Sp1-like protein KLF13 acts as a negative feedback regulator of TGF-(3 signaling and fibrosis

Transforming growth factor (3 (TGF-(3) 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-(3 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-(3 target genes, limiting the profi-brotic effects of TGF-(3. Temporary upregulation of TGF-(3 induces KLF13 expression, creating a negative feedback loop that triggers the anti-fibrotic effect of KLF13. However, persistent activation of TGF-(3 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-(3 signaling and fibrosis.

Automated summary

This study identifies the role of KLF13 in regulating TGF-(3 signaling and fibrosis. KLF13 recruits a repressor complex to the target genes of TGF-(3, limiting its fibrotic effects. However, persistent activation of TGF-(3 signaling reduces KLF13 levels through degradation and transcriptional inhibition mechanisms, offsetting the anti-fibrotic effect of KLF13.