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Experimental in vitro approach in detecting early nephrotoxic effects of natural products

par Bunel, Valérian ;Antoine, Marie-Hélène ;Nguyen, Van;Nortier, Joëlle ;Duez, Pierre ;Stévigny, Caroline
Référence 9th meeting of the Groupe de Contact FNRS devoted to oxidative and antioxidative processes - Oxidative stress and cellular death (22 Décembre 2010: Bruxelles, Belgique)
Publication Non publié, 2010

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Résumé :

Background: natural products are components of a wide variety of complementary and alternative medicines (CAM) treatments. Although an increasing number of patients are nowadays relying on such medicines, it is not clear whether these products (mostly herbs) are safe or not. As an example, we might consider the "Aristolochia" case, which took place in Belgium during the '90s: 120 cases of interstitial fibrosis have been related to the ingestion of slimming pills containing aristolochic acids (AA), which finally led to end-stage renal failure requiring dialysis and transplantation. Introduction: this study aims to elaborate in vitro tools to rapidly detect renal toxicity, based on two phenomena recognized as renal wound inducers: (i) epithelial to mesenchymal transition (EMT), an early event in the fibrosis onset, and (ii) apoptosis. Material and method: our model relies on HK-2 cell line, originating from human renal proximal tubular epithelial cells (hRPTEC), the main targets of nephrotoxic compounds. Cells were exposed during 72h to AA (50 µM) or to a crude methanolic extract of ginseng (Panax ginseng C.A. Meyer, Araliaceae) (5 and 50 µg/ml). EMT evolution was evaluated by immunofluorescence microscopy of specific markers: β-catenin (protein mostly occurring in tight-junctions of epithelial cells) and vimentin (intermediate filament especially found in connective tissue, i.e. mesenchymal cells). Results: AA treated cells lost β-catenin and acquired vimentin, thus suggesting an EMT induction; whereas a crude methanolic extract of ginseng didn't produce any dedifferentiation effect. Conclusion: in order to rapidly evaluate if medicinal herbs may present a potential nephrotoxicity, we set up a model which reproduced some of the effects of AA as described in vivo on the renal proximal tubule, and which allowed us to begin assessing the empiric-known safety of ginseng. The next steps of our work will investigate, along with AA, two other nephrotoxic drugs: ciclosporin and cis-platin. Considering that oxidative stress is involved in their toxic activity, we will study the effect of several natural antioxidants on hRPTEC exposed to these drugs.