Transcription factor TFAP2A drives EMT progress by activating BDKRB1 transcription: The potential mechanism by which TFAP2A promotes idiopathic pulmonary fibrosis.

Abstract

Epithelial-mesenchymal transition (EMT)-inducing signals trigger the accumulation of extracellular matrix, thereby contributing to organ pathology, including idiopathic pulmonary fibrosis (IPF). Transcription factor AP-2 alpha (TFAP2A) has been reported to facilitate the EMT process, but its function in IPF remain unknown. A mouse IPF model was established via single intratracheal instillation of bleomycin (BLM). Adenovirus carrying shRNA specifically targeting TFAP2A was administered 24 h prior to BLM challenge to achieve TFAP2A silencing. For in vitro studies, human bronchial epithelial cells (BEAS-2B) underwent lentivirus infection for 48 h to achieve TFAP2A silencing, followed by BLM treatment. We found that the expression of TFAP2A at both mRNA and protein levels was significantly upregulated in fibrotic lung tissue. TFAP2A knockdown alleviated BLM-induced lung injury and fibrosis, as evidenced by reduced collagen deposition and decreased expression of the fibrotic biomarkers α-SMA and Collagen I. Furthermore, TFAP2A silencing inhibited BLM-induced EMT in in the lungs of fibrotic mice, characterized by the upregulation of epithelial markers (Cytokeratin-8 and E-cadherin) and downregulation of mesenchymal markers (Fibronectin, Vimentin, and N-cadherin). In vitro assays demonstrated that BLM exposure increased α-SMA protein expression and promoted the EMT process in BEAS-2B cells, which were reversed by TFAP2A knockdown. Interestingly, TFAP2A significantly upregulated the RNA level of bradykinin receptor B1 (BDKRB1), a fibrosis-inducing factor. Mechanistically, TFAP2A activated BDKRB1 transcription by binding to the promoter of BDKRB1. Overexpression of BDKRB1 abrogated the protective effects of TFAP2A knockdown against lung fibrosis. Overall, our findings demonstrate that TFAP2A drives EMT progression and promotes IPF development by transcriptionally activating BDKRB1, identifying the TFAP2A/BDKRB1 axis as a potential therapeutic target in IPF.