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

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 PGE 2 synthase but can metabolize PGH 2 to malondialdehyde by forming a complex with heme. However, the role and mechanism of action of mPG...

Full description

Saved in:
Bibliographic Details
Published inCell death & disease Vol. 14; no. 10; pp. 710 - 12
Main Authors Zhong, Dandan, Quan, Lingling, Hao, Chang, Chen, Jingshuo, Qiao, Ranran, Lin, Tengfei, Ying, Changjiang, Sun, Dong, Jia, Zhanjun, Sun, Ying
Format Journal Article
LanguageEnglish
Published London Nature Publishing Group UK 31.10.2023
Springer Nature B.V
Nature Publishing Group
Subjects
13/1
13/109
13/89
14/19
14/28
45/90
45/91
631/80/82
692/699/1585/4
Antibodies
Biochemistry
Biomedical and Life Sciences
Cell Biology
Cell Culture
Cell injury
Cisplatin
Ferroptosis
Heme
Immunology
Ischemia
Kidneys
Life Sciences
Morbidity
p53 Protein
Prostaglandin E
Prostaglandin E2
Renal function
Reperfusion
Online AccessGet full text

Cover

More Information
Summary: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 PGE 2 synthase but can metabolize PGH 2 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.
Bibliography:ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 14
content type line 23
ISSN:2041-4889
2041-4889
DOI:10.1038/s41419-023-06236-7