Vitamin C attenuates the toxic effect of aristolochic acid on renal tubular cells via decreasing oxidative stress-mediated cell death pathways

Wu, Tsai‐Kun; Wei, Chyou‐Wei; Pan, Y.; Cherng, Shur Hueih; Chang, Wen Hsin; Wang, Hsueh‐Fang; Yu, Yung-Luen

doi:10.3892/mmr.2015.4167

Cited by 29 publications

(24 citation statements)

References 54 publications

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“…Growing evidence suggests that oxidative stress, tubular cell apoptosis, inflammation, and fibrosis are important pathogenic processes for AAN, although its detailed molecular mechanisms are still unclear [1,2]. Among them, oxidative stress is known to play an essential role in AA-induced cytotoxicity, because previous in vitro and in vivo studies have reported that AA treatment induces ROS generation and resultant oxidative injury [25][26][27]. In the present study, we performed IHC staining with a monoclonal antibody directed to 4-HNE, a product of lipid peroxidation, to detect oxidative injury.…”

Section: Discussionmentioning

confidence: 99%

Protective Effects of Melatonin Against Aristolochic Acid-Induced Nephropathy in Mice

2019

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Melatonin, a pineal hormone, is well known to regulate the sleep-wake cycle. Besides, the hormone has been shown to display pleiotropic effects arising from its powerful anti-oxidant and anti-inflammatory activities. Recent studies have reported that melatonin exerts protective effects in animal models of kidney disease. However, the potential effects of melatonin on aristolochic acid (AA)-induced nephropathy (AAN) have not yet been investigated. Here, we found that the administration of melatonin ameliorated AA-induced renal dysfunction, as evidenced by decreased plasma levels of blood urea nitrogen and creatinine and histopathological abnormalities such as tubular dilatation and cast formation. The upregulation of tubular injury markers after AA injection was reversed by melatonin. Melatonin also suppressed AA-induced oxidative stress, as evidenced by the downregulation of 4-hydroxynonenal and reduced level of malondialdehyde, and modulated expression of pro-oxidant and antioxidant enzymes. In addition, p53-dependent apoptosis of tubular epithelial cells, infiltration of macrophages and CD4 + T cells into damaged kidneys, and renal expression of cytokines and chemokines were inhibited by melatonin. Moreover, melatonin attenuated AA-induced tubulointerstitial fibrosis through suppression of the tumor growth factor-β/Smad signaling pathway. These results suggest that melatonin might be a potential therapeutic agent for AAN.

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Section: Discussionmentioning

confidence: 99%

Protective Effects of Melatonin Against Aristolochic Acid-Induced Nephropathy in Mice

2019

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“…A few in vitro studies described that cells treated with AA led to generation of high amounts of reactive oxygen and nitrogen species (ROS/RNS) [122,123,124,125]. Oxidative stress therefore constitutes the primary triggering event of AA cytotoxicity and could be responsible for related DNA damage through activation of the MEK/ERK1/2 signaling pathway and depletion of intracellular glutathione (GSH) [122] resulting in cell cycle arrest in G2/M phase [123].…”

Section: Properties Of Aa and Mechanisms Of Nephrotoxicity And Carmentioning

confidence: 99%

“…Oxidative stress therefore constitutes the primary triggering event of AA cytotoxicity and could be responsible for related DNA damage through activation of the MEK/ERK1/2 signaling pathway and depletion of intracellular glutathione (GSH) [122] resulting in cell cycle arrest in G2/M phase [123]. Treatment of the cells with antioxidants showed cytoprotective effects by reducing AA-induced ROS and genotoxicity, indicating that AA may induce DNA damage through oxidative stress [122,124]. Oxidative stress has also been described in in vivo models.…”

Section: Properties Of Aa and Mechanisms Of Nephrotoxicity And Carmentioning

confidence: 99%

“…It is now clear that AA treatment induce apoptosis in vitro as observed in cultured murine PTEC (mProx24) [128], in renal epithelial cells from pig (LLC-PK 1 ) [78], in Mardin-Darby canine kidney (MDCK) cells [129] and in human PTEC (HK-2) [124]. A rapid rise in intracellular Ca 2+ concentration has been described [129,130], which in turn determines endoplasmic reticulum and mitochondria stress [129], resulting in release of cytochrome c [130], caspases activation and finally apoptosis.…”

Section: Properties Of Aa and Mechanisms Of Nephrotoxicity And Carmentioning

confidence: 99%

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An Integrated View of Aristolochic Acid Nephropathy: Update of the Literature

Jadot

Declèves

Nortier

et al. 2017

IJMS

176

180

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The term “aristolochic acid nephropathy” (AAN) is used to include any form of toxic interstitial nephropathy that is caused either by ingestion of plants containing aristolochic acids (AA) as part of traditional phytotherapies (formerly known as “Chinese herbs nephropathy”), or by the environmental contaminants in food (Balkan endemic nephropathy). It is frequently associated with urothelial malignancies. Although products containing AA have been banned in most of countries, AAN cases remain regularly reported all over the world. Moreover, AAN incidence is probably highly underestimated given the presence of AA in traditional herbal remedies worldwide and the weak awareness of the disease. During these two past decades, animal models for AAN have been developed to investigate underlying molecular and cellular mechanisms involved in AAN pathogenesis. Indeed, a more-in-depth understanding of these processes is essential to develop therapeutic strategies aimed to reduce the global and underestimated burden of this disease. In this regard, our purpose was to build a broad overview of what is currently known about AAN. To achieve this goal, we aimed to summarize the latest data available about underlying pathophysiological mechanisms leading to AAN development with a particular emphasis on the imbalance between vasoactive factors as well as a focus on the vascular events often not considered in AAN.

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“…Vitamin C is another natural antioxidant compound. It has been reported that pretreatment with vitamin C exerted protective effects on NRK-52E treated with AA, through decreasing the high ratio of hydrogen peroxide (H 2 O 2 ) and caspase-3 activity generated by AA [92].…”

Section: Agents Exerting Antioxidative Effectsmentioning

confidence: 99%

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

Anger

2020

IJMS

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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.

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Vitamin C attenuates the toxic effect of aristolochic acid on renal tubular cells via decreasing oxidative stress-mediated cell death pathways

Cited by 29 publications

References 54 publications

Protective Effects of Melatonin Against Aristolochic Acid-Induced Nephropathy in Mice

Protective Effects of Melatonin Against Aristolochic Acid-Induced Nephropathy in Mice

An Integrated View of Aristolochic Acid Nephropathy: Update of the Literature

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

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