Hiromura K, Haseley L A, Zhang P, Monkawa T, Durvasula R, Petermann A T, Alpers C E, Mundel P, Shankland S J
Department of Medicine, Division of Nephrology, University of Washington School of Medicine, Seattle, Washington 98195, USA.
Kidney Int. 2001 Dec;60(6):2235-46. doi: 10.1046/j.1523-1755.2001.00057.x.
The mature podocyte is a terminally differentiated cell with a limited proliferative capacity. The precise cell cycle proteins necessary for establishing podocyte quiescence during development or permitting podocyte cell cycle re-entry in disease states have not been fully defined. Accordingly, we studied the role of the cyclin dependent kinase (CDK)-inhibitor p57Kip2 (p57) in modulating these processes.
The expression of p57 protein in relation to markers of DNA synthesis was examined in developing mouse kidneys, and in the passive Heymann nephritis (PHN) and anti-glomerular antibody models of glomerular disease by immunohistochemistry. The role of p57 in glomerulogenesis was explored by examining renal tissue from embryonic p57-/- mice, and the expression of p21, p27 and p57 protein and mRNA was examined in podocytes in vitro.
The de novo expression of p57 during glomerulogenesis coincides with the cessation of podocyte proliferation, and the establishment of a mature phenotype, and p57 is expressed exclusively in podocytes in mature glomeruli. However, p57 knockout mice have normal glomerular podocyte development. In addition, mRNA but not protein levels of p57 increased upon differentiation of podocytes in vitro. There was a marked decrease in p57 expression in both animal models of podocyte injury. This was diffuse in PHN, whereas in the murine model, loss of expression of p57 occurred predominantly in proliferating podocytes, expressing proliferating cell nuclear antigen (PCNA).
Despite the de novo expression of p57 protein coinciding with the cessation of primitive podocyte proliferation during glomerulogenesis, embryonic p57-/- mice glomeruli were histologically normal. Cultured podocytes did not require changes in p57 protein levels to undergo differentiation. These data suggest that p57 alone is not required for podocyte differentiation, and that other cell cycle regulators may play a role. Furthermore, although injury to mature podocytes in experimental glomerular disease is associated with a decrease in p57, the levels of all three members of the Cip/Kip family of CDK inhibitors appear to determine the capability of podocytes to proliferate.
成熟足细胞是终末分化细胞，增殖能力有限。在发育过程中建立足细胞静止状态或在疾病状态下允许足细胞重新进入细胞周期所必需的精确细胞周期蛋白尚未完全明确。因此，我们研究了细胞周期蛋白依赖性激酶（CDK）抑制剂p57Kip2（p57）在调节这些过程中的作用。
通过免疫组织化学检测发育中小鼠肾脏、被动型Heymann肾炎（PHN）和肾小球疾病的抗肾小球抗体模型中p57蛋白表达与DNA合成标志物的关系。通过检查胚胎p57基因敲除小鼠的肾组织来探讨p57在肾小球发生中的作用，并在体外检测足细胞中p21、p27和p57蛋白及mRNA的表达。
肾小球发生过程中p57的从头表达与足细胞增殖停止及成熟表型的建立同时发生，且p57仅在成熟肾小球的足细胞中表达。然而，p57基因敲除小鼠的肾小球足细胞发育正常。此外，体外足细胞分化时p57的mRNA水平升高，但蛋白水平未升高。在两种足细胞损伤动物模型中，p57表达均显著降低。在PHN中这种降低是弥漫性的，而在小鼠模型中，p57表达缺失主要发生在表达增殖细胞核抗原（PCNA）的增殖足细胞中。
尽管在肾小球发生过程中p57蛋白的从头表达与原始足细胞增殖停止同时发生，但胚胎p57基因敲除小鼠的肾小球在组织学上是正常的。培养的足细胞分化不需要p57蛋白水平的变化。这些数据表明，足细胞分化不需要单独的p57，其他细胞周期调节因子可能起作用。此外，尽管实验性肾小球疾病中成熟足细胞损伤与p57降低有关，但CDK抑制剂Cip/Kip家族的所有三个成员的水平似乎决定了足细胞的增殖能力。
