Frontiers in Immunology (Sep 2024)

GSTT1/GSTM1 deficiency aggravated cisplatin-induced acute kidney injury via ROS-triggered ferroptosis

  • Peipei Li,
  • Peipei Li,
  • Peipei Li,
  • Peipei Li,
  • Duopin Li,
  • Duopin Li,
  • Duopin Li,
  • Duopin Li,
  • Yanfang Lu,
  • Yanfang Lu,
  • Yanfang Lu,
  • Yanfang Lu,
  • Shaokang Pan,
  • Shaokang Pan,
  • Shaokang Pan,
  • Shaokang Pan,
  • Fei Cheng,
  • Fei Cheng,
  • Fei Cheng,
  • Fei Cheng,
  • Shen Li,
  • Xiaonan Zhang,
  • Xiaonan Zhang,
  • Xiaonan Zhang,
  • Xiaonan Zhang,
  • Jinling Huo,
  • Jinling Huo,
  • Jinling Huo,
  • Jinling Huo,
  • Dongwei Liu,
  • Dongwei Liu,
  • Dongwei Liu,
  • Dongwei Liu,
  • Zhangsuo Liu,
  • Zhangsuo Liu,
  • Zhangsuo Liu,
  • Zhangsuo Liu

DOI
https://doi.org/10.3389/fimmu.2024.1457230
Journal volume & issue
Vol. 15

Abstract

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IntroductionCisplatin is a widely used chemotherapeutic agent prescribed to treat solid tumors. However, its clinical application is limited because of cisplatin- induced nephrotoxicity. A known complication of cisplatin is acute kidney injury (AKI). Deletion polymorphisms of GSTM1 and GSTT1, members of the glutathione S-transferase family, are common in humans and are presumed to be associated with various kidney diseases. However, the specific roles and mechanisms of GSTM1 and GSTT1 in cisplatin induced AKI remain unclear.MethodsTo investigate the roles of GSTM1 and GSTT1 in cisplatin-induced AKI, we generated GSTM1 and GSTT1 knockout mice using CRISPR-Cas9 technology and assessed their kidney function under normal physiological conditions and cisplatin treatment. Using ELISA kits, we measured the levels of oxidative DNA and protein damage, along with MDA, SOD, GSH, and the GSH/GSSG ratio in wild-type and GSTM1/GSTT1 knockout mice following cisplatin treatment. Additionally, oxidative stress levels and the expression of ferroptosis-related proteins in kidney tissues were examined through Western blotting, qPCR, immunohistochemistry, and immunofluorescence techniques.ResultsHere, we found that GSTT1 and GSTM1 were downregulated in the renal tubular cells of AKI patients and cisplatin-treated mice. Compared with WT mice, Gstm1/Gstt1-DKO mice were phenotypically normal but developed more severe kidney dysfunction and exhibited increased ROS levels and severe ferroptosis after injecting cisplatin.DiscussionOur study revealed that GSTM1 and GSTT1 can protect renal tubular cells against cisplatin-induced nephrotoxicity and ferroptosis, and genetic screening for GSTM1 and GSTT1 polymorphisms can help determine a standard cisplatin dose for cancer patients undergoing chemotherapy.

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