Caspase-3 gene deletion prolongs survival in polycystic kidney disease.

Pan-caspase inhibition reduces tubular apoptosis and proliferation and slows progression of disease in a rat model of polycystic kidney disease (PKD). It is unknown, however, which specific caspases are involved in PKD progression. Because is a major mediator of apoptosis, its role in autosomal recessive PKD was determined. Mice with gene deletion were crossed with mice harboring the congenital polycystic kidney () mutation to generate double-mutant mice. mice lived nearly 4 times longer than littermate control mice (mean survival of 117 d 32 d, < 0.01), and ; mice lived slightly longer than controls (mean survival of 56 d). In addition, the kidney weight, relative to body weight, was significantly lower in the mice than in the and mice. Despite deletion of , however, apoptosis occurred and cysts formed; therefore, the alternative pathways of apoptosis in cystic kidneys were investigated. Caspase-7 was up-regulated and the anti-apoptotic protein Bcl-2 was down-regulated in , , and mice compared with wild-type controls. In summary, homozygous deletion of markedly prolongs survival of mice, but a caspase-7-mediated pathway may compensate for the deficiency of functional . These findings suggest that pan-caspase inhibition may have a greater therapeutic effect than selective caspase inhibition in PKD.