title: Possible role of mitochondrial injury in Caulis Aristolochia manshuriensis-induced chronic aristolochic acid nephropathy.
abstract: BACKGROUND
  The proximal tubular epithelial cells (PTECs) are the primary target of aristolochic acids and especially vulnerable to mitochondrial injury from insults of toxic xenobiotics.
  
  
  OBJECTIVE
  This study aimed to investigate the possible role of mitochondrial injury in Caulis Aristolochia manshuriensis (CAM)-induced aristolochic acid nephropathy (AAN).
  
  
  METHODS
  Male Sprague-Dawley rats were gavaged with CAM extract every other week for 1, 4, 8 and 12 weeks, respectively.
  
  
  RESULTS
  The rats in the model group showed chronic AAN as evidenced by worsening kidney function evaluated by blood urea nitrogen, creatinine and proteinuria levels, and severe tubulointerstitial injury marked by massive tubular atrophy and interstitial fibrosis in kidney tissues. Moreover, overt apoptosis and impaired regeneration of PTECs were observed in AAN rats. Furthermore, the study revealed that mitochondria in PTECs were fragmented into small, punctuate suborganelles in AAN rats. Two mitochondrial respiratory chain proteins, mitochondrial DNA (mtDNA)-encoded cytochrome c oxidase subunit І (COX-І) and nuclear DNA-encoded nicotinamide adenine dinucleotide dehydrogenase (ubiquinone)-1β subcomplex 8 (NDUFβ8), were both down-regulated after one week of CAM treatment. However, with AAN progression, NDUFβ8 level restored, while COX-І level maintained low. Peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α), master regulator of mitochondrial biogenesis, was significantly down-regulated at week 4 and week 8, but significantly up-regulated at week 12. In addition, mtDNA copy number reduced markedly along with AAN progression.
  
  
  CONCLUSIONS
  A rat model of chronic AAN was successfully reproduced by gavage with CAM extract. Dynamic changes of mitochondrial injury induced by CAM might contribute to the AAN progression.
authors.affiliation: a Department of Nephrology , The First Affiliated Hospital, Sun Yat-Sen University , Guangzhou , Guangdong , China.|b Key Laboratory of Nephrology, Ministry of Health and Guangdong Province , Guangzhou , Guangdong , China , and.|c Department of Nephrology , Shenzhen Traditional Chinese Medicine Hospital, Guangzhou University of Chinese Medicine , Shenzhen , Guangdong , China.
authors.forename: Xinhui
authors.initials: X
authors.lastname: Liu
authors.affiliation: a Department of Nephrology , The First Affiliated Hospital, Sun Yat-Sen University , Guangzhou , Guangdong , China.|b Key Laboratory of Nephrology, Ministry of Health and Guangdong Province , Guangzhou , Guangdong , China , and.
authors.forename: Juan
authors.initials: J
authors.lastname: Wu
authors.affiliation: a Department of Nephrology , The First Affiliated Hospital, Sun Yat-Sen University , Guangzhou , Guangdong , China.|b Key Laboratory of Nephrology, Ministry of Health and Guangdong Province , Guangzhou , Guangdong , China , and.
authors.forename: Juan
authors.initials: J
authors.lastname: Wang
authors.affiliation: a Department of Nephrology , The First Affiliated Hospital, Sun Yat-Sen University , Guangzhou , Guangdong , China.|b Key Laboratory of Nephrology, Ministry of Health and Guangdong Province , Guangzhou , Guangdong , China , and.
authors.forename: Jinjin
authors.initials: J
authors.lastname: Fan
authors.affiliation: a Department of Nephrology , The First Affiliated Hospital, Sun Yat-Sen University , Guangzhou , Guangdong , China.|b Key Laboratory of Nephrology, Ministry of Health and Guangdong Province , Guangzhou , Guangdong , China , and.
authors.forename: Xiaoran
authors.initials: X
authors.lastname: Feng
authors.affiliation: a Department of Nephrology , The First Affiliated Hospital, Sun Yat-Sen University , Guangzhou , Guangdong , China.|b Key Laboratory of Nephrology, Ministry of Health and Guangdong Province , Guangzhou , Guangdong , China , and.
authors.forename: Xueqing
authors.initials: X
authors.lastname: Yu
authors.affiliation: a Department of Nephrology , The First Affiliated Hospital, Sun Yat-Sen University , Guangzhou , Guangdong , China.|b Key Laboratory of Nephrology, Ministry of Health and Guangdong Province , Guangzhou , Guangdong , China , and.
authors.forename: Xiao
authors.initials: X
authors.lastname: Yang
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D030022:Aristolochia / Q000737:chemistry*; D034341:Aristolochic Acids / Q000302:isolation & purification / Q000633:toxicity*; D015415:Biomarkers / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004365:Drugs, Chinese Herbal / Q000302:isolation & purification / Q000633:toxicity*; D007672:Kidney Cortex / Q000187:drug effects / Q000648:ultrastructure; D007677:Kidney Function Tests; D007687:Kidney Tubules, Proximal / Q000187:drug effects / Q000648:ultrastructure; D008297:Male; D008928:Mitochondria / Q000187:drug effects* / Q000648:ultrastructure; D009395:Nephritis, Interstitial / Q000097:blood / Q000139:chemically induced* / Q000473:pathology / Q000652:urine; D017207:Rats, Sprague-Dawley
chemical_list: D034341:Aristolochic Acids; D015415:Biomarkers; D004365:Drugs, Chinese Herbal; C000228:aristolochic acid I
keywords: Proximal tubular epithelial cells; apoptosis; regeneration disorder