Targeting mPGES-2 to protect against acute kidney injury via inhibition of ferroptosis dependent on p53.
Targeting mPGES-2 to protect against acute kidney injury via inhibition of ferroptosis dependent on p53.
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DOI：
10.1038/s41419-023-06236-7
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发表时间：
2023-10-31
影响因子：
9
通讯作者：
Sun, Ying
中科院分区：
文献类型：
--
作者：
Zhong, Dandan;Quan, Lingling;Hao, Chang;Chen, Jingshuo;Qiao, Ranran;Lin, Tengfei;Ying, Changjiang;Sun, Dong;Jia, Zhanjun;Sun, Ying
急性肾损伤（Acute kidney injury， AKI）是一种高发病率、高死亡率的临床综合征，目前尚无特效药。微粒体前列腺素E合成酶-2 （mPGES-2）是一种PGE2合成酶，但可以通过与血红素形成复合物将PGH2代谢为丙二醛。然而，mPGES-2在AKI中的作用和作用机制尚不清楚。为了检验mPGES-2的作用，用顺铂治疗全局和小管特异性mPGES-2缺陷小鼠诱导AKI。顺铂作用下mPGES-2敲低或HK-2过表达细胞可引起急性肾小管细胞损伤。使用mPGES-2抑制剂SZ0232来测试靶向mPGES-2治疗AKI的转化潜力。此外，通过小鼠单侧肾缺血再灌注来进一步验证mPGES-2对AKI的作用。有趣的是，mPGES-2的遗传和药理学阻断均可降低顺铂和单侧肾缺血再灌注引起的肾功能和形态学损害。机制探索表明，mPGES-2缺乏通过血红素依赖性调节p53/SLC7A11/GPX4轴抑制铁下垂。目前的研究表明，阻断mPGES-2可能是一种很有前途的治疗AKI的策略。
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.
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影响因子：
64.5
作者：
Dixon SJ;Lemberg KM;Lamprecht MR;Skouta R;Zaitsev EM;Gleason CE;Patel DN;Bauer AJ;Cantley AM;Yang WS;Morrison B 3rd;Stockwell BR
通讯作者：
Stockwell BR
影响因子：
81.5
作者：
Kellum, John A.;Romagnani, Paola;Anders, Hans-Joachim
通讯作者：
Anders, Hans-Joachim
DOI：
10.1152/ajprenal.1996.270.4.f700
发表时间：
1996-04-01
期刊：
AMERICAN JOURNAL OF PHYSIOLOGY-RENAL FLUID AND ELECTROLYTE PHYSIOLOGY
影响因子：
--
作者：
Lieberthal, W;Triaca, V;Levine, J
通讯作者：
Levine, J
影响因子：
21.3
作者：
Friedmann Angeli JP;Schneider M;Proneth B;Tyurina YY;Tyurin VA;Hammond VJ;Herbach N;Aichler M;Walch A;Eggenhofer E;Basavarajappa D;Rådmark O;Kobayashi S;Seibt T;Beck H;Neff F;Esposito I;Wanke R;Förster H;Yefremova O;Heinrichmeyer M;Bornkamm GW;Geissler EK;Thomas SB;Stockwell BR;O'Donnell VB;Kagan VE;Schick JA;Conrad M
通讯作者：
Conrad M
影响因子：
64.8
作者：
Jiang, Le;Kon, Ning;Li, Tongyuan;Wang, Shang-Jui;Su, Tao;Hibshoosh, Hanina;Baer, Richard;Gu, Wei
通讯作者：
Gu, Wei