Abstract: TH-PO0382
Targeting mTORC1/S6K1/rpS6 Phosphorylation Prevents Podocyte Hypertrophy and FSGS Lesion Formation
Session Information
- Glomerular Diseases: Genetics to Therapeutics
October 22, 2026 | Location: Exhibit Hall A, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Glomerular Diseases
- 1401 Glomerular Diseases: Mechanisms, including Podocyte Biology
Authors
- Li, Fang, Zhongshan Hospital Fudan University, Shanghai, China
- Wu, Huijuan, Fudan University School of Basic Medical Sciences, Shanghai, China
- Ding, Xiaoqiang, Zhongshan Hospital Fudan University, Shanghai, China
Background
rpS6 phosphorylation drives hypertrophic growth in kidney proximal tubule cells, but its role in podocyte hypertrophy and podocyte loss during focal segmental glomerulosclerosis (FSGS) remains unclear. In this study, we assessed mTORC1/S6K1/rpS6 phosphorylation in kidney biopsy specimens from patients with FSGS and in podocytes from Adriamycin-induced FSGS mouse models.
Methods
Using Multi-omics data, combined with genetic and pharmacologic approaches in both human and transgenic mouse model, we investigated the role of rpS6 phosphorylation in podocyte hypertrophy and loss during development and progression of FSGS.
Results
We found that phosphorylated rpS6 was markedly elevated in podocytes of FSGS patients and Adriamycin-treated mice. Genetic deletion of the Tuberous sclerosis 1 (Tsc1) gene in glomerular podocytes activated mTORC1 signaling, induced rpS6 phosphorylation, and triggered podocyte hypertrophy with pathological changes resembling human FSGS, including podocyte loss and segmental glomerulosclerosis. Consistent with the role of protein phosphatase 1 as a negative regulator of rpS6 phosphorylation, its inhibition further increased rpS6 phosphorylation, promoted podocyte hypertrophy, and worsened FSGS lesion formation. Importantly, blocking rpS6 phosphorylation—either by generating knock-in mice expressing non-phosphorylatable rpS6 or by pharmacologic inhibition of S6K1-mediated rpS6 phosphorylation—significantly attenuated podocyte hypertrophy, reduced podocyte loss, and diminished FSGS lesion development.
Conclusion
Together, these findings provide genetic and pharmacologic evidence that mTORC1/S6K1/rpS6 phosphorylation is a critical mediator of podocyte hypertrophy and depletion in FSGS, and that selective inhibition of rpS6 phosphorylation represents a promising therapeutic strategy to mitigate disease progression.
Acknowledgment
None