Aristolochic acid induces proximal tubule apoptosis and epithelial to mesenchymal transformation

Pozdzik, Agnieszka; Salmon, Isabelle; Debelle, Frédéric; Decaestecker, Christine; Branden, Christiane Van Den; Verbeelen, Dierik; Deschodt-Lanckman, M; Vanherweghem, Jean‐Louis; Nortier, Joëlle

doi:10.1038/sj.ki.5002714

Cited by 170 publications

(196 citation statements)

References 48 publications

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“…Indeed, apoptotic cells were detected in vivo within renal tubules of AA-treated rodents (Okada et al, 2003;Pozdzik et al, 2008). Others have demonstrated that AA induces apoptosis in vitro in renal tubular cells (Balachandran et al, 2005;Hsin et al, 2006;Li et al, 2006;Qi et al, 2007).…”

Section: Discussionmentioning

confidence: 98%

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Gene expression profiles modulated by the human carcinogen aristolochic acid I in human cancer cells and their dependence on TP53

Simões

Hockley

Schwerdtle

et al. 2008

Toxicology and Applied Pharmacology

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Aristolochic acid (AA) is the causative agent of urothelial tumours associated with aristolochic acid nephropathy. These tumours contain TP53 mutations and over-express TP53. We compared transcriptional and translational responses of two isogenic HCT116 cell lines, one expressing TP53 (p53-WT) and the other with this gene knocked out (p53-null), to treatment with aristolochic acid I (AAI) (50−100 µM) for 6−48 h. Modulation of 118 genes was observed in p53-WT cells and 123 genes in p53-null cells. Some genes, including INSIG1, EGR1, CAV1, LCN2 and CCNG1, were differentially expressed in the two cell lines. CDKN1A was selectively up-regulated in p53-WT cells, leading to accumulation of TP53 and CDKN1A. Apoptotic signalling, measured by caspase-3 and -7 activity, was TP53-dependent. Both cell types accumulated in S phase, suggesting that AAI-DNA adducts interfere with DNA replication, independently of TP53 status. The oncogene MYC, frequently over-expressed in urothelial tumours, was up-regulated by AAI, whereas FOS was downregulated. Observed modulation of genes involved in endocytosis, e.g. RAB5A, may be relevant to the known inhibition of receptor-mediated endocytosis, an early sign of AA-mediated proximal tubule injury. AAI-DNA adduct formation was significantly greater in p53-WT cells than in p53-null cells. Collectively, phenotypic anchoring of the AAI-induced expression profiles to DNA adduct formation, cell-cycle parameters, TP53 expression and apoptosis identified several genes linked to these biological outcomes, some of which are TP53-dependent. These results strengthen the importance of TP53 in AA-induced cancer, and indicate that other alterations, e.g. to MYC oncogenic pathways, may also contribute.

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Section: Discussionmentioning

confidence: 98%

“…Tubular atrophy is a pathohistological feature in AAN (Cosyns, 2003) and AA-induced apoptosis in tubular cells may be responsible for it (Pozdzik et al, 2008). Indeed, apoptotic cells were detected in vivo within renal tubules of AA-treated rodents (Okada et al, 2003;Pozdzik et al, 2008).…”

Section: Discussionmentioning

confidence: 99%

Gene expression profiles modulated by the human carcinogen aristolochic acid I in human cancer cells and their dependence on TP53

Simões

Hockley

Schwerdtle

et al. 2008

Toxicology and Applied Pharmacology

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“…Ki-67 is commonly used to assess the proliferative capacities of tumors. It has also been used in vitro and in vivo for the assessment of RPTEC regeneration (Docherty et al, 2006;Pozdzik et al, 2008).…”

Section: Factors Possibly Enhancing Tubular Regenerationmentioning

confidence: 99%

Potential nephroprotective effects of the Chinese herbAngelica sinensisagainst cisplatin tubulotoxicity

Bunel

Antoine

Nortier

et al. 2014

Pharmaceutical Biology

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Context: Acute kidney injury (AKI) is often encountered in patients receiving cisplatin (CisPt), a chemotherapeutic drug that induces numerous toxic side effects. Techniques used to limit nephrotoxicity during CisPt treatment are not fully effective; about a third of patients experience AKI. New nephroprotective strategies, including pharmacological approaches, must be developed. Objective: The present study investigated the nephroprotective potential of Angelica sinensis (Oliv.) Diels (Apiaceae) root towards CisPt tubulotoxicity. Materials and methods: HK-2 cells were incubated with CisPt (10 mM) and/or with a methanolic extract of A. sinensis (AS). Nephroprotective capacity was evaluated by means of cellular viability (resazurin assay) and apoptosis (annexin-V/PI staining), oxidative stress generation (H 2 DCF-DA oxidation), Ki-67 index (immunofluorescence), cell cycle analysis (DNA staining), cell migration rate (scratch assay), extracellular matrix deposition (collagen determination), and b-catenin relocalization. Results: CisPt decreased cell viability [76% versus Ctrl], which was associated with an increased apoptosis. Simultaneous treatment with 50 mg/ml AS enhanced cell survival [84% versus Ctrl] and decreased the apoptosis rate. AS could not alleviate CisPt-induced oxidative stress; but doses of 5 and 50 mg/ml raised the Ki-67 index [135 and 244% versus Ctrl] and cell migration rates [1.2 and 1.3-fold versus Ctrl]. Finally, both doses of AS limited the amount of collagen deposition [121.6 and 119.6% for 5 and 50 mg/ml, respectively, versus 131.0% for CisPt-treated cells] and prevented the relocalization of b-catenin from the membrane to the nucleus. Conclusion: These results confirm the nephroprotective potential of A. sinensis and require further investigations aiming at identifying its active compounds.

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“…The most important changes due to AA exposure were increases in urine levels of succinate and changes in the TMA/TMAO ratio, which could reflect alteration in the Krebs cycle activity and a response to oxidative stress and/or osmoprotection, respectively. Another group has previously highlighted the role of mitochondrial impairment and lack of activation of antioxidants enzymes in the process of tubular toxicity of AA [24]. Although less influencing, other metabolic changes were also noticed, including higher urine levels of glucose, lactate, and various amino acids accompanied with decreases in creatinine and hippurate.…”

Section: Discussionmentioning

confidence: 99%

Metabonomics: on the Road to Detect Diagnostic Biomarkers in Endemic (Balkan) Nephropathy. Evaluation in a Retrospective Pilot Project

Duquesne¹,

Goossens²,

Dika³

et al. 2013

J Cancer Sci Ther

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Introduction: Endemic (Balkan) Nephropathy is a chronic renal disease mainly affecting rural populations in the valleys of the Danube. In the absence of renal replacement therapy, it leads to fatal kidney failure and is significantly associated with upper urothelial carcinoma. Bread poisoning with aristolochic acids is now widely accepted. The source of this toxic substance is considered to be Aristolochia clematitis, a perennial plant that invades farming fields. The poisoning with aristolochic acids was suggested when clinical and histopathological changes similar to those observed in the Balkan patients were reported in several cases of nephropathy in Belgian patients unintentionally exposed to aristolochic acids during a Chinese herbs diet. Those clinical and histopathological features were then reproduced in laboratory experimental models. Methods:Using metabonomics, an emerging dynamic technique that allows an effective mapping of alterations in endogenous metabolites levels in biofluids and tissues, we evaluated early signs of renal toxicity from extra urine samples collected in a rat model of intoxication with aristolochic acids.Results: Changes in urine composition were consistent with a proximal tubular damage, most likely initiated by a mitochondrial default and an inappropriate response to oxidative stress. The same metabonomic approach was applied to surplus of urine samples collected from Belgian and Croatian patients in clinical and epidemiological studies, respectively. It allowed a clear discrimination of the Belgian patients from a database of healthy volunteers. On the other hand, a trend to discrimination was noticed when comparing urine samples collected from individuals living in Croatian endemic regions as compared to Croatian non endemic villages. Finally, when included in the same analysis, both Belgian and Croatian patients displayed similar urine metabolic signatures, suggesting a common etiology of both diseases.

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Aristolochic acid induces proximal tubule apoptosis and epithelial to mesenchymal transformation

Cited by 170 publications

References 48 publications

Gene expression profiles modulated by the human carcinogen aristolochic acid I in human cancer cells and their dependence on TP53

Gene expression profiles modulated by the human carcinogen aristolochic acid I in human cancer cells and their dependence on TP53

Potential nephroprotective effects of the Chinese herbAngelica sinensisagainst cisplatin tubulotoxicity

Metabonomics: on the Road to Detect Diagnostic Biomarkers in Endemic (Balkan) Nephropathy. Evaluation in a Retrospective Pilot Project

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