Amelioration of rhabdomyolysis-induced renal mitochondrial injury and apoptosis through suppression of Drp-1 translocation

J Nephrol. Nov-Dec 2013;26(6):1073-82. doi: 10.5301/jn.5000268. Epub 2013 Apr 3.

Abstract

Introduction: 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acute Kidney Injury / etiology
  • Acute Kidney Injury / metabolism
  • Acute Kidney Injury / prevention & control*
  • Adenosine Triphosphate / biosynthesis
  • Animals
  • Apoptosis / physiology*
  • Caspase 3 / metabolism
  • Creatinine / blood
  • Cytochromes c / metabolism
  • Cytosol / metabolism
  • Dynamins / metabolism*
  • Epithelial Cells / drug effects
  • GTP Phosphohydrolases
  • Glycerol
  • Kidney / drug effects
  • Kidney / pathology
  • Kidney / physiopathology
  • Kidney Tubules / drug effects
  • Kidney Tubules / pathology
  • Kidney Tubules / ultrastructure
  • Male
  • Membrane Proteins / metabolism
  • Mitochondria / metabolism*
  • Mitochondrial Diseases / etiology
  • Mitochondrial Diseases / metabolism
  • Mitochondrial Diseases / prevention & control*
  • Mitochondrial Dynamics / drug effects*
  • Mitochondrial Dynamics / physiology
  • Mitochondrial Proteins / metabolism
  • Myoglobin / metabolism
  • Proliferating Cell Nuclear Antigen / metabolism
  • Quinazolinones / pharmacology
  • Rats
  • Rats, Sprague-Dawley
  • Reactive Oxygen Species
  • Rhabdomyolysis / chemically induced
  • Rhabdomyolysis / complications*
  • Rhabdomyolysis / metabolism
  • Solvents
  • bcl-2-Associated X Protein / metabolism

Substances

  • 3-(2,4-dichloro-5-methoxyphenyl)-2-sulfanyl-4(3H)-quinazolinone
  • Membrane Proteins
  • Mitochondrial Proteins
  • Myoglobin
  • Proliferating Cell Nuclear Antigen
  • Quinazolinones
  • Reactive Oxygen Species
  • Solvents
  • bcl-2-Associated X Protein
  • Adenosine Triphosphate
  • Cytochromes c
  • Creatinine
  • Caspase 3
  • GTP Phosphohydrolases
  • Mfn2 protein, rat
  • Dnm1l protein, rat
  • Dynamins
  • Glycerol