Depleting Yes-Associated Protein in Gli1-Expressing Cells Attenuates Peritoneal Dialysis-Induced Peritoneal Fibrosis

Abstract

Long-term peritoneal dialysis (PD) leads to peritoneal damage and chronic inflammation, resulting in peritoneal fibrosis (PF). Emerging evidence suggests that yes-associated protein (YAP) is a key player in fibrogenesis across various organs. However, its role in PD-induced PF remains unclear. We used NIH/3T3 cells, primary mouse fibroblasts, and conditional YAP knockout (CKO) mice with glioma-associated oncogene 1 (Gli1)-specific YAP deletion. The effects of YAP knockdown and verteporfin, a YAP inhibitor, on fibroblast-to-mesenchymal transition (FMT) and angiogenesis were evaluated. Transforming growth factor-beta (TGF-β) induced YAP expression and promoted fibroblast-to-myofibroblast transition (FMT) in 3T3 fibroblasts, upregulating collagen 1A1, α-smooth muscle actin (α-SMA), and connective tissue growth factor (CTGF). YAP knockdown and verteporfin treatment reduced these FMT markers and inhibited smad2/3 phosphorylation. In vivo, YAP and Gli1-expressing cells were upregulated in PD-induced PF. Conditional YAP knockout in Gli1⁺ cells and verteporfin treatment significantly reduced fibrosis and α-SMA, collagen 1, TGF-β, CTGF, and phosphorylated smad2/3 expression in the peritoneum and peritoneal angiogenesis. YAP plays a pivotal role in FMT during PD-induced PF. Conditional YAP deletion in Gli1-expressing cells and verteporfin treatment represent promising antifibrotic strategies for long-term PD patients.

Keywords: Gli1; myofibroblast; peritoneal fibrosis; yes‐associated protein.