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

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 alpha 3 beta 1 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 alpha 3 beta 1 integrin and podocyte adhesion. Yap KO aggravated the ADR-induced reduction in alpha 3 beta 1 integrin and podocyte adhesion, resulting in significantly increased segmental or global glomerulosclerosis and proteinuria. Notably, treatment with a beta 1 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 alpha 3- and beta 1 integrin via transcriptional enhanced associate domain 3 (TEAD3), with TEAD3 binding to the promoter region of Itga3. Furthermore, Itga3 KO or knockdown abolished the beneficial effects of YAP activation on podocyte adhesion and FSGS progression. In conclusion, our results demonstrate that YAP regulates podocyte adhesion and FSGS progression through its transcriptional regulation of alpha 3 beta 1 integrin via TEAD3. This suggests that the YAP-TEAD3-alpha 3 beta 1 integrin axis may serve as a promising therapeutic target for FSGS. (c) 2024 The Pathological Society of Great Britain and Ireland.