Role of cyclin-dependent kinase 2 in the progression of mouse juvenile cystic kidney disease

A hallmark of polycystic kidney diseases (PKDs) is aberrant proliferation, which leads to the formation and growth of renal cysts. Proliferation is mediated by cyclin-dependent kinases (Cdks), and the administration of roscovitine (a pan-Cdk inhibitor) attenuates renal cystic disease in juvenile cystic kidney (jck) mice. Cdk2is a key regulator of cell proliferation, but its specific role in PKD remains unknown. The aim of this study was to test the hypothesis that Cdk2deficiency reduces renal cyst growth in PKD. Three studies were undertaken: (i) a time course (days 28, 56, and 84) of cyclin and Cdk activity was examined in jckmice and compared with wild-type mice; (ii) the progression was compared in jckmice with or without Cdk2ablation from birth; and (iii) the effect of sirolimus (an antiproliferative agent) on Cdk2activity in jckmice was investigated. Renal disease in jckmice was characterized by diffuse tubular cyst growth, interstitial inflammation and fibrosis, and renal impairment, peaking on day 84. Renal cell proliferation peaked during earlier stages of disease (days 28–56), whereas the expression of Cdk2-cyclin partners (A and E) and Cdk1and 2activity, was maximal in the later stages of disease (days 56–84). Cdk2ablation did not attenuate renal disease progression and was associated with persistent Cdk1activity. In contrast, the postnatal treatment of jckmice with sirolimus reduced both Cdk2and Cdk1activity and reduced renal cyst growth. In conclusion, (i) the kinetics of Cdk2and Cdk2-cyclin partners did not correlate with proliferation in jckmice; and (ii) the absence of Cdk2did not alter renal cyst growth, most likely due to compensation by Cdk1. Taken together, these data suggest that Cdk2is dispensable for the proliferation of cystic epithelial cells and progression of PKD.