Abstract: TH-PO0233
Tubular Mst1 Deletion Aggravates Tubular Cell Apoptosis and Renal Fibrosis via Non-YAP Mechanisms
Session Information
- CKD: Mechanisms of Injury and Fibrosis - 1
October 22, 2026 | Location: Exhibit Hall A, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: CKD (Non-Dialysis)
- 2203 CKD (Non-Dialysis): Mechanisms
Authors
- Yang, Jinghan, The Chinese University of Hong Kong Faculty of Medicine, Hong Kong, Hong Kong
- Xia, Yin, The Chinese University of Hong Kong Faculty of Medicine, Hong Kong, Hong Kong
Background
Mammalian Ste20-like kinases 1 and 2 (MST1/2), core components of the Hippo pathway, regulate multiple biological processes. Our previous study showed that tubular double knockout of Mst1 and Mst2 leads to tubular damage, spontaneous inflammation and fibrosis via both YAP-dependent and YAP-independent mechanisms. However, the individual roles of tubular Mst1 and Mst2 remain unknown.
Methods
We generated mice with renal tubule-specific deletion of Mst1 (M1KO), Mst2 (M2KO), two alleles of the Mst1/2 genes (2fKO), and three alleles of the Mst1/2 genes (3fKO). Kidney injury was induced by UUO or cisplatin. MTS, Picrosirius red staining, PAS and TUNEL assay were employed to evaluate kidney injury and fibrosis. qPCR, Western blotting, CCK-8 assay, immunoprecipitation, ATP assay and flow cytometry were used to determine the mechanisms underlying Mst1’s anti-apoptotic activity.
Results
MST1 and MST2 protein levels increased in injured kidneys without changes in respective mRNA levels. M1KO, M2KO, and 2fKO mice showed no alterations in YAP/TAZ phosphorylation under basal conditions or after UUO. 3fKO activated YAP/TAZ signaling only after UUO. These results suggest intrinsic protective mechanisms restrict YAP/TAZ activation in response to Mst1/2 deficiency. M1KO mice exhibited increased tubular cell apoptosis and renal fibrosis following UUO or cisplatin treatment. In vitro, Mst1 knockdown enhanced tubular cell apoptosis by various stressors, while Mst1 overexpression inhibited apoptosis, without affecting YAP/TAZ phosphorylation. RNA-seq showed enrichment of oxidative stress, p53, and P38 MAPK pathways following Mst1 knockdown in renal tubular cells. Mst1 knockdown lowered ATP levels, indicating mitochondrial dysfunction. Finally, IP-mass spectrometry with kidney lysates identified Rassf1a, Rassf3, Rassf4, and Rassf5 as MST1-interacting proteins, and the functions of these interactions are under investigation.
Conclusion
Kidney injury upregulated MST1/2 protein expression. Tubular Mst1 deletion exacerbated kidney injury and fibrosis independent of YAP/TAZ, identifying tubular MST1 as an anti-apoptotic and anti-fibrotic factor in AKI and CKD. The role of MST2 requires further investigation.
Funding
- Government Support – Non-U.S.