Abstract: TH-PO0299
pSTAT3 Inhibitor S3I-201 Preserves Podocyte Integrity and Attenuates Parietal Epithelial Cells and Fibroblast Activation Against an FSGS Model
Session Information
- Glomerular Diseases: Cell Biology
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
- Sriramulu Indhu Kumar, Kirankumar, Stony Brook Medicine, Stony Brook, New York, United States
- Salant, David J., Boston University Chobanian & Avedisian School of Medicine, Boston, Massachusetts, United States
- Juma, Laila Othman Khamis/OK, Stony Brook Medicine, Stony Brook, New York, United States
- Guo, Yiqing, Stony Brook Medicine, Stony Brook, New York, United States
- Mallipattu, Sandeep K., Stony Brook Medicine, Stony Brook, New York, United States
Background
Previous studies have demonstrated that STAT3 activation promotes parietal epithelial cell (PEC) activation and podocyte (podo) loss, contributing to the development of focal segmental glomerulosclerosis (FSGS), glomerulosclerosis, and fibroblast. Podo STAT3 deletion has been shown to prevent podo loss and subsequent PEC activation. Here, we demonstrate that pSTAT3 inhibition (S3I-201, binds to the STAT3 SH2 domain, preventing STAT3 phosphorylation, dimerization, and DNA-binding activity) exerts protective effects across different nephrotoxic serum (NTS)-induced FSGS models.
Methods
FVB/NJ and 129/SvJ mice were preimmunized with sheep IgG and, 5 days later, administered immune-mediated NTS (IM-NTS) and non-immune-mediated NTS (non-IM-NTS) (100 μL, IP), as crescentic glomerulonephritis and FSGS models, respectively. PBS/IgG-treated mice served as controls. Mice were collected at days 7 and 14 post-NTS, and S3I-201 (DMSO control) was administered every other day starting 24 hours post-NTS until sacrifice. Urine albumin was measured by ELISA. pSTAT3 inhibition was validated by Western blot, RT-PCR, and immunostaining. PAS and H&E staining for histology. RT-PCR and immunostaining to assess podo (WT1, SYNPO), PEC (AKAP12, CD44), fibroblast (αSMA, Vimentin), collagen (Col1a1, Picrosirius Red), and proliferation (Ki-67) markers.
Results
IM-NTS-treated mice exhibited increased podo loss (WT1, SYNPO), PEC activation (CD44), crescent formation, albuminuria, FSGS lesions, Glomerular cellular proliferation (Ki-67), tubular injury (LTL, NGAL, KIM-1), and interstitial fibrosis (Sirius red, αSMA). S3I-201 significantly attenuated these changes by day 7. These changes were sustained through day 14, along with reduced αSMA and vimentin expression in glomerular and interstitial regions. Similarly, in the non-IM-NTS model, pSTAT3 inhibition was confirmed as early as day 7 and reduced UACR beginning at day 7, with significant reductions in podocyte injury, FSGS lesions, tubular injury, and interstitial fibrosis as compared to vehicle-treated groups.
Conclusion
S3I-201 attenuated FSGS and glomerulosclerosis by reducing podo injury, PEC activation, fibrosis, and tubular damage while preserving kidney function, suggesting its therapeutic potential in glomerular disease.
Funding
- NIDDK Support