[No authors listed]
Xâlinked inhibitor of apoptosis protein (XIAP) negatively regulates apoptotic pathways at a postâmitochondrial level. XIAP functions by directly binding and inhibiting activation of specific caspases. Upon apoptotic stimuli, mitochondrial second mitochondriaâderived activator of caspases (Smac)/direct IAPâbinding protein with low PI (Diablo) is released into the cytosol, which results in displacement of XIAP from caspases. Heat shock protein 72 (HSP72), an antiâapoptotic protein, prevents mitochondrial injury resulting from acute renal ischemia/reperfusion (I/R), its role in Smac/Diablo and XIAP signaling remains to be elucidated. In the present study, the hypothesis that HSP72 prevents XIAP degradation in vivo and in vitro was assessed. To this purpose, a rat model of I/R injury was used to investigate the renoprotective role of HSP72 by treatment with geranylgeranylacetone (GGA), a specific inducer of HSP72. The mechanism of the cytoprotective properties of HSP72 was also investigated in vitro using adenovirusâmediated overexpression of HSP72 in adenosine triphosphate (ATP)âdepleted human kidney 2 (HKâ2) cells. Preâconditioning rats with GGA attenuated renal tubular cell damage, reduced cell apoptosis, preserved XIAP protein content and improved renal function following I/R injury. An in vitro study was performed in which cells were transiently exposed to 5 mM sodium cyanide in a glucoseâfree medium in order to induce apoptosis. Compared with the control, overexpression of HSP72 inhibited Smac/Diablo release from the mitochondria and increased levels of XIAP and proâcaspase 3 in ATPâdepleted HKâ2 cells. In addition, HSP72 interacted with Smac/Diablo. The present data demonstrates that HSP72 preserves renal function in I/R injury through its antiâapoptotic effects, which act by suppressing mitochondrial Smac/Diablo release and preserving XIAP protein content.
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