Centre for Transplant and Renal Research, Westmead Institute for Medical Research, The University of Sydney, 176 Hawkesbury Road, PO Box 412, Westmead, NSW, 2145, Australia.
Department of Renal Medicine, Westmead Hospital, Westmead, NSW, 2145, Australia.
Lab Invest. 2020 May;100(5):696-711. doi: 10.1038/s41374-019-0360-4. Epub 2020 Jan 8.
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. Cdk2 is 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 Cdk2 deficiency 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 jck mice and compared with wild-type mice; (ii) the progression was compared in jck mice with or without Cdk2 ablation from birth; and (iii) the effect of sirolimus (an antiproliferative agent) on Cdk2 activity in jck mice was investigated. Renal disease in jck mice 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 Cdk1 and 2 activity, was maximal in the later stages of disease (days 56-84). Cdk2 ablation did not attenuate renal disease progression and was associated with persistent Cdk1 activity. In contrast, the postnatal treatment of jck mice with sirolimus reduced both Cdk2 and Cdk1 activity and reduced renal cyst growth. In conclusion, (i) the kinetics of Cdk2 and Cdk2-cyclin partners did not correlate with proliferation in jck mice; and (ii) the absence of Cdk2 did not alter renal cyst growth, most likely due to compensation by Cdk1. Taken together, these data suggest that Cdk2 is dispensable for the proliferation of cystic epithelial cells and progression of PKD.
多囊肾病的一个标志是异常增殖，这导致了肾囊肿的形成和生长。增殖是由细胞周期蛋白依赖性激酶（Cdks）介导的，罗西维汀（一种泛 Cdk 抑制剂）的给药可减轻青少年多囊肾病（jck）小鼠的肾囊性疾病。Cdk2 是细胞增殖的关键调节因子，但它在多囊肾病中的具体作用尚不清楚。本研究旨在检验 Cdk2 缺乏可减少多囊肾病中肾囊肿生长的假设。进行了三项研究：（i）在 jck 小鼠和野生型小鼠中检查了细胞周期蛋白和 Cdk 活性的时间过程（第 28、56 和 84 天），并进行了比较；（ii）比较了从出生时就缺乏 Cdk2 的 jck 小鼠和不缺乏 Cdk2 的 jck 小鼠的进展情况；（iii）研究了西罗莫司（一种抗增殖剂）对 jck 小鼠 Cdk2 活性的影响。jck 小鼠的肾脏疾病表现为弥漫性管状囊肿生长、间质炎症和纤维化以及肾功能损害，在第 84 天达到高峰。肾细胞增殖在疾病的早期阶段达到高峰（第 28-56 天），而 Cdk2-细胞周期蛋白伙伴（A 和 E）和 Cdk1 和 2 活性的表达在疾病的晚期阶段达到高峰（第 56-84 天）。Cdk2 缺失并未减轻肾脏疾病的进展，并伴有持续的 Cdk1 活性。相比之下，西罗莫司对 jck 小鼠的出生后治疗降低了 Cdk2 和 Cdk1 的活性，并减少了肾囊肿的生长。总之，（i）jck 小鼠中 Cdk2 和 Cdk2-细胞周期蛋白伙伴的动力学与增殖无关；（ii）Cdk2 的缺失并未改变肾囊肿的生长，这很可能是由于 Cdk1 的代偿作用。综上所述，这些数据表明 Cdk2 对于囊性上皮细胞的增殖和多囊肾病的进展是可有可无的。
