title: Aristolochic acid causes albuminuria by promoting mitochondrial DNA damage and dysfunction in podocyte.
abstract: Aristolochic acid nephropathy, initially found in patients intaking of slimming herbs containing aristolochic acid (AA), was previously considered as a progressive renal interstitial fibrosis and urothelial malignancy. However, the presence of albuminuria in some patients with AAN suggests that AA may also damage the glomerular filtration barrier. In this study, mice AAN model was generated by daily administration of aristolochic acid I sodium salt intraperitoneally at a dose of 6 mg/kg body weight for 3 days. All of the mice developed heavy albuminuria at day 3 and 7 after receiving AA. In the mice received AA, morphologic change of glomeruli was minor under light microscopy but podocyte foot-process effacement was evident under electron microscopy. In mitochondria isolated from kidney, prominent mitochondrial DNA (mtDNA) damage was accompanied with marked decrease of mtDNA copy number and mitochondrial protein expression level. Similar to those in vivo results, AA treatment impaired the filtration barrier function of cultured podocytes. AA promoted mtDNA damage, decreased mtDNA copy number and mitochondrial protein expression in cultured podocytes. In addition, AA treatment also decreased ATP content, oxygen consumption rate and mitochondrial membrane potential as well as increased cellular reactive oxygen species in cultured podocytes. This study highlighted that AA could induce podocyte damage and albuminuria, which may be mediated by promoting mtDNA damage and mitochondrial dysfunction in podocytes.
authors.affiliation: Center for Kidney Disease, 2nd Affiliated Hospital, Nanjing Medical University, Nanjing, Jiangsu Province, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: Center for Kidney Disease, 2nd Affiliated Hospital, Nanjing Medical University, Nanjing, Jiangsu Province, China.
authors.forename: Xueqin
authors.initials: X
authors.lastname: Bian
authors.affiliation: Center for Kidney Disease, 2nd Affiliated Hospital, Nanjing Medical University, Nanjing, Jiangsu Province, China.
authors.forename: Li
authors.initials: L
authors.lastname: Fang
authors.affiliation: Center for Kidney Disease, 2nd Affiliated Hospital, Nanjing Medical University, Nanjing, Jiangsu Province, China.
authors.forename: Weichun
authors.initials: W
authors.lastname: He
authors.affiliation: Center for Kidney Disease, 2nd Affiliated Hospital, Nanjing Medical University, Nanjing, Jiangsu Province, China.
authors.forename: Chunsun
authors.initials: C
authors.lastname: Dai
authors.affiliation: Center for Kidney Disease, 2nd Affiliated Hospital, Nanjing Medical University, Nanjing, Jiangsu Province, China.
authors.forename: Junwei
authors.initials: J
authors.lastname: Yang
mesh_terms: D000419:Albuminuria / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D034341:Aristolochic Acids / Q000009:adverse effects* / Q000494:pharmacology; D002273:Carcinogens / Q000494:pharmacology*; D002461:Cell Line, Transformed; D004249:DNA Damage; D004272:DNA, Mitochondrial / Q000378:metabolism*; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D008928:Mitochondria / Q000378:metabolism* / Q000648:ultrastructure; D050199:Podocytes / Q000378:metabolism* / Q000648:ultrastructure
chemical_list: D034341:Aristolochic Acids; D002273:Carcinogens; D004272:DNA, Mitochondrial; C000228:aristolochic acid I