Podocyte YAP ablation decreases podocyte adhesion and exacerbates FSGS progression through α3β1 integrin

作者：Guangze Shao, Jitu Xu, Chencheng Hu, Wenlu Jia, Xitong Xu, Yue Gu, Luming Zhang, Zhihuang Zheng, Jiayan Zhong, Siqi Zhu, Shenghao Meng, Zhonghua Zhao, Zhigang Zhang, Jun Liu, Yanyong Xu, Huijuan Wu · 发表于：The Journal of Pathology · 年份：2024 · DOI：10.1002/path.6370 · 被引用次数：5 · 研究领域：Renal Diseases and Glomerulopathies、Hippo pathway signaling and YAP/TAZ、Renal and related cancers

Severe proteinuria in focal segmental glomerulosclerosis (FSGS) is closely associated with decreased adhesion, and subsequent loss, of podocytes. Yes-associated protein (YAP) is a key transcriptional coactivator that plays a significant role in maintaining cellular homeostasis. However, its role in podocyte adhesion and its specific mechanism in FSGS progression remain unclear. In this study, an adriamycin (ADR)-induced FSGS model was established using podocyte-specific Yap knockout (KO) mice and control mice. These mice were further treated with Pyrintegrin, an agonist of α3β1 integrin, or a vehicle. Additionally, an ADR-induced FSGS model was constructed using podocyte-specific Itga3 KO mice, which were subsequently treated with 1-oleoyl lysophosphatidic acid (LPA), a YAP activator, or a vehicle. Our findings demonstrated that YAP was positively correlated with podocyte adhesion. Podocyte-specific Yap KO mice exhibited reduced levels of α3β1 integrin and podocyte adhesion. Yap KO aggravated the ADR-induced reduction in α3β1 integrin and podocyte adhesion, resulting in significantly increased segmental or global glomerulosclerosis and proteinuria. Notably, treatment with a β1 integrin agonist partially ameliorated the decrease of podocyte adhesion and the worsening FSGS progression caused by Yap KO. Mechanistically, YAP was found to transcriptionally regulate α3- and β1 integrin via transcriptional enhanced associate domain 3 (TEAD3), with TEAD3 binding to the promoter regio...