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.

中文翻译：

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褪黑激素减轻马兜铃酸诱导的急性肾损伤中的线粒体损伤。

马兜铃酸 (AA) 从马兜铃科植物中提取，在传统草药中起着重要作用，可用于治疗不同的疾病。然而，已发现 AA 具有肾毒性，并已知会导致马兜铃酸肾病 (AAN)。AA 诱发的急性肾损伤 (AKI) 是 AAN 中的一种综合征，具有高发病率，表现为线粒体损伤作为其病理进展的关键部分。褪黑激素主要用作靶向线粒体的抗氧化剂。然而，其在 AA 诱导的 AKI 中的线粒体保护作用几乎没有报道。在这项研究中，小鼠被给予 2.5 mg/kg AA 以诱导 AKI。褪黑激素减少了 Upro 和 Scr 的增加，并减轻了暴露于 AA 的小鼠肾近端小管的坏死和萎缩。褪黑激素抑制 ROS 的产生，体内和体外。有趣的是，体内研究表明，褪黑激素减少了肾近端小管细胞中的线粒体断裂，并增加了肾组织中对 AA 的 ATP 水平。体外，褪黑激素恢复了 NRK-52E 和 HK-2 细胞中的线粒体膜电位 (MMP)，并导致 ATP 水平升高。共聚焦免疫荧光数据显示，含有 Mito-tracker 和 GFP-LC3A/B 的斑点减少，从而阻碍了肾小管上皮细胞的线粒体自噬。此外，褪黑激素降低了 LC3A/B-II 的表达并增加了 p62 的表达。AA诱导的肾小管上皮细胞凋亡减少。因此，我们的研究结果表明，褪黑激素可以通过减轻线粒体损伤来预防 AA 诱导的 AKI，这可能为肾 AA 毒性提供一种潜在的治疗方法。