title: Amelioration of rhabdomyolysis-induced renal mitochondrial injury and apoptosis through suppression of Drp-1 translocation.
abstract: BACKGROUND
  Mitochondrial dysfunction plays an important role in acute kidney injury (AKI). Mitochondrial fission regulated by dynamin-related protein 1 (Drp-1) impairs the function of the mitochondria and the survival of cells. This study was conducted to explore the effects of suppression of Drp-1 accumulation in the mitochondria, on mitochondrial function and renal tubular cell apoptosis in rhabdomyolysis (RM)-induced AKI.
  
  
  METHODS
  An RM model was induced by intramuscular injection of glycerol in Sprague Dawley rats. Twenty-four and 48 hours after intraperitoneal injections of mitochondrial division inhibitor 1 (Mdivi-1), we observed the functions of the kidney, changes in pathology, expressions of Drp-1 in tubular tissues (by immunohistochemistry and Western blot) and accumulation of Drp-1 and mitofusin 2 in tubular mitochondria (by Western blot). Mitochondrial function (ATP and ROS) and tubular epithelial cell apoptosis (by TUNEL) were also measured.
  
  
  RESULTS
  RM induced Drp-1 accumulation, decreased ATP production and increased ROS in mitochondria. With increasing cytochrome c expression, cell apoptosis increased, whereas kidney function decreased. These changes were time-dependent. At different time points, despite not significantly influencing the overall expression of Drp-1, Mdivi-1 suppressed the accumulation of Drp-1, inhibited the insertion of proapoptotic Bax in mitochondria and inhibited the release of cytochrome c, thus ameliorating cell apoptosis.
  
  
  CONCLUSIONS
  To conclude, in RM-induced AKI, suppression of Drp-1 accumulation in mitochondria favors the maintenance of mitochondrial function and reduces the apoptosis of tubular cells. Regulation of the mitochondrial fusion-fission balance may offer a novel strategy for the prevention and treatment of RM-induced AKI.
authors.affiliation: Division of Nephrology, West China Hospital of Sichuan University, Chengdu, Sichuan - PR China.
authors.forename: Wan-Xin
authors.initials: WX
authors.lastname: Tang
authors.forename: Wei-Hua
authors.initials: WH
authors.lastname: Wu
authors.forename: Hong-Yu
authors.initials: HY
authors.lastname: Qiu
authors.forename: Hong
authors.initials: H
authors.lastname: Bo
authors.forename: Song-Min
authors.initials: SM
authors.lastname: Huang
mesh_terms: D058186:Acute Kidney Injury / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control*; D000255:Adenosine Triphosphate / Q000096:biosynthesis; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D053148:Caspase 3 / Q000378:metabolism; D003404:Creatinine / Q000097:blood; D045304:Cytochromes c / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism; D034281:Dynamins / Q000378:metabolism*; D004847:Epithelial Cells / Q000187:drug effects; D020558:GTP Phosphohydrolases; D005990:Glycerol; D007668:Kidney / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D007684:Kidney Tubules / Q000187:drug effects / Q000473:pathology / Q000648:ultrastructure; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism*; D028361:Mitochondrial Diseases / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control*; D063154:Mitochondrial Dynamics / Q000187:drug effects* / Q000502:physiology; D024101:Mitochondrial Proteins / Q000378:metabolism; D009211:Myoglobin / Q000378:metabolism; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D052999:Quinazolinones / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species; D012206:Rhabdomyolysis / Q000139:chemically induced / Q000150:complications* / Q000378:metabolism; D012997:Solvents; D051028:bcl-2-Associated X Protein / Q000378:metabolism
chemical_list: C549041:3-(2,4-dichloro-5-methoxyphenyl)-2-sulfanyl-4(3H)-quinazolinone; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D009211:Myoglobin; D018809:Proliferating Cell Nuclear Antigen; D052999:Quinazolinones; D017382:Reactive Oxygen Species; D012997:Solvents; D051028:bcl-2-Associated X Protein; D000255:Adenosine Triphosphate; D045304:Cytochromes c; D003404:Creatinine; D053148:Caspase 3; D020558:GTP Phosphohydrolases; C489710:Mfn2 protein, rat; C519851:Dnm1l protein, rat; D034281:Dynamins; D005990:Glycerol