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

• Published in: Journal of nephrology Vol. 26; no. 6; p. 1073
• Main Authors: Tang, Wan-Xin, Wu, Wei-Hua, Qiu, Hong-Yu, Bo, Hong, Huang, Song-Min
• Format: Journal Article
• Language: English
• Published: Italy 01.11.2013
• Subjects: Acute Kidney Injury - etiology; Acute Kidney Injury - metabolism; Acute Kidney Injury - prevention & control; Adenosine Triphosphate - biosynthesis; Animals; Apoptosis - physiology; bcl-2-Associated X Protein - metabolism; Caspase 3 - metabolism; Creatinine - blood; Cytochromes c - metabolism; Cytosol - metabolism; Dynamins - metabolism; Epithelial Cells - drug effects; 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
• ISSN: 1724-6059
• DOI: 10.5301/jn.5000268

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. 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. 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. 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.