Adenovirus-mediated bcl-2 gene transfer inhibits renal ischemia/reperfusion induced tubular oxidative stress and apoptosis

被引:100
作者
Chien, CT
Chang, TC
Tsai, CY
Shyue, SK
Lai, MK [1 ]
机构
[1] Natl Taiwan Univ Hosp, Dept Med, Taipei, Taiwan
[2] Natl Taiwan Univ Hosp, Coll Med, Dept Med Res, Taipei, Taiwan
[3] Natl Taiwan Univ, Coll Med, Taipei, Taiwan
[4] Acad Sinica, Inst Biomed Sci, Taipei, Taiwan
关键词
apoptosis; bcl-2; gene transfer; ischemia/reperfusion; kidney; oxidative stress;
D O I
10.1111/j.1600-6143.2005.00826.x
中图分类号
R61 [外科手术学];
学科分类号
摘要
Ischemia/reperfusion induces oxidative injury to proximal and distal renal tubular cells. We hypothesize that Bcl-2 protein augmentation with adenovirus vector mediated bcl-2 (Adv-bcl-2) gene transfer may improve ischemia/reperfusion induced renal proximal and distal tubular apoptosis through the mitochondrial control of Bax and cytochrome C translocation. Twenty-four hours of Adv-bcl-2 transfection to proximal and distal tubular cells in vitro upregulated Bcl-2/Bax ratio and inhibited hypoxia/reoxygenation induced cytochrome C translocation, O-2(-) production and tubular apoptosis. Intra-renal arterial Adv-bcl-2 administration with renal venous clamping augmented Bcl-2 protein of rat kidney in vivo in a time-dependent manner. The maximal Bcl-2 protein expression appeared at 7 days after Adv-bcl-2 administration and the primary location of Bcl-2 augmentation was in proximal and distal tubules, but not in glomeruli. With a real-time monitoring O-2(-) production and apoptosis analysis of rat kidneys, ischemia/reperfusion increased renal O-2(-) level, potentiated proapoptotic mechanisms, including decrease in Bcl-2/Bax ratio, increases in caspase 3 expression and poly-(ADP-ribose)-polymerase fragments and subsequent proximal and distal tubular apoptosis. However, Adv-bcl-2 administration significantly enhanced Bcl-2/Bax ratio, decreased ischemia/reperfusion induced O-2(-) amount, inhibited proximal and distal tubular apoptosis and improved renal function. Our results suggest that Adv-bcl-2 gene transfer significantly reduces ischemia/reperfusion induced oxidative injury in the kidney.
引用
收藏
页码:1194 / 1203
页数:10
相关论文
共 42 条
[1]   The Bcl-2 protein family: Arbiters of cell survival [J].
Adams, JM ;
Cory, S .
SCIENCE, 1998, 281 (5381) :1322-1326
[2]   Bax oligomerization is required for channel-forming activity in liposomes and to trigger cytochrome c release from mitochondria [J].
Antonsson, B ;
Montessuit, S ;
Lauper, S ;
Eskes, R ;
Martinou, JC .
BIOCHEMICAL JOURNAL, 2000, 345 :271-278
[3]   Expression of bcl-2 and bax in regenerating rat renal tubules following ischemic injury [J].
Basile, DP ;
Liapis, H ;
Hammerman, MR .
AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY, 1997, 272 (05) :F640-F647
[4]   Glutathione protects the rat liver against reperfusion injury after hypothermic preservation [J].
Bilzer, M ;
Paumgartner, G ;
Gerbes, AL .
GASTROENTEROLOGY, 1999, 117 (01) :200-210
[5]   Acute renal failure. I. Relative importance of proximal vs. distal tubular injury [J].
Bonventre, JV ;
Brezis, M ;
Siegel, N ;
Rosen, S ;
Portilla, D ;
Venkatachalam, M ;
Lieberthal, W ;
Nigam, SK .
AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY, 1998, 275 (05) :F623-F631
[6]   Recent advances in the pathophysiology of ischemic acute renal failure [J].
Bonventre, JV ;
Weinberg, JM .
JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY, 2003, 14 (08) :2199-2210
[7]   DISPARATE MECHANISMS FOR HYPOXIC CELL INJURY IN DIFFERENT NEPHRON SEGMENTS - STUDIES IN THE ISOLATED PERFUSED RAT-KIDNEY [J].
BREZIS, M ;
SHANLEY, P ;
SILVA, P ;
SPOKES, K ;
LEAR, S ;
EPSTEIN, FH ;
ROSEN, S .
JOURNAL OF CLINICAL INVESTIGATION, 1985, 76 (05) :1796-1806
[8]   Mitochondrial control of apoptosis:: the role of cytochrome c [J].
Cai, JY ;
Yang, J ;
Jones, DP .
BIOCHIMICA ET BIOPHYSICA ACTA-BIOENERGETICS, 1998, 1366 (1-2) :139-149
[9]   Pentoxifylline attenuates experimental mesangial proliferative glomerulonephritis [J].
Chen, YM ;
Chien, CT ;
Hu-Tsai, MI ;
Wu, KD ;
Tsai, CC ;
Wu, MS ;
Tsai, TJ .
KIDNEY INTERNATIONAL, 1999, 56 (03) :932-943
[10]  
Chien CT, 2001, J AM SOC NEPHROL, V12, P973, DOI 10.1681/ASN.V125973