J ZHANG1,2, J BURGESS1,2, D STEPANOVA1,2, P KALDIS3, G RANGAN1,2
1Centre for Transplant and Renal Research, Westmead Institute for Medical Research, University of Sydney, Westmead, Australia, 2Department of Renal Medicine, Westmead Hospital, Westmead, Australia, 3Institute of Molecular and Cell Biology (IMCB), , Singapore
Aim: To determine if cyclin-dependent kinase (Cdk)-2 deficiency attenuates renal cyst growth in polycystic kidney disease (PKD) in vivo.
Background: Cdk2 is a key regulator of cell proliferation. In vitro, the loss of polycystin-1 promotes Cdk2 activity, and in vivo, the pan-Cdk inhibitor, roscovitine, reduced the progression of renal cystic disease in juvenile cystic kidney (jck) disease mice. However, the specific in vivo role of Cdk2 in PKD remains unclear.
Methods: Three studies were undertaken: (i) the time course of Cdk2 was examined in jck mice (which have a homozygous point mutation of Nek8) on day 28 (D28), D56, and D84 (n=6 per group); (ii) the progression of renal cystic disease was compared in compound jck mice with or without Cdk2 deficiency; and (iii) the effect of sirolimus on Cdk2 activity in jck mice.
Results: Renal disease in jck mice was characterised by diffuse tubular cyst growth, interstitial inflammation and fibrosis, and renal impairment peaking on D84. Renal epithelial cell proliferation peaked on D28, whereas whole-kidney expression of Cdk2-cyclin partners (A and E), as well as the kinase activity of Cdk2 and Cdk1, was only maximal on D84 in jck mice. However, renal disease progression was not attenuated by Cdk2 deficiency in jck mice, and was associated with persistent Cdk1 activity. In contrast, treatment of jck mice with sirolimus (D28-56) reduced both Cdk2 and Cdk1 activity, and decreased renal cyst growth.
Conclusions: Cdk2 kinase activity was maximal only in late-stage PKD, and the absence of Cdk2 did not reduce renal cyst growth, most likely due to compensation by Cdk1. These data suggest that specifically targeting Cdk2 is unlikely to attenuate cyst growth in PKD.
Jennifer is currently a PhD student in the Polycystic Kidney Disease Group at the Westmead Institute for Medical Research, University of Sydney, under the supervision of Associate Professor Gopi Rangan. She previously completed a Bachelor of Science (Physiology and Nutrition & Metabolism), followed by a Master of Nutrition and Dietetics. Her PhD is focused on preclinical research into what triggers cyst formation in autosomal dominant polycystic kidney disease. She is also currently working as a research dietitian on the PREVENT-ADPKD study.