Targeting mPGES-2 to protect against acute kidney injury via inhibition of ferroptosis dependent on p53

  • Cell Death Dis. 2023 Oct 31;14(10):710. doi: 10.1038/s41419-023-06236-7.
Dandan Zhong  #  1 ,  Lingling Quan  #  1 ,  Chang Hao  1 ,  Jingshuo Chen  1  2 ,  Ranran Qiao  1  3 ,  Tengfei Lin  1 ,  Changjiang Ying  4  5 ,  Dong Sun  5  6 ,  Zhanjun Jia  7  8 ,  Ying Sun  9
Affiliations
  • 1. Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, Jiangsu, 221004, P. R. China.
  • 2. Nanjing Key Laboratory of Pediatrics, Children's Hospital of Nanjing Medical University, Nanjing, Jiangsu, 210008, P. R. China.
  • 3. Public Experimental Research Center of Xuzhou Medical University, Xuzhou Medical University, Xuzhou, Jiangsu, 221004, P. R. China.
  • 4. Department of Endocrinology, Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, 221000, P. R. China.
  • 5. Institute of Nephrology, Xuzhou Medical University, Xuzhou, Jiangsu, 221004, P. R. China.
  • 6. Department of Nephrology, Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, 221002, P. R. China.
  • 7. Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, Jiangsu, 221004, P. R. China. [email protected].
  • 8. Nanjing Key Laboratory of Pediatrics, Children's Hospital of Nanjing Medical University, Nanjing, Jiangsu, 210008, P. R. China. [email protected].
  • 9. Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, Jiangsu, 221004, P. R. China. [email protected].
  • # Contributed equally.
PMID: 37907523 DOI: 10.1038/s41419-023-06236-7
Abstract

Acute kidney injury (AKI) is a clinical syndrome with high morbidity and mortality but no specific therapy. Microsomal prostaglandin E synthase-2 (mPGES-2) is a PGE2 synthase but can metabolize PGH2 to malondialdehyde by forming a complex with heme. However, the role and mechanism of action of mPGES-2 in AKI remain unclear. To examine the role of mPGES-2, both global and tubule-specific mPGES-2-deficient mice were treated with cisplatin to induce AKI. mPGES-2 knockdown or overexpressing HK-2 cells were exposed to cisplatin to cause acute renal tubular cell injury. The mPGES-2 inhibitor SZ0232 was used to test the translational potential of targeting mPGES-2 in treating AKI. Additionally, mice were subjected to unilateral renal ischemia/reperfusion to further validate the effect of mPGES-2 on AKI. Interestingly, both genetic and pharmacological blockage of mPGES-2 led to decreased renal dysfunction and morphological damage induced by cisplatin and unilateral renal ischemia/reperfusion. Mechanistic exploration indicated that mPGES-2 deficiency inhibited Ferroptosis via the heme-dependent regulation of the p53/SLC7A11/GPX4 axis. The present study indicates that mPGES-2 blockage may be a promising therapeutic strategy for AKI.

Products