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Abstract: TH-PO432

Ferroptosis Is Activated in TGF-β/Smad3 Dependent Renal Fibrosis

Session Information

Category: Glomerular Diseases

  • 1301 Glomerular Diseases: Fibrosis and Extracellular Matrix

Authors

  • Liu, Kaixiang, Sichuan Academy of Medical Sciences and Sichuan People's Hospital, Chengdu, Sichuan, China
  • Min, Yu, Sichuan Academy of Medical Sciences and Sichuan People's Hospital, Chengdu, Sichuan, China
  • Li, Yi, Sichuan Academy of Medical Sciences and Sichuan People's Hospital, Chengdu, Sichuan, China
  • Li, Guisen, Sichuan Academy of Medical Sciences and Sichuan People's Hospital, Chengdu, Sichuan, China
  • Wang, Li, Sichuan Academy of Medical Sciences and Sichuan People's Hospital, Chengdu, Sichuan, China
  • Zhong, Xiang, Sichuan Academy of Medical Sciences and Sichuan People's Hospital, Chengdu, Sichuan, China
Background

Renal fibrosis is not only the main pathological feature of chronic kidney disease (CKD), but also a reliable prognostic index for disease progression. Ferroptosis is a new pattern of cell death, which is involved in many diseases. However, the role of ferroptosis in renal fibrosis is still unclear. The aim of the study was to explore the functional role and potential mechanism of ferroptosis in renal fibrosis of unilateral ureteral obstruction (UUO) mice.

Methods

Male C57 mice aged from 6 to 8 weeks were operated by UUO surgery to construct kidney fibrosis models. Erastin and Ferrostatin was seperately intraperitoneally injected into UUO mice after ligating the ureter to increase or inhibit the expression of ferroptosis in the kidney. The expression of fibrosis markers (FN, Col-1, α-SMA), TGF-β/Smad3 signaling and ferroptosis indexes(GPX4 and SLC7A11) were determined by immunohistochemistry(IHC), western blotting and electron microscopy. The mechanism of ferroptosis in renal fibrosis was investigated in Smad3 KO mice, and full-length transcriptome was also applied in Sham and UUO group.

Results

The results showed that the fibrosis markers (FN, Col-1, α-SMA) and TGF-β, P-Smad3 were increased, and the expression of GPX4 and SLC7A11 were decreased in UUO group, further electron microscopy also revealed mitochondrial changes of ferroptosis. After treated with Erastin in UUO mice, the degree of renal fibrosis was significantly increased compared with UUO group. In contrast, Ferrostatin alleviated the expression of renal fibrosis by inhibiting ferroptosis. With knockdown of Smad3, ferroptosis were decreased while renal fibrosis was alleviated by IHC and western blotting. Full-length transcriptome showed the activation of TGF-β/smad3 pathway was related to the inhibition of GPX4 in renal fibrosis. Moreover, the result of Co-IP showed there is an interaction between GPX4 and P-Smad3.

Conclusion

This study found that ferroptosis played an important role in TGF-β/Smad3-depended renal fibrosis and the inhibition of Smad3 could attenuated kidney fibrosis by inhibiting GPX4 mediated ferroptosis.