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 Gli1cells 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.
Overview
- The study investigates the role of yes-associated protein (YAP) in peritoneal dialysis (PD)-induced peritoneal fibrosis (PF).
- NIH/3T3 cells, primary mouse fibroblasts, and conditional YAP knockout (CKO) mice with glioma-associated oncogene 1 (Gli1)-specific YAP deletion were used to evaluate the effects of YAP knockdown and verteporfin on fibroblast-to-mesenchymal transition (FMT) and angiogenesis.
- The primary objective of the study is to understand the mechanisms of PD-induced PF and to identify potential therapeutic targets for long-term PD patients.
Comparative Analysis & Findings
- YAP knockdown and verteporfin treatment reduced fibroblast-to-myofibroblast transition (FMT) markers, including collagen 1A1, α-smooth muscle actin (α-SMA), and connective tissue growth factor (CTGF), in NIH/3T3 cells and primary mouse fibroblasts.
- In vivo, YAP and Gli1-expressing cells were upregulated in PD-induced PF, and conditional YAP knockout in Gli1cells 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.
- These findings suggest that YAP plays a pivotal role in FMT during PD-induced PF and that conditional YAP deletion in Gli1-expressing cells and verteporfin treatment represent promising antifibrotic strategies for long-term PD patients.
Implications and Future Directions
- The study's findings highlight the potential of targeting YAP as a therapeutic strategy for preventing or treating PD-induced PF, which can have significant implications for the long-term management of patients on peritoneal dialysis.
- Future studies could investigate the molecular mechanisms underlying YAP's role in PD-induced PF and evaluate the efficacy of YAP inhibition in preventing or treating PF in patients.
- Additionally, the study's findings could be used to develop novel biomarkers for identifying patients at high risk of developing PF, allowing for earlier interventions to prevent or delay disease progression.