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Cell death & disease
09 11, 2021;12 (9): 843.

Liproxstatin-1 attenuates unilateral ureteral obstruction-induced renal fibrosis by inhibiting renal tubular epithelial cells ferroptosis.

Bo Zhang, Xiang Chen, Feng Ru, Yu Gan, Bingsheng Li, Weiping Xia, Guoyu Dai, Yao He, Zhi Chen
Author Information
  1. Bo Zhang: Department of Urology, Xiangya Hospital, Central South University, Changsha, Hunan, People's Republic of China.
  2. Xiang Chen: Department of Urology, Xiangya Hospital, Central South University, Changsha, Hunan, People's Republic of China. ORCID
  3. Feng Ru: Department of Urology, Xiangya Hospital, Central South University, Changsha, Hunan, People's Republic of China.
  4. Yu Gan: Department of Urology, Xiangya Hospital, Central South University, Changsha, Hunan, People's Republic of China.
  5. Bingsheng Li: Department of Urology, Xiangya Hospital, Central South University, Changsha, Hunan, People's Republic of China.
  6. Weiping Xia: Department of Urology, Xiangya Hospital, Central South University, Changsha, Hunan, People's Republic of China.
  7. Guoyu Dai: Department of Urology, Xiangya Hospital, Central South University, Changsha, Hunan, People's Republic of China.
  8. Yao He: Department of Urology, Xiangya Hospital, Central South University, Changsha, Hunan, People's Republic of China. heyao1984@163.com. ORCID
  9. Zhi Chen: Department of Urology, Xiangya Hospital, Central South University, Changsha, Hunan, People's Republic of China. czhi1011@126.com. ORCID
PMID: 34511597 DOI: 10.1038/s41419-021-04137-1

Abstract

Renal fibrosis is a common pathological process that occurs with diverse etiologies in chronic kidney disease. However, its regulatory mechanisms have not yet been fully elucidated. Ferroptosis is a form of non-apoptotic regulated cell death driven by iron-dependent lipid peroxidation. It is currently unknown whether ferroptosis is initiated during unilateral ureteral obstruction (UUO)-induced renal fibrosis and its role has not been determined. In this study, we demonstrated that ureteral obstruction induced ferroptosis in renal tubular epithelial cells (TECs) in vivo. The ferroptosis inhibitor liproxstatin-1 (Lip-1) reduced iron deposition, cell death, lipid peroxidation, and inhibited the downregulation of GPX4 expression induced by UUO, ultimately inhibiting ferroptosis in TECs. We found that Lip-1 significantly attenuated UUO-induced morphological and pathological changes and collagen deposition of renal fibrosis in mice. In addition, Lip-1 attenuated the expression of profibrotic factors in the UUO model. In vitro, we used RSL3 treatment and knocked down of GPX4 level by RNAi in HK2 cells to induce ferroptosis. Our results indicated HK2 cells secreted various profibrotic factors during ferroptosis. Lip-1 was able to inhibit ferroptosis and thereby inhibit the secretion of the profibrotic factors during the process. Incubation of kidney fibroblasts with culture medium from RSL3-induced HK2 cells promoted fibroblast proliferation and activation, whereas Lip-1 impeded the profibrotic effects. Our study found that Lip-1 may relieve renal fibrosis by inhibiting ferroptosis in TECs. Mechanistically, Lip-1 could reduce the activation of surrounding fibroblasts by inhibiting the paracrine of profibrotic factors in HK2 cells. Lip-1 may potentially be used as a therapeutic approach for the treatment of UUO-induced renal fibrosis.

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Grants

  1. 81770693/National Natural Science Foundation of China (National Science Foundation of China)

MeSH Term

Animals
Carbolines
Cell Death
Cell Line
Cell Proliferation
Cell Shape
Collagen
Disease Models, Animal
Epithelial Cells
Ferroptosis
Fibrosis
Humans
Iron
Kidney Tubules
Lipid Peroxidation
Male
Mice, Inbred C57BL
Myofibroblasts
Phospholipid Hydroperoxide Glutathione Peroxidase
Quinoxalines
Spiro Compounds
Ureteral Obstruction
Mice

Chemicals

Carbolines
Quinoxalines
RSL3 compound
Spiro Compounds
liproxstatin-1
Collagen
Iron
Phospholipid Hydroperoxide Glutathione Peroxidase
glutathione peroxidase 4, mouse
Journal Article Research Support, Non-U.S. Gov't

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