Biomolecules & Therapeutics  https://doi.org/10.4062/biomolther.2022.054
Melatonin Attenuates Mitochondrial Damage in Aristolochic Acid-Induced Acute Kidney Injury
Jian Sun1,†, Jinjin Pan1,†, Qinlong Liu1,†, Jizhong Cheng2, Qing Tang1, Yuke Ji1, Ke Cheng1, Rui wang1, Liang Liu1, Dingyou Wang1, Na Wu1, Xu Zheng1, Junxia Li1, Xueyan Zhang1, Zhilong Zhu1, Yanchun Ding1, Feng Zheng1, Jia Li3,*, Ying Zhang4,* and Yuhui Yuan1,*
1The Second Affiliated Hospital, Institute of Cancer Stem Cell, Dalian Medical University, Dalian 116044, China
2Section of Nephrology, Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA
3The First Affiliated Hospital, Dalian Medical University, Dalian 116044, China
4Sixth Department of Liver Disease, Dalian Public Health Clinical Center, Dalian 116000, China
*E-mail: lijia2995@dmu.edu.cn (Li J), zy730302@aliyun.com (Zhang Y), yuhuiyuan@hotmail.com (Yuan Y)
Tel: +86-0411-83635936-2188 (Li J), +86-0411-39728761 (Zhang Y), +86-411-86110154 (Yuan Y)
Fax: +86-0411-86110515 (Li J), +86-0411-39536666 (Zhang Y), +86-0411-86110515 (Yuan Y)
The first three authors contributed equally to this work.
Received: April 22, 2022; Revised: July 24, 2022; Accepted: August 11, 2022; Published online: September 13, 2022.
© The Korean Society of Applied Pharmacology. All rights reserved.

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
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: Melatonin, Aristolochic acid, Acute kidney injury, Mitochondrial damage, Mitophagy, Oxidative stress


This Article


Cited By Articles
  • CrossRef (0)

e-submission

Archives