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

Anger, Etienne Empweb; Yu, Feng; Ji, Li

doi:10.3390/ijms21031157

Cited by 63 publications

(49 citation statements)

References 112 publications

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“…The other 10 compounds ( 1 – 8 and 11 – 12 ) were identified as aristolochic acid II [ 1 ], aristolactam I [ 2 ], aristolochic acid I [ 3 ], aristolactam AII [ 4 ], aristolochic acid VIIa [ 5 ], aristolochic acid IVa [ 6 ], aristolochic acid IIIa [ 7 ], aristolactam I N -β, d -glucoside [ 8 ], aristolactam IIIa N -β, d -glucoside [ 11 ], and aristolactam Ia N -β, d -glucoside [ 12 ] by comparison with the NMR data present in the literature [ 18 , 19 ].…”

Section: Resultsmentioning

confidence: 99%

“…These adducts can lead to A→T transversions and thus cause renal disease and cancers. Therefore, a nitro group in position 10 may play a key role in AAI mutagenicity and genotoxicity [ 11 ]. Similarly, aristolochic acid analogues with a nitro group located at C10 are mutagenic and genotoxic [ 21 ].…”

Section: Resultsmentioning

confidence: 99%

“…Various studies have revealed several mechanisms of aristolochic acid nephropathy. Aristolochic acid analogues with nitro groups at position 10 could be metabolized and activated by hepatic enzymes, which promotes the occurrence of aristolochic acid nephropathy [ 11 ]. Specific organic anion transporters mechanism of aristolochic acid derivatives into renal cells may greatly contribute to AA-mediated nephrotoxicity [ 12 ].…”

Section: Introductionmentioning

confidence: 99%

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Two New Aristolochic Acid Analogues from the Roots of Aristolochia contorta with Significant Cytotoxic Activity

et al. 2020

Molecules

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Twelve compounds, including two new aristolochic acid analogues with a formyloxy moiety (9–10) and 10 known aristolochic acid derivates (1–8 and 11–12), were obtained from the roots of Aristolochiacontorta. Their structures were elucidated using extensive spectroscopic methods. Their cytotoxic activity in human proximal tubular cells HK-2 was evaluated by the MTT method, which has been widely used to assess cell viability. Among these molecules, compounds 3 and 9 were found to be more cytotoxic. Furthermore, molecular modeling was used to evaluate, for the first time, the interactions of compounds 3 and 9 with the target protein organic anionic transporter 1 (OAT1) that plays a key role in mediating aristolochic acid nephropathy. Structure–activity relationships are briefly discussed.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Two New Aristolochic Acid Analogues from the Roots of Aristolochia contorta with Significant Cytotoxic Activity

et al. 2020

Molecules

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“…Long-term administration of foods or traditional Chinese medicines containing AA can lead to pathological changes in the urinary system and digestive system and even organ fibrosis, urothelial malignancies, colon adenocarcinoma, invasive lobular breast carcinoma, and other conditions [ 1 ]. Researchers currently believe that the mechanism of AA-induced renal interstitial fibrosis may involve renal tubular epithelial cell (RTEC) apoptosis, renal interstitial fibroblast proliferation or activation, renal interstitial inflammatory cell infiltration, RTEC transdifferentiation, myofibroblast (MyoF) aggregation, renal small blood vessel wall ischemia, and increased production and decreased degradation of extracellular matrix (ECM), a condition that may become chronic after acute injury, i.e., acute kidney injury (AKI)-chronic kidney disease (CKD) [ 2 ].…”

Section: Introductionmentioning

confidence: 99%

Ultrasound enhances the therapeutic potential of mesenchymal stem cells wrapped in greater omentum for aristolochic acid nephropathy

et al. 2021

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Background Mesenchymal stem cells (MSCs) have been reported to promote regeneration in both subjects with acute kidney injury (AKI) and chronic kidney disease (CKD), but their efficacy remains limited, probably because most of the cells accumulate in the lungs, liver, and spleen after an intravenous infusion. Therefore, ultrasound-guided administration of MSCs represents a possible approach to solve this problem. The greater omentum is used to promote cell survival due to its rich vasculature. We hypothesized that ultrasound-guided administration of MSCs combined with greater omentum might be more curative than currently available approaches. Methods In this study, we established an aristolochic acid nephropathy (AAN) model by intraperitoneally administering aristolochic acid I sodium salt (AA-I) at a dose of 5 mg/kg body weight on alternate days for 4 weeks. Subsequently, a laparotomy was performed, and the left kidney from which the capsule had been removed was wrapped with the greater omentum. A dose of 2 × 107 MSCs was injected into the space between the greater omentum and the left kidney. Equal amounts of MSCs were administered under ultrasound guidance every second week for a total of 4 treatments. Mice were sacrificed 4 weeks after surgery. Serum creatinine and blood urea levels were measured to assess renal function. qPCR, Western blot, and histological analyses were conducted to further investigate the therapeutic mechanism of MSCs. Results Ultrasound-guided injection of MSCs into the greater omentum that surrounds the kidney enriched cells in the kidney region for up to 5 days. Renal function tests indicated that MSCs improved renal function to a great extent, as reflected by decreased blood urea nitrogen and serum creatinine levels. In addition, histological analyses showed that MSCs noticeably attenuated kidney injury, as evidenced by the amelioration of tubular necrosis and peritubular interstitial fibrosis. Mitigation of renal interstitial fibrosis was further confirmed by immunohistochemistry, qPCR, and western blotting after MSC treatment. Moreover, immunofluorescence staining revealed that MSCs alleviated inflammatory responses by increasing the counts of CD206+ cells and decreasing the counts of CD68+ cells. MSC migration was initiated in response to AA-I-treated renal epithelial cells in an in vitro migration assay. Conclusions These findings suggested that administration of MSCs into the cavity formed by the injured kidney and the greater omentum under ultrasound guidance improved renal function, attenuated kidney injury, and mitigated renal interstitial fibrosis and inflammatory responses. Thus, this approach might be a safe and effective therapy for CKD.

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“…Among these, the chronic food poisoning by aristolochic acid (AA), a toxin present in plants of the genus Aristolochia, seems to be the most acceptable theory. AA promotes kidney damage in BEN, associated with the hepatic enzymes metabolizing AA, which may have high cancerogenic potential [ 12 – 14 ]. A prolonged exposure to AA-contaminated food grown in polluted soil could be one of the main aetiological mechanisms of BEN observed in the Balkan area.…”

Section: Introductionmentioning

confidence: 99%

Local and Systemic Oxidative Stress in Balkan Endemic Nephropathy Is Not Associated with Xanthine Oxidase Activity

Veljković

Hadži-Đokić

Sokolović

et al. 2020

Oxidative Medicine and Cellular Longevity

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Balkan endemic nephropathy (BEN) represents a chronic tubulointerstitial nephropathy which is followed by the progression of kidney fibrosis to end-stage kidney failure. The critical involvement of poisons in food (aristolochic acid (AA), ochratoxin, and heavy metals) and selenium deficiency are among nutritive factors which contribute to the pathogenesis of BEN, due to reactive oxygen species (ROS) liberation and/or decreased antioxidative defence system. The aim of the study is to distinguish a possible systemic and local origin of ROS through the measurement of xanthine oxidase (XO) activity in urine and plasma, along with the determination of the oxidative changes in lipids and proteins. The study included 50 patients with BEN and 38 control healthy subjects. We noted increased levels of both thiobarbituric acid-reactive substances (TBARS) and advanced oxidation protein products (AOPPs) in the plasma of patients with BEN, compared to the control group (p<0.001). The urinary levels of AOPPs were higher in patients with BEN in comparison to the control (p<0.001). The specific activity of XO was significantly lower in plasma and urine in BEN samples, compared to controls (p<0.005). Based on these results, we hypothesize that XO might not be considered a direct systemic or local contributor to ROS production in BEN, most probably because of the diminished kidney functional tissue mass and/or AA-induced changes in purine nucleotide conformation. The increased AOPP and TBARS level in both plasma and urine in BEN may predict ROS systemic liberation with toxic local effects.

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

Cited by 63 publications

References 112 publications

Two New Aristolochic Acid Analogues from the Roots of Aristolochia contorta with Significant Cytotoxic Activity

Two New Aristolochic Acid Analogues from the Roots of Aristolochia contorta with Significant Cytotoxic Activity

Ultrasound enhances the therapeutic potential of mesenchymal stem cells wrapped in greater omentum for aristolochic acid nephropathy

Local and Systemic Oxidative Stress in Balkan Endemic Nephropathy Is Not Associated with Xanthine Oxidase Activity

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