title: Critical role of organic anion transporters 1 and 3 in kidney accumulation and toxicity of aristolochic acid I.
abstract: Ingestion of aristolochic acid (AA), especially its major constituent aristolochic acid I (AAI), results in severe kidney injury known as aristolochic acid nephropathy (AAN). Although hepatic cytochrome P450s metabolize AAI to reduce its kidney toxicity in mice, the mechanism by which AAI is uptaken by renal cells to induce renal toxicity is largely unknown. In this study, we found that organic anion transporters (OATs) 1 and 3, proteins known to transport drugs from the blood into the tubular epithelium, are responsible for the transportation of AAI into renal tubular cells and the subsequent nephrotoxicity. AAI uptake in HEK 293 cells stably transfected with human OAT1 or OAT3 was greatly increased compared to that in the control cells, and this uptake was dependent on the AAI concentration. Administration of probenecid, a well-known OAT inhibitor, to the mice reduced AAI renal accumulation and its urinary excretion and protected mice from AAI-induced acute tubular necrosis. Further, AAI renal accumulation and severe kidney lesions induced by AAl in Oat1 and Oat3 gene knockout mice all were markedly suppressed compared to those in the wild-type mice. Together, our results suggest that OAT1 and OAT3 have a critical role in AAl renal accumulation and toxicity. These transporters may serve as a potential therapeutic target against AAN.
authors: State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Shanghai Institutes for Biological Sciences, Shanghai, China.
authors: Xiang
authors: X
authors: Xue
authors: Li-Kun
authors: LK
authors: Gong
authors: Kazuya
authors: K
authors: Maeda
authors: Yang
authors: Y
authors: Luan
authors: Xin-Ming
authors: XM
authors: Qi
authors: Yuichi
authors: Y
authors: Sugiyama
authors: Jin
authors: J
authors: Ren
mesh_terms: D000818:Animals; D034341:Aristolochic Acids / Q000633:toxicity*; D057809:HEK293 Cells; D006801:Humans; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism* / Q000473:pathology; D007674:Kidney Diseases / Q000139:chemically induced / Q000517:prevention & control; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008954:Models, Biological; D009153:Mutagens / Q000633:toxicity; D027362:Organic Anion Transport Protein 1 / Q000235:genetics / Q000378:metabolism*; D029362:Organic Anion Transporters, Sodium-Independent / Q000235:genetics / Q000378:metabolism*; D013997:Time Factors
chemical_list: D034341:Aristolochic Acids; D009153:Mutagens; D027362:Organic Anion Transport Protein 1; D029362:Organic Anion Transporters, Sodium-Independent; C114338:organic anion transport protein 3; C000228:aristolochic acid I