Abstract: SA-PO161
Fibroblast Growth Factor 23 (FGF-23) Inhibits Gasdermin E (GSDME)-Mediated Pyroptosis via Autophagy in Folic Acid-Induced AKI
Session Information
- AKI: Metabolism and Cell Death
October 26, 2024 | Location: Exhibit Hall, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Acute Kidney Injury
- 103 AKI: Mechanisms
Authors
- Zhang, Lina, Henan Provincial People's Hospital, Zhengzhou, Henan, China
- Wang, Limeng, Henan Provincial People's Hospital, Zhengzhou, Henan, China
- Shao, Fengmin, Henan Provincial People's Hospital, Zhengzhou, Henan, China
- Qin, Wei, Sichuan University West China Medical Center, Chengdu, Sichuan, China
Background
Fibroblast growth factor 23 (FGF23) increases rapidly after acute kidney injure (AKI); however, the precise role of FGF23 in AKI remains unclear.
Methods
In vitro and in vivo folic acid (FA)-induced AKI models were utilized to investigate the role of FGF23, via inhibition with FGFR inhibitors or enhancement with recombinant human FGF23 (rhFGF23) protein.
Results
Serum FGF3 and renal FGF23 protein levels were significantly increased in mice with FA-AKI (Fig. 1 A and B). In vitro, FGF23 levels were observed to rise progressively with higher FA concentrations and extended stimulation periods (Fig. 1 C). Transmission electron microscopy (TEM) strongly suggests the occurrence of pyroptosis in FA-AKI characterized by balloon-like bubbles on the cell membrane and membrane rupture (Fig. 1 D). The expression levels of GSDME-NT and cleaved-caspase 3 experienced an increase with higher concentrations of FA or extended stimulation periods (Fig. 1 E). Similarly, significant increases in GSDME-NT and cleaved-caspase 3 levels were detected in the kidney tissues of the mice with FA-AKI (Fig. 1 F). Furthermore, the presence of autophagy in FA-AKI was confirmed by the observation of autophagosomes and autolysosomes in the FA group, as well as the upregulation of LC3B-II proteins in both in vivo and in vitro FA-AKI models.
The addition of the FGFR pan-inhibitor PD173074 led to reduced cell viability and increased LDH levels compared to the FA group. Additionally, the levels of LC3B-II were significantly reduced, while the levels of cleaved-caspase 3 and GSDME-NT were significantly elevated. The FGFR4 specific inhibitor BLU9931 showed similar results. In contrast, administration of rhFGF23 resulted in opposite results (Fig. 1G, H, and I). In summary, FGF23 can facilitate autophagy then inhibit caspase-3/GSDME-mediated pyroptosis in FA-AKI.
Conclusion
Our study elucidated the protective role of FGF23 in AKI and clarified its underlying mechanism by targeting GSDME-mediated pyroptosis through autophagy.