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

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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.

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