Abstract: TH-PO0301
Glomerulonephritis-Associated Thrombin-Induced Podocyte Injury Is PAR4-Gα13 Dependent
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
Author
- Khawaja, Hamzah, Universitat Leipzig, Leipzig, SN, Germany
Group or Team Name
- Group Isermann
Background
Glomerulonephritis (GN) is characterized by proteinuria and renal dysfunction. Increased thrombin generation is linked with GN and podocyte injury, but the mechanism underlying thrombin-induced renal dysfunction in GN is not well known.
Methods
To explore how thrombin effects NLRP3 inflammasome activation in podocytes, we conducted a time kinetic study. To assess thrombin-PAR4 induced podocyte effacement and NLRP3 inflammasome activation, we employed two approaches. First, we used PAR4 knockout (KO) mouse podocytes, and second, we treated human podocytes with inhibitors (BMS3 for PAR4, P1pal-12 for PAR1 and P4pal-10 for PAR1 and PAR4 both). We also explored the therapeutic potential of these inhibitors (BMS3, P1pal-12 and P4pal-10) in mice nephritis model. Finally, we silenced Gαq and Gα13 in human podocytes and stimulated the cells with thrombin, PAR1 activating peptides, and PAR4 activating peptides to elucidate the G-protein subunits involved in the pathways leading to podocyte effacement and NLRP3 inflammasome activation.
Results
PAR4 inhibition alleviated thrombin-induced podocyte effacement and suppressed NLRP3 inflammasome activation in mouse and human podocytes, while PAR1 inhibition did not reduce thrombin-induced NLRP3 inflammasome activation or podocyte effacement. In NTS-induced nephritis mouse model, targeting PAR4 alleviated NLRP3 inflammasome and albuminuria. Whereas, targeting PAR-1 (p1pal-12) failed to restrict NLRP3 activation. Finally, we observed that silencing Gα13 inhibited podocyte effacement whereas silencing both g-protein subunits (Gαq and Gα13) mediated PAR4-thrombin NLRP3 inflammasome activation.
Conclusion
Our findings suggest that targeting PAR4 effectively reduces thrombin-induced podocyte damage and inflammasome activation, providing a potential therapeutic strategy for nephrotic syndrome. These results highlight the crucial role of PAR4 and Gα13 mediated signaling in disease progression, offering a promising approach for future treatments.
Funding
- Government Support – Non-U.S.