2. Academic Validation
  3. Melatonin suppresses ferroptosis via activation of the Nrf2/HO-1 signaling pathway in the mouse model of sepsis-induced acute kidney injury

Melatonin suppresses ferroptosis via activation of the Nrf2/HO-1 signaling pathway in the mouse model of sepsis-induced acute kidney injury

  • Int Immunopharmacol. 2022 Sep 5;112:109162. doi: 10.1016/j.intimp.2022.109162.
Weihuang Qiu 1,  Sheng An 2,  Tingjie Wang 3,  Jiaxin Li 4,  Binmei Yu 5,  Zhenhua Zeng 6,  Zhongqing Chen 7,  Bo Lin 8,  Xianzhong Lin 9,  Youguang Gao 10
Affiliations

Affiliations

  • 1 Department of Anesthesiology, Anesthesiology Research Institute, the First Affiliated Hospital, Fujian Medical University, Fuzhou, Fujian 350005, China; Guangdong Provincial Key Laboratory of Shock and Microcirculation, School of Basic Medical Sciences, Southern Medical University, Baiyun District, Guangzhou, Guangdong 510515, China. Electronic address: qiuweihuang@fjmu.edu.cn.
  • 2 Department of Critical Care Medicine, Nanfang Hospital, Southern Medical University, Baiyun District, Guangzhou, Guangdong 510515, China; Guangdong Provincial Key Laboratory of Shock and Microcirculation, School of Basic Medical Sciences, Southern Medical University, Baiyun District, Guangzhou, Guangdong 510515, China. Electronic address: ansheng10257@163.com.
  • 3 Department of Anesthesiology, Anesthesiology Research Institute, the First Affiliated Hospital, Fujian Medical University, Fuzhou, Fujian 350005, China; Guangdong Provincial Key Laboratory of Shock and Microcirculation, School of Basic Medical Sciences, Southern Medical University, Baiyun District, Guangzhou, Guangdong 510515, China. Electronic address: wangtingjie@fjmu.edu.cn.
  • 4 Department of Critical Care Medicine, Nanfang Hospital, Southern Medical University, Baiyun District, Guangzhou, Guangdong 510515, China; Guangdong Provincial Key Laboratory of Shock and Microcirculation, School of Basic Medical Sciences, Southern Medical University, Baiyun District, Guangzhou, Guangdong 510515, China. Electronic address: cocoljx2020@163.com.
  • 5 Department of Anesthesiology, Anesthesiology Research Institute, the First Affiliated Hospital, Fujian Medical University, Fuzhou, Fujian 350005, China; Guangdong Provincial Key Laboratory of Shock and Microcirculation, School of Basic Medical Sciences, Southern Medical University, Baiyun District, Guangzhou, Guangdong 510515, China. Electronic address: yubinmei@fjmu.edu.cn.
  • 6 Department of Critical Care Medicine, Nanfang Hospital, Southern Medical University, Baiyun District, Guangzhou, Guangdong 510515, China; Guangdong Provincial Key Laboratory of Shock and Microcirculation, School of Basic Medical Sciences, Southern Medical University, Baiyun District, Guangzhou, Guangdong 510515, China. Electronic address: zhenhuazeng.2008@163.com.
  • 7 Department of Critical Care Medicine, Nanfang Hospital, Southern Medical University, Baiyun District, Guangzhou, Guangdong 510515, China; Guangdong Provincial Key Laboratory of Shock and Microcirculation, School of Basic Medical Sciences, Southern Medical University, Baiyun District, Guangzhou, Guangdong 510515, China. Electronic address: zhongqingchen2008@163.com.
  • 8 Department of Anesthesiology, Anesthesiology Research Institute, the First Affiliated Hospital, Fujian Medical University, Fuzhou, Fujian 350005, China. Electronic address: linbo2472@fjmu.edu.cn.
  • 9 Department of Anesthesiology, Anesthesiology Research Institute, the First Affiliated Hospital, Fujian Medical University, Fuzhou, Fujian 350005, China. Electronic address: lxzyjs@fjmu.edu.cn.
  • 10 Department of Anesthesiology, Anesthesiology Research Institute, the First Affiliated Hospital, Fujian Medical University, Fuzhou, Fujian 350005, China. Electronic address: gaoyouguang259@fjmu.edu.cn.
PMID: 36067654 DOI: 10.1016/j.intimp.2022.109162
Abstract

Background: Ferroptosis is a regulated form of cell death. At present, the role of Ferroptosis in sepsis-induced acute kidney injury (SAKI) has not been studied. Melatonin (MEL) has been reported to be an effective Ferroptosis inhibitor, but it is unclear whether Melatonin can regulate Ferroptosis in SAKI and whether its downstream mechanism correlates with the Nrf2/HO-1 pathway.

Methods: The cecal ligation and puncture (CLP) method and LPS injection were used to induce SAKI in mouse model. Ferroptosis markers, including malondialdehyde (MDA) and Glutathione Peroxidase 4 (GPX4), were assessed. The Ferroptosis inhibitor ferrostatin-1 (Fer-1) was used to explore the role of Ferroptosis in SAKI. The GPX4 inhibitor RSL3, the HO-1 inhibitor zinc protoporphyrin(ZnPP), and the Nrf2 inhibitor ML385 were used to explore the specific mechanism of MEL in alleviation of SAKI.

Results: The Ferroptosis level was increased in the renal tissue of CLP- and LPS-induced septic mice. Both Fer-1 and MEL administration could suppress Ferroptosis and attenuate kidney injury upon sepsis challenge. RSL3 partially blocked MEL's beneficial renal-protective effects. MEL up-regulated Nrf2 and HO-1 in CLP mice, and both ZnPP and ML385 blocked the MEL-mediated effects of Ferroptosis inhibition and renal protection.

Conclusions: Ferroptosis aggravates SAKI. Melatonin treatment suppresses Ferroptosis and alleviates kidney injury in the context of experimental sepsis by upregulating Nrf2/HO-1 pathway.

Keywords

Acute kidney injury; Ferroptosis; HO-1; Melatonin; Nrf2; Sepsis.

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