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Mitochondrial Pathway Is Responsible for Aging-Related Increase of Tubular Cell Apoptosis in Renal Ischemia/Reperfusion Injury

Department of Nephrology, Kidney Center & Key Lab of PLA, Chinese General Hospital of PLA, Beijing, China.

Address correspondence to Xiangmei Chen, MD, PhD, Department of Nephrology, Kidney Center and Key Lab of PLA, Chinese General Hospital of PLA, Fuxing Road 28, Beijing 100853, P.R. China. E-mail: xmchen{at}public.bta.net.cn

Aging-related changes of tubular cell apoptosis and its mechanisms in renal ischemia/reperfusion (I/R) injury are unclear. In the present study, aged (27-month-old) and young (3-month-old) Wistar rats were used to investigate aging-related tubular cell apoptosis in the setting of renal I/R injury. The renal I/R model was induced by clamping bilateral renal arteries for 30 minutes followed by reperfusion for 18 hours. Cyclosporine A (CsA, 2 mg/kg) or mycophenolate mofetil (MMF, 20 mg/kg/d) was used before ischemia. Age-matched sham-operated rats served as controls. We found that tubular cell apoptosis increased more significantly in aged rats than in young rats after renal I/R. More pronounced increases of Bax/Bcl-2 ratio, cytosolic cytochrome c, and caspase-9, which are involved in mitochondria-mediated apoptosis, were found in aged rats than in young rats, and were associated with a more pronounced decrease in superoxide dismutase activity and increase of malondialdehyde content. However, increases of tumor necrosis factor- and caspase-8, two components of death receptor-mediated apoptosis, showed no aging-related differences. Interfering mitochondria and death receptor pathways with CsA and MMF, respectively, reduced the apoptosis in both age groups, whereas CsA was more effective in aged rats. Our results have demonstrated that there was an aging-related increase of tubular cell apoptosis in the renal I/R model, which may be, at least partly, due to an enhanced mitochondrial pathway resulting possibly from increased oxidative stress.