title: Possible role of mtDNA depletion and respiratory chain defects in aristolochic acid I-induced acute nephrotoxicity.
abstract: This report describes an investigation of the pathological mechanism of acute renal failure caused by toxic tubular necrosis after treatment with aristolochic acid I (AAI) in Sprague-Dawley (SD) rats. The rats were gavaged with AAI at 0, 5, 20, or 80 mg/kg/day for 7 days. The pathologic examination of the kidneys showed severe acute tubular degenerative changes primarily affecting the proximal tubules. Supporting these results, we detected significantly increased concentrations of blood urea nitrogen (BUN) and creatinine (Cr) in the rats treated with AAI, indicating damage to the kidneys. Ultrastructural examination showed that proximal tubular mitochondria were extremely enlarged and dysmorphic with loss and disorientation of their cristae. Mitochondrial function analysis revealed that the two indicators for mitochondrial energy metabolism, the respiratory control ratio (RCR) and ATP content, were reduced in a dose-dependent manner after AAI treatment. The RCR in the presence of substrates for complex I was reduced more significantly than in the presence of substrates for complex II. In additional experiments, the activity of respiratory complex I, which is partly encoded by mitochondrial DNA (mtDNA), was more significantly impaired than that of respiratory complex II, which is completely encoded by nuclear DNA (nDNA). A real-time PCR assay revealed a marked reduction of mtDNA in the kidneys treated with AAI. Taken together, these results suggested that mtDNA depletion and respiratory chain defects play critical roles in the pathogenesis of kidney injury induced by AAI, and that the same processes might contribute to aristolochic acid-induced nephrotoxicity in humans.
authors: Jiangsu Center for Drug Screening, China Pharmaceutical University, Nanjing 210009, China. jiangcpu@yahoo.com.cn
authors: Zhenzhou
authors: Z
authors: Jiang
authors: Qingli
authors: Q
authors: Bao
authors: Lixin
authors: L
authors: Sun
authors: Xin
authors: X
authors: Huang
authors: Tao
authors: T
authors: Wang
authors: Shuang
authors: S
authors: Zhang
authors: Han
authors: H
authors: Li
authors: Luyong
authors: L
authors: Zhang
mesh_terms: D058186:Acute Kidney Injury / Q000139:chemically induced*; D000818:Animals; D034341:Aristolochic Acids / Q000008:administration & dosage / Q000633:toxicity*; D001806:Blood Urea Nitrogen; D003404:Creatinine / Q000378:metabolism; D004272:DNA, Mitochondrial / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D042967:Electron Transport Complex I / Q000187:drug effects / Q000378:metabolism; D042963:Electron Transport Complex II / Q000187:drug effects / Q000378:metabolism; D004734:Energy Metabolism / Q000187:drug effects; D007683:Kidney Tubular Necrosis, Acute / Q000139:chemically induced*; D028361:Mitochondrial Diseases / Q000139:chemically induced*; D051381:Rats; D017207:Rats, Sprague-Dawley; D060888:Real-Time Polymerase Chain Reaction
chemical_list: D034341:Aristolochic Acids; D004272:DNA, Mitochondrial; C478189:respiratory complex II; C000228:aristolochic acid I; D003404:Creatinine; D042963:Electron Transport Complex II; D042967:Electron Transport Complex I