Aristolactam I (ALI) is an active component derived from some Traditional Chinese medicines (TCMs), and also the important metabolite of aristolochic acid. Long-term administration of medicine-containing ALI was reported to be related to aristolochic acid nephropathy (AAN), which was attributed to ALI-induced nephrotoxicity. However, the toxic mechanism of action involved is still unclear. Recently, pathogenic ferroptosis mediated lipid peroxidation was demonstrated to cause kidney injury. Therefore, this study explored the role of ferroptosis induced by mitochondrial iron overload in ALI-induced nephrotoxicity, aiming to identify the possible toxic mechanism of ALI-induced chronic nephropathy. Our results showed that ALI inhibited HK-2 cell activity in a dose-dependent manner and significantly suppressed glutathione (GSH) levels, accompanying by significant increases in intracellular 4-hydroxynonenal (4-HNE) and intracellular iron ions. Moreover, the ALI-mediated cytotoxicity could be reversed by deferoxamine mesylate (DFO). Compared with other inhibitors, Ferrostatin-1 (Fer-1), a ferroptosis inhibitor, obviously alleviated ALI-induced cytotoxicity. Furthermore, we have shown that ALI could remarkably increase the levels of superoxide anion and ferrous ions in mitochondria, and induce mitochondrial damage and condensed mitochondrial membrane density, the morphological characteristics of ferroptosis, all of which could be reversed by DFO. Interestingly, ALI dose-dependently inhibited these protein contents of nuclear factor erythroid 2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1), and glutathione peroxidase 4 (GPX4), which could be partly rescued by Tin-protoporphyrin IX (SnPP) and mitoTEMPO co-treatment. In conclusion, our results demonstrated that mitochondrial iron overload-mediated antioxidant system inhibition would assist ALI-induced ferroptosis in renal tubular epithelial cells, and Nrf2-HO-1/GPX4 antioxidative system could be an important intervention target to prevent medicine containing ALI-induced nephropathy.

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Mitochondrial Iron Overload-Mediated Inhibition of Nrf2-HO-1/GPX4 Assisted ALI-Induced Nephrotoxicity

Aristolochic acid (AA) is a generic term that describes a group of structurally related compounds found in the Aristolochiaceae plants family. These plants have been used for decades to treat various diseases. However, the consumption of products derived from plants containing AA has been associated with the development of nephropathy and carcinoma, mainly the upper urothelial carcinoma (UUC). AA has been identified as the causative agent of these pathologies. Several studies on mechanisms of action of AA nephrotoxicity have been conducted, but the comprehensive mechanisms of AA-induced nephrotoxicity and carcinogenesis have not yet fully been elucidated, and therapeutic measures are therefore limited. This review aimed to summarize the molecular mechanisms underlying AA-induced nephrotoxicity with an emphasis on its enzymatic bioactivation, and to discuss some agents and their modes of action to reduce AA nephrotoxicity. By addressing these two aspects, including mechanisms of action of AA nephrotoxicity and protective approaches against the latter, and especially by covering the whole range of these protective agents, this review provides an overview on AA nephrotoxicity. It also reports new knowledge on mechanisms of AA-mediated nephrotoxicity recently published in the literature and provides suggestions for future studies.

Aristolochic Acid-Induced Nephrotoxicity: Molecular Mechanisms and Potential Protective Approaches.

Aristolochic acid (AA) is a compound extracted from the Aristolochia species of herbs. AA exposure is associated with kidney injury known as aristolochic acid nephropathy (AAN). Proximal tubular epithelial cell (PTEC) is the primary target of AA and rich in mitochondria. Recently, increasing evidence suggests that mitochondrial dysfunction plays a critical role in the pathogenesis of kidney disease. However, the status of mitochondrial function in PTEC after exposure to AA remains largely unknown. The aim of this study was to explore the effect of aristolochic acid I (AAI) on cell apoptosis and mitochondrial function in PTEC. Normal rat kidney-52E (NRK-52E) cells were exposed to different concentrations of AAI for different time periods. Cell viability was detected by 3-(4,5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide, cell apoptosis was analyzed by flow cytometry, and the expression of cleaved caspase-3 by Western blotting. Mitochondrial function was evaluated by reactive oxygen species (ROS), mitochondrial membrane potential (MMP), mitochondrial DNA (mtDNA) copy number, and adenosine triphosphate (ATP). It was found that AAI reduced cell viability and increased cell apoptosis in a dose- and time-dependent manner. In parallel to increased apoptosis, NRK-52E cell manifested signs of mitochondrial dysfunction in response to AAI treatment. The data indicated that AAI could increase ROS level, lower MMP, decrease mtDNA copy number, and reduce ATP production. In addition, Szeto-Schiller 31, a mitochondria-targeted antioxidant peptide, attenuated AAI-induced mitochondrial dysfunction and apoptosis. Our study depicted significant aberrant of mitochondrial function in AAI-treated NRK-52E cell, which suggested that mitochondrial dysfunction may be involved in AAI-induced apoptosis in PTEC.

Mitochondrial dysfunction is involved in aristolochic acid I-induced apoptosis in renal proximal tubular epithelial cells:

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Protective role of relaxin in a mouse model of aristolochic acid nephropathy

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Protective role of relaxin in a mouse model of aristolochic acid nephropathy