[P2-3-02] PRIP, a regulatory molecule for AKT signaling, negatively modulates renal fibrosis progression
Keywords:Renal fibrosis、PRIP、AKT/YAP signaling
[Background & Purpose] Chronic kidney disease (CKD) is a worldwide disease and the most important cause of end-stage renal failure. Renal fibrosis and excessive deposition of extracellular matrix (ECM) are the main pathological changes of progressive CKD. The PI3K-AKT-mTORC signaling pathway was known to be involved in fibrosis. PLC-related catalytically inactive protein (PRIP), which was discovered in our previous study, is a molecule that inhibits the recognition of PI3K substrate and suppresses runaway PI3K-AKT signaling. Thus, the purpose of this study is to investigate whether PRIP is involved in renal fibrosis through PI3K-AKT signaling pathway.
[Materials & Methods] Mouse embryonic fibroblasts (MEFs) obtained from wild-type and Prip knockout (Prip-KO) mice were treated with TGF-β1 and analyzed the activation of PI3K/AKT signaling and alterations of YAP/TAZ subcellular location by western blotting. We also evaluated renal fibrosis by histological analysis (Masson’s trichrome staining) in wild-type and Prip knockout mice injected with angiotensin II.
[Results & Conclusion] Activation of PI3K/AKT signaling was more pronounced in TGF-β-stimulated Prip-KO-MEFs than that in WT-MEFs. Consistently, enhanced down-regulation of phospho-YAP and increased YAP nuclear translocation were observed in TGF-β-stimulated Prip-KO MEFs compared to WT-MEFs. Furthermore, angiotensin II injection increased collagen accumulation in Prip-KO mice compared to WT mice. In conclusion, PRIP negatively regulates renal fibrosis progression by modulating YAP/TAZ pathway through PI3K/AKT signaling. We propose PRIP as a novel therapeutic target for CKD.
[Materials & Methods] Mouse embryonic fibroblasts (MEFs) obtained from wild-type and Prip knockout (Prip-KO) mice were treated with TGF-β1 and analyzed the activation of PI3K/AKT signaling and alterations of YAP/TAZ subcellular location by western blotting. We also evaluated renal fibrosis by histological analysis (Masson’s trichrome staining) in wild-type and Prip knockout mice injected with angiotensin II.
[Results & Conclusion] Activation of PI3K/AKT signaling was more pronounced in TGF-β-stimulated Prip-KO-MEFs than that in WT-MEFs. Consistently, enhanced down-regulation of phospho-YAP and increased YAP nuclear translocation were observed in TGF-β-stimulated Prip-KO MEFs compared to WT-MEFs. Furthermore, angiotensin II injection increased collagen accumulation in Prip-KO mice compared to WT mice. In conclusion, PRIP negatively regulates renal fibrosis progression by modulating YAP/TAZ pathway through PI3K/AKT signaling. We propose PRIP as a novel therapeutic target for CKD.