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

Abstract

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 <i>caspase-3</i> is a major mediator of apoptosis, its role in autosomal recessive PKD was determined. Mice with <i>caspase-3</i> gene deletion were crossed with mice harboring the congenital polycystic kidney (<i>cpk</i>) mutation to generate double-mutant mice. <i>cpk;casp3</i>^−/− mice lived nearly 4 times longer than littermate control <i>cpk</i> mice (mean survival of 117 d <i>versus</i> 32 d, <i>P</i> < 0.01), and <i>cpk</i>;<i>casp3</i>^+/− 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 <i>cpk;casp3</i>^−/− mice than in the <i>cpk</i> and <i>cpk;casp3</i>^+/− mice. Despite deletion of <i>caspase-3</i>, 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 <i>cpk</i>, <i>cpk;casp3</i>^+/−, and <i>cpk;casp3</i>^−/− mice compared with wild-type controls. In summary, homozygous deletion of <i>caspase-3</i> markedly prolongs survival of <i>cpk</i> mice, but a caspase-7-mediated pathway may compensate for the deficiency of functional <i>caspase-3</i>. These findings suggest that pan-caspase inhibition may have a greater therapeutic effect than selective caspase inhibition in PKD.