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Abstract: SA-PO1003

Mechanisms of TMEM30A/NLRP3 Inflammasome Pathway-Mediated Podocyte Pyroptosis in FSGS

Session Information

Category: Glomerular Diseases

  • 1403 Podocyte Biology

Authors

  • Hou, Yanpei, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, sichuan, China
  • Li, Yi, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, sichuan, China
  • Wang, Li, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, sichuan, China
  • Li, Guisen, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, sichuan, China
Background

Primary Focal and Segmental Glomerulosclerosis (FSGS) is a renal histological disease characterized by podocyte injury. Transmembrane Protein 30A (TMEM30A) is involved in FSGS podocyte injury, but the underlying mechanism remains unclear.

Methods

Bioinformatics techniques were used to screen datasets related to FSGS in GEO database and search for keygenes. 20 FSGS patients and 20 normal control renal tissues were collected, and multispectral fluorescence staining was used to detect the expression levels of TMEM30A, Nephrin and NLRP3 in renal podocytes. In vivo study, adriamycin(ADR)-induced podocyte injury mice were constructed, and the expression levels of TMEM30A, Nephrin and NLRP3 were observed by multispectral fluorescence staining. Meanwhile, Podocyte specific Tmem30a knockout mice were constructed, and the expression levels of Nephrin and NLRP3 in renal podocytes were detected by multispectral fluorescence staining. In vitro study, ADR was used to induce mouse podocytes and Tmem30a knockdown mouse podocytes were constructed to observe the expression levels of podocyte protective marker and pyroptosis related proteins. After the intervention of NLRP3 inhibitor, the changes of podocyte marker protein and pyroptosis related protein were observed.

Results

In kidney tissues of FSGS patients and ADR-induced mice, We found that the level of TMEM30A and Nephrin significantly reduced and the level of NLRP3 significantly increased with obvious colocalization. In addition, multi-spectral fluorescence staining showed that NLRP3 was significantly increased in the kidney tissue of podocyte-specific Tmem30a knockout mice, colocalized with podocyte-related protein Nephrin. In vitro study, we successfully constructed adriamycin induce mouse podocytes and Tmem30a knockdown mouse podocytes with decreased podocyte marker WT1 and Nephrin. Then, We further found the expressions of pyroptosis-related proteins NLRP3, Caspase 1 and GSDMD were significantly increased. The NLRP3 inhibitor MCC950 could inhibit podocyte pyroptosis and improve podocyte injury.

Conclusion

TMEM30A could inhibit the activation of NLRP3 inflammasome, prevent the production of active Caspase 1 and the cleavage of GSDMD, reduce the podocytes pyroptosis, weaken the damage of podocytes, and improve FSGS.