that triggers the anti-fibrotic effect of KLF13.