Transforming growth factor beta (TGF-?) is activated by the CtBP2-p300-AP1 transcriptional complex in chronic renal failure.

ABSTRACT: Chronic renal failure (CRF), also known as chronic kidney disease (CKD), is a common renal disorder characterized by gradual kidney dysfunction. Molecular dissection reveals that transforming growth factor beta (TGF-?) plays a central role in the pathogenesis of CRF. However, the mechanism underlying TGF-? upregulation has not been demonstrated. Here, we verified that the elevated level of TGF-? was associated with the severity of CRF stages and the activation of TGF-?-mediated signaling in 120 renal biopsies from CRF patients. By analyzing the promoter region of the TGFB1 gene, we identified one AP-1 (activator protein 1) and four NF-?B (nuclear factor kappa-light-chain-enhancer of activated B cells) binding sites. Knockdown of two AP-1 subunits (c-Jun and c-FOS) or blockage of AP-1 signaling with two inhibitors T-5224 and SR11302 could cause the downregulation of TGFB1, whereas knockdown of two NF-?B subunits (p65 and p50) or blockage of NF-?B signaling with two inhibitors TPCA1 and BOT-64 could not change the expression of TGFB1. Using mass spectrometry and coimmunoprecipitation analyses, we found that both c-Jun and c-FOS formed a complex with CtBP2 (C-terminal binding protein 2) and histone acetyltransferase p300. Our in vitro data demonstrated that induction of CtBP2 by recombinant IL-1? (interleukin-1 beta) led to the upregulation of TGFB1 and the activation of TGF-? downstream signaling, while knockdown of CtBP2 resulted in the reversed effects. Using chromatin immunoprecipitation assays, we revealed that the CtBP2-p300-AP1 complex specifically bound to the promoter of TGFB and that knockdown or blockage of CtBP2 significantly decreased the occupancies of the p300 and AP-1 subunits. Our results support a model in which the CtBP2-p300-AP1 transcriptional complex activates the expression of TGFB1, increasing its production and extracellular secretion. The secreted TGF-? binds to its receptors and initiates downstream signaling.

SUBMITTER: Zhou P 

PROVIDER: S-EPMC6949151 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature