Caspase inhibition prevents the increase in caspase-3, -2, -8 and -9 activity and apoptosis in the cold ischemic mouse kidney.
Prolonged cold ischemic time is a risk factor for the development of delayed graft function. The adverse impact of cold ischemia may be associated with tubular cell death in the kidney. Caspase-3 is a major mediator of apoptotic cell death. We hypothesized that caspase inhibition would reduce apoptosis and other features of cold ischemia. Kidneys of C57BL/6 mice were perfused with cold University of Wisconsin solution containing a pancaspase inhibitor or vehicle via the left ventricle. The contralateral right kidney was used as a control. The left kidney was stored for 48 h at 4 degrees C to produce cold ischemia. Caspase-3 activity was massively (100-fold) increased in cold ischemic kidneys compared with controls. On immunoblot analysis, the processed form of caspase-3 was increased in cold ischemic kidneys compared with controls. The increase in caspase-3 was associated with significantly more renal tubular apoptosis and brush-border injury. In addition, caspase-2, -8 and -9 activities were increased in cold ischemic kidneys. The pancaspase inhibitor prevented the formation of the processed form of caspase-3 and the increase in caspase activity, and reduced apoptosis and brush-border injury. Caspase inhibition may prove useful in kidney preservation.
University of Colorado Health Sciences Center, Denver, Colorado, USA.
Alkesh
A
Jani
Danica
D
Ljubanovic
Sarah
S
Faubel
Jun
J
Kim
Ron
R
Mischak
Charles L
CL
Edelstein
D000818:Animals; D017209:Apoptosis; D002154:Calpain / Q000378:metabolism; D020170:Caspase 1 / Q000096:biosynthesis; D053143:Caspase 2; D053148:Caspase 3; D053181:Caspase 8; D053453:Caspase 9; D061945:Caspase Inhibitors; D020169:Caspases / Q000096:biosynthesis / Q000378:metabolism; D003080:Cold Temperature; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology*; D053938:DNA Fragmentation; D015151:Immunoblotting; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D007511:Ischemia; D007668:Kidney / Q000473:pathology; D007672:Kidney Cortex / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008871:Microvilli / Q000378:metabolism; D010477:Perfusion; D013696:Temperature; D013697:Thermosensing; D013997:Time Factors
D061945:Caspase Inhibitors; D015853:Cysteine Proteinase Inhibitors; D002154:Calpain; C505409:Casp3 protein, mouse; C505526:Casp8 protein, mouse; C506434:Casp9 protein, mouse; D053143:Caspase 2; D053148:Caspase 3; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases; D020170:Caspase 1