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 caspase-3 is a major mediator of apoptosis, its role in autosomal recessive PKD was determined. Mice with caspase-3 gene deletion were crossed with mice harboring the congenital polycystic kidney (cpk) mutation to generate double-mutant mice. cpk;casp3^−/− mice lived nearly 4 times longer than littermate control cpk mice (mean survival of 117 d versus 32 d, P < 0.01), and cpk;casp3^+/− 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 cpk;casp3^−/− mice than in the cpk and cpk;casp3^+/− mice. Despite deletion of caspase-3, 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 cpk, cpk;casp3^+/−, and cpk;casp3^−/− mice compared with wild-type controls. In summary, homozygous deletion of caspase-3 markedly prolongs survival of cpk mice, but a caspase-7-mediated pathway may compensate for the deficiency of functional caspase-3. These findings suggest that pan-caspase inhibition may have a greater therapeutic effect than selective caspase inhibition in PKD.Inherited polycystic kidney disease (PKD) is one of the leading causes of end-stage kidney disease requiring dialysis and kidney transplantation in children and adults.¹ Inherited PKD includes both autosomal dominant and autosomal recessive forms. Autosomal dominant polycystic kidney disease (ADPKD) results from mutations in one of two genes, PKD1 or PKD2. The prevalence of ADPKD varies between 1 in 400 and 1 in 1000, thus making it one of the most common hereditary diseases in the United States. ADPKD progresses to end-stage renal disease (ESRD) over a period of decades in 50% to 75% of affected people. Autosomal recessive polycystic kidney disease (ARPKD) results from a mutation in a single gene, PKHD1. ARPKD is less common, affecting about 1 in 20,000 live births and results in ESRD in childhood.²The congenital polycystic kidney (cpk) mouse is the most extensively characterized mouse model of PKD.² The inheritance, cyst localization in the kidney, and severity of kidney disease in the cpk mouse resembles ARPKD. Cys1, the cpk gene, encodes a cilia-associated protein called cystin that is disrupted in the cpk mouse.³ Increased apoptosis in polycystic kidneys has been described in cpk mice^4–8 as well as in human and other rat and mouse models of PKD.⁹ In support of a deleterious effect of apoptosis in PKD, we have recently demonstrated that pan-caspase inhibition reduces tubular apoptosis and proliferation and slows disease progression in the Han:SPRD rat model of PKD.¹⁰ The effect of caspase or apoptosis inhibition in other rat and mouse models of PKD is not known. Caspase-3 is the major mediator of apoptosis (i.e., the so-called “executioner” caspase) and caspase-1 is a pro-inflammatory caspase. However, the effect of inhibition of a specific caspase on PKD is not known. We tested the hypothesis that specific inhibition of caspase-3 would prolong life and reduce cyst formation in PKD.In the present study, we developed cpk mice that were either heterozygous or homozygous for caspase-3 deletion to determine the effect of specific caspase-3 deletion on the development of PKD.