Bcl-xL Augmentation Potentially Reduces Ischemia/Reperfusion Induced Proximal and Distal Tubular Apoptosis and Autophagy

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Abstract
Background. Apoptosis and autophagy may contribute to cell homeostasis in the kidney subjected to ischemia/reperfusion injury via mitochondrial injury. Ischemia/reperfusion induces differential sensitivity between proximal and distal tubules via a dissociated Bcl-xL expression. We hypothesized Bcl-xL augmentation in the proximal and distal tubules may potentially reduce ischemia/reperfusion induced renal dysfunction. Methods. We augmented Bcl-xL protein expression in the kidney with intrarenal adenoviral bcl-xL gene transfer and evaluated the potential effect of Bcl-xL augmentation on ischemia/reperfusion induced renal oxidative stress, apoptosis, and autophagy in the rat. Results. Intrarenal arterial Adv-bcl-xL administration augmented maximal Bcl-xL protein expression of rat kidney after 7 days of transfection. The primary location of Bcl-xL augmentation was found in proximal and distal tubules, but not in glomeruli. Ischemia/reperfusion increased mitochondrial cytochrome C release, renal O2−. level and renal 3-nitrosine and 4-hydroxyneonal accumulation, potentiated tubular apoptosis and autophagy, including increase in microtubule-associated protein 1 light chain 3 (LC-3) and Beclin-1 expression, Bax/Bcl-xL ratio, caspase 3 expression and poly-(ADP-ribose)-polymerase fragments, and subsequent proximal and distal tubular apoptosis/autophagy. However, Adv-bcl-xL administration significantly reduced ischemia/reperfusion enhanced mitochondrial cytochrome C release, O2−. production, 3-nitrotyrosine and 4-hydroxynonenal accumulation, Beclin-1 expression, Bax/Bcl-xL ratio, and proximal and distal tubular apoptosis/autophagy, consequently improving renal dysfunction. Further study showed that Bcl-xL augmentation was more efficiently than Bcl-2 augmentation in amelioration of ischemia/reperfusion induced proximal and distal tubular apoptosis and renal dysfunction. Conclusions. Our results suggest that Adv-bcl-xL gene transfer significantly improves ischemia/reperfusion-induced renal dysfunction via the downregulation of renal tubular apoptosis and autophagy.