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Leonurine alleviates ferroptosis in cisplatin-induced acute kidney injury by activating the Nrf2 signaling pathway
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  • Jianqiang HU,
  • Wenjing Gu,
  • Ning Ma,
  • Xiaoye Fan,
  • Xinxin Ci
Jianqiang HU
Jilin University First Hospital

Corresponding Author:[email protected]

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Wenjing Gu
Jilin University First Hospital
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Ning Ma
Jilin University First Hospital
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Xiaoye Fan
Institute of Translational Medicine, The First Hospital, Jilin University
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Xinxin Ci
Jilin University First Hospital
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Background and purpose: Increasing evidence suggests that ferroptosis plays a key role in the pathophysiology of acute kidney injury induced by cisplatin. The Nrf2 signaling pathway regulates oxidative stress and lipid peroxidation and positively regulates cisplatin-induced AKI (CI-AKI). However, Nrf2 and its activator leonurine on ferroptosis after CI-AKI remain unclear. Experimental Approach: The anti-ferroptotic effects of Nrf2 and its activator leonurine were assessed using a mouse model of cisplatin-induced AKI. In vitro, the potential effects of leonurine on erastin- and RSL3-induced HK-2 human PTEC ferroptosis were examined. Key Results: As expected, Nrf2 deletion induced ferroptosis-related protein expression and iron accumulation in vivo, further aggravating CI-AKI. The Nrf2 activator leonurine prevented iron accumulation and lipid peroxidation and inhibited ferroptosis in vitro, while these effects were abolished in siNrf2-treated cells. Moreover, leonurine potently ameliorated cisplatin-induced renal damage, as indicated by the assessment of SCr, BUN, KIM-1, and NGAL. Importantly, leonurine activated the Nrf2 antioxidative signaling pathway and prohibited changes in ferroptosis-related morphological and biochemical indicators, such as the MDA level, SOD and GSH depletion and GPX4 and xCT downregulation, in CI-AKI. Moreover, Nrf2 KO mice were more susceptible to ferroptosis after CI-AKI than control mice, and the protective effects of leonurine on AKI and ferroptosis were largely abolished in Nrf2 KO mice. Conclusion and Implications: These data suggest that the renal protective effects of Nrf2 and its activator leonurine on CI-AKI are achieved at least partially by inhibiting lipid peroxide-mediated ferroptosis and highlight the potential of leonurine as a CI-AKI treatment.
19 Oct 2021Submitted to British Journal of Pharmacology
20 Oct 2021Submission Checks Completed
20 Oct 2021Assigned to Editor
28 Oct 2021Reviewer(s) Assigned
16 Nov 2021Review(s) Completed, Editorial Evaluation Pending
16 Nov 2021Editorial Decision: Revise Minor
14 Dec 20211st Revision Received
06 Jan 2022Assigned to Editor
06 Jan 2022Submission Checks Completed
08 Jan 2022Reviewer(s) Assigned
20 Jan 2022Review(s) Completed, Editorial Evaluation Pending
21 Jan 2022Editorial Decision: Revise Minor
14 Feb 20222nd Revision Received
16 Feb 2022Submission Checks Completed
16 Feb 2022Assigned to Editor
19 Feb 2022Reviewer(s) Assigned
05 Mar 2022Review(s) Completed, Editorial Evaluation Pending
07 Mar 2022Editorial Decision: Accept