Department of Biochemistry 1, Hamamatsu University School of Medicine, 1-20-1 Handayama, Hamamatsu 431-3192, Japan.
Genes Cells. 2011 Nov;16(11):1110-20. doi: 10.1111/j.1365-2443.2011.01553.x.
The cyclin-dependent kinase (CDK) inhibitor p27 level is associated with progression of renal damage. We previously reported that mRNA of Skp2, a component of Skp/Cullin/F-box (SCF)-ubiquitin ligase which targets to p27, was increased in unilateral ureteral obstructive kidneys in mice and that the nephritis was attenuated in Skp2-deficient mice. However, the details have not been fully clarified. Here, we found that not only Skp2 but also cdc kinase subunit 1 (Cks1), an essential cofactor for the SCF-Skp2 ubiquitin ligase in targeting p27, was increased in another chronic progressive model, anti-thymocyte serum (ATS) rat nephropathy. After induction of ATS nephropathy, Skp2(+) /Cks1(+) /Ki67(+) tubular epithelial cell numbers increased, and p27(+) tubular epithelial cells decreased transiently. Moreover, we found that TNFα was involved in expression of both Skp2 and Cks1 in NRK cell line as well as the in ATS nephropathy. Nuclear accumulations of NF-κB subunits RelB and p52 were increased in the tubular epithelial cells of the nephritic kidney. Both Skp2 and Cks1 were colocalized with RelB in these cells. These data suggest that both Skp2 and Cks1 are up-regulated by the TNFα-RelB/p52 pathway in the early stages of renal damage and are collaboratively involved in down-regulation of p27 in proliferative tubular dilation and the progression of chronic nephropathy.
细胞周期蛋白依赖性激酶 (CDK) 抑制剂 p27 的水平与肾损伤的进展有关。我们之前曾报道，Skp2（Skp/Cullin/F-box (SCF)-泛素连接酶的一个组成部分，其靶标是 p27）的 mRNA 在单侧输尿管梗阻小鼠的肾脏中增加，并且 Skp2 缺陷型小鼠的肾炎减轻。然而，其细节尚未完全阐明。在这里，我们发现不仅 Skp2，而且细胞周期蛋白依赖性激酶亚单位 1（Cks1），即 SCF-Skp2 泛素连接酶靶向 p27 的必需辅因子，在另一种慢性进行性模型，抗胸腺细胞血清（ATS）大鼠肾病中也增加。在 ATS 肾病诱导后，Skp2(+) /Cks1(+) /Ki67(+)肾小管上皮细胞数量增加，而 p27(+)肾小管上皮细胞短暂减少。此外，我们发现 TNFα 参与 NRK 细胞系以及 ATS 肾病中 Skp2 和 Cks1 的表达。核因子-κB 亚基 RelB 和 p52 的核积累在肾炎肾脏的肾小管上皮细胞中增加。在这些细胞中，Skp2 和 Cks1 均与 RelB 共定位。这些数据表明，Skp2 和 Cks1 均通过 TNFα-RelB/p52 通路在肾损伤的早期阶段上调，并协同参与增殖性管状扩张和慢性肾病进展中 p27 的下调。
