Bcl-xL augmentation potentially reduces ischemia/reperfusion induced proximal and distal tubular apoptosis and autophagy.
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.
Chien
Chiang-Ting
CT
Department of Medical Research, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan.
Shyue
Song-Kuen
SK
Lai
Ming-Kuen
MK
D000818:Animals; D017209:Apoptosis; D001343:Autophagy; D005260:Female; D018014:Gene Transfer Techniques; D006801:Humans; D007511:Ischemia / Q000517:prevention & control*; D007686:Kidney Tubules, Distal / Q000098:blood supply* / Q000166:cytology / Q000502:physiology; D007687:Kidney Tubules, Proximal / Q000098:blood supply* / Q000166:cytology / Q000502:physiology; D011401:Promoter Regions, Genetic; D051381:Rats; D017208:Rats, Wistar; D015427:Reperfusion Injury / Q000517:prevention & control*; D051028:bcl-2-Associated X Protein / Q000235:genetics; D051020:bcl-X Protein / Q000235:genetics* / Q000502:physiology*
C494811:BCL2L1 protein, human; C494813:Bcl2l1 protein, rat; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein