Biomolecules & Therapeutics

The Korean Society of Applied Pharmacology (한국응용약물학회)
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Melatonin Attenuates Mitochondrial Damage in Aristolochic Acid-Induced Acute Kidney Injury

  • Jian, Sun (The Second Affiliated Hospital, Institute of Cancer Stem Cell, Dalian Medical University) ;
  • Jinjin, Pan (The Second Affiliated Hospital, Institute of Cancer Stem Cell, Dalian Medical University) ;
  • Qinlong, Liu (The Second Affiliated Hospital, Institute of Cancer Stem Cell, Dalian Medical University) ;
  • Jizhong, Cheng (Section of Nephrology, Department of Medicine, Baylor College of Medicine) ;
  • Qing, Tang (The Second Affiliated Hospital, Institute of Cancer Stem Cell, Dalian Medical University) ;
  • Yuke, Ji (The Second Affiliated Hospital, Institute of Cancer Stem Cell, Dalian Medical University) ;
  • Ke, Cheng (The Second Affiliated Hospital, Institute of Cancer Stem Cell, Dalian Medical University) ;
  • Rui, wang (The Second Affiliated Hospital, Institute of Cancer Stem Cell, Dalian Medical University) ;
  • Liang, Liu (The Second Affiliated Hospital, Institute of Cancer Stem Cell, Dalian Medical University) ;
  • Dingyou, Wang (The Second Affiliated Hospital, Institute of Cancer Stem Cell, Dalian Medical University) ;
  • Na, Wu (The Second Affiliated Hospital, Institute of Cancer Stem Cell, Dalian Medical University) ;
  • Xu, Zheng (The Second Affiliated Hospital, Institute of Cancer Stem Cell, Dalian Medical University) ;
  • Junxia, Li (The Second Affiliated Hospital, Institute of Cancer Stem Cell, Dalian Medical University) ;
  • Xueyan, Zhang (The Second Affiliated Hospital, Institute of Cancer Stem Cell, Dalian Medical University) ;
  • Zhilong, Zhu (The Second Affiliated Hospital, Institute of Cancer Stem Cell, Dalian Medical University) ;
  • Yanchun, Ding (The Second Affiliated Hospital, Institute of Cancer Stem Cell, Dalian Medical University) ;
  • Feng, Zheng (The Second Affiliated Hospital, Institute of Cancer Stem Cell, Dalian Medical University) ;
  • Jia, Li (The First Affiliated Hospital, Dalian Medical University) ;
  • Ying, Zhang (Sixth Department of Liver Disease, Dalian Public Health Clinical Center) ;
  • Yuhui, Yuan (The Second Affiliated Hospital, Institute of Cancer Stem Cell, Dalian Medical University)
  • Received : 2022.04.22
  • Accepted : 2022.08.11
  • Published : 2023.01.01
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Abstract

Aristolochic acid (AA), extracted from Aristolochiaceae plants, plays an essential role in traditional herbal medicines and is used for different diseases. However, AA has been found to be nephrotoxic and is known to cause aristolochic acid nephropathy (AAN). AA-induced acute kidney injury (AKI) is a syndrome in AAN with a high morbidity that manifests mitochondrial damage as a key part of its pathological progression. Melatonin primarily serves as a mitochondria-targeted antioxidant. However, its mitochondrial protective role in AA-induced AKI is barely reported. In this study, mice were administrated 2.5 mg/kg AA to induce AKI. Melatonin reduced the increase in Upro and Scr and attenuated the necrosis and atrophy of renal proximal tubules in mice exposed to AA. Melatonin suppressed ROS generation, MDA levels and iNOS expression and increased SOD activities in vivo and in vitro. Intriguingly, the in vivo study revealed that melatonin decreased mitochondrial fragmentation in renal proximal tubular cells and increased ATP levels in kidney tissues in response to AA. In vitro, melatonin restored the mitochondrial membrane potential (MMP) in NRK-52E and HK-2 cells and led to an elevation in ATP levels. Confocal immunofluorescence data showed that puncta containing Mito-tracker and GFP-LC3A/B were reduced, thereby impeding the mitophagy of tubular epithelial cells. Furthermore, melatonin decreased LC3A/B-II expression and increased p62 expression. The apoptosis of tubular epithelial cells induced by AA was decreased. Therefore, our findings revealed that melatonin could prevent AA-induced AKI by attenuating mitochondrial damage, which may provide a potential therapeutic method for renal AA toxicity.

Keywords

Acknowledgement

This work was funded by Dengfeng Clinical Medicine Grant Support (No. 2021024) and the National Natural Science Foundation of China (No. 81770617). We thank Dr. Feng Zheng for providing the human kidney proximal tubular epithelial cell HK-2 and rat kidney proximal tubular epithelial cell NRK-52E.

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