title: Probenecid prevents acute tubular necrosis in a mouse model of aristolochic acid nephropathy.
abstract: Experimental aristolochic acid nephropathy is characterized by early tubulointerstitial injury followed by fibrosis, reproducing chronic lesions seen in humans. In vitro, probenecid inhibits aristolochic acid entry through organic anion transporters, reduces specific aristolochic acid-DNA adduct formation, and preserves cellular viability. To test this in vivo, we used a mouse model of aristolochic acid nephropathy displaying severe tubulointerstitial injuries consisting of proximal tubular epithelial cell necrosis associated to transient acute kidney injury followed by mononuclear cell infiltration, tubular atrophy, and interstitial fibrosis. Treatment with probenecid prevented increased plasma creatinine and tubulointerstitial injuries, and reduced both the extent and the severity of ultrastructural lesions induced by aristolochic acid, such as the loss of brush border, mitochondrial edema, and the disappearance of mitochondrial crests. Further, the number of proliferating cell nuclear antigen-positive cells and total aristolochic acid-DNA adducts were significantly reduced in mice receiving aristolochic acid plus probenecid compared with mice treated with aristolochic acid alone. Thus, we establish the nephroprotective effect of probenecid, an inhibitor of organic acid transporters, in vivo toward acute proximal tubular epithelial cell toxicity in a mouse model of aristolochic acid nephropathy.
authors.affiliation: Experimental Nephrology Unit, Faculty of Medicine, Université Libre de Bruxelles, Brussels, Belgium.
authors.forename: Thomas E R
authors.initials: TE
authors.lastname: Baudoux
authors.forename: Agnieszka A
authors.initials: AA
authors.lastname: Pozdzik
authors.forename: Volker M
authors.initials: VM
authors.lastname: Arlt
authors.forename: Eric G
authors.initials: EG
authors.lastname: De Prez
authors.forename: Marie-Hélène
authors.initials: MH
authors.lastname: Antoine
authors.forename: Nathalie
authors.initials: N
authors.lastname: Quellard
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Goujon
authors.forename: Joëlle L
authors.initials: JL
authors.lastname: Nortier
mesh_terms: D000818:Animals; D034341:Aristolochic Acids; D001284:Atrophy; D015415:Biomarkers / Q000097:blood; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003404:Creatinine / Q000097:blood; D019610:Cytoprotection; D018736:DNA Adducts / Q000378:metabolism; D004195:Disease Models, Animal; D005355:Fibrosis; D007683:Kidney Tubular Necrosis, Acute / Q000097:blood / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control*; D007684:Kidney Tubules / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009395:Nephritis, Interstitial / Q000097:blood / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control*; D027361:Organic Anion Transporters / Q000037:antagonists & inhibitors / Q000378:metabolism; D011339:Probenecid / Q000494:pharmacology*; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D020011:Protective Agents / Q000494:pharmacology*; D013997:Time Factors
chemical_list: D034341:Aristolochic Acids; D015415:Biomarkers; D018736:DNA Adducts; D027361:Organic Anion Transporters; D018809:Proliferating Cell Nuclear Antigen; D020011:Protective Agents; C000228:aristolochic acid I; D003404:Creatinine; D011339:Probenecid