局灶节段性肾小球硬化细胞病变中足细胞增殖所涉及的细胞周期机制。

Cell-cycle mechanisms involved in podocyte proliferation in cellular lesion of focal segmental glomerulosclerosis.

作者信息

Wang Suxia, Kim Ji Hoon, Moon Kyung Chul, Hong Hye Kyoung, Lee Hyun Soon

机构信息

Department of Pathology, Seoul National University College of Medicine, Seoul, South Korea.

出版信息

Am J Kidney Dis. 2004 Jan;43(1):19-27. doi: 10.1053/j.ajkd.2003.09.010.

DOI:10.1053/j.ajkd.2003.09.010

PMID:14712423

Abstract

BACKGROUND

Podocyte injury may induce podocyte proliferation, which results in glomerular scarring. The cellular lesion, seen in some patients with primary focal segmental glomerulosclerosis (FSGS), is characterized by proliferation of cells covering the sclerotic or collapsed glomerular tufts. Cell-cycle mechanisms by which podocyte proliferation occurs in the cellular lesion of FSGS are unclear.

METHODS

We examined expression patterns of cyclin D1; cyclin E; cyclin A; cyclin B1; cyclin-dependent kinase (CDK)2; CDK4; such CDK inhibitors as p21WAF1/CIP1 (p21), p27kip1 (p27), and p57kip2 (p57); and Wilms' tumor protein-1 (WT-1) in 12 renal biopsy specimens with the cellular lesion of FSGS and 6 renal biopsy specimens with no detectable abnormalities by immunohistochemistry and immunoelectron microscopy. Messenger RNA (mRNA) expression patterns of cyclin D1, cyclin E, p21, p27, and p57 were evaluated further by in situ hybridization.

RESULTS

In controls, immunostaining for cyclin A, cyclin B1, CDK2, CDK4, and p21 was almost negligible, but positive signals for cyclin D1, cyclin E, p27, and p57 were observed in glomerular epithelial cells (GECs). In the cellular lesion of FSGS, positive signals for cyclin E, cyclin A, cyclin B1, CDK2, and p21 were present in GEC nuclei, in which WT-1, p27, p57, and cyclin D1 were undetected. Immunoelectron microscopy showed that cyclin E-, CDK2-, and p21-specific gold particles were increased significantly in GEC nuclei in the cellular lesion in which cyclin D- and p57-specific particles were absent compared with controls. An in situ hybridization study showed specific signals of cyclin D1, cyclin E, p21, p27, and p57 mRNA in GECs forming the cellular lesion of FSGS.

CONCLUSION

Our results suggest that damaged podocytes may inhibit p27 and p57 protein expression, but activate a cyclin D1-independent cell-cycle mechanism and mitotic cell cyclins to promote GEC proliferation in the cellular lesion of FSGS.

摘要

背景

足细胞损伤可能诱导足细胞增殖，进而导致肾小球瘢痕形成。在一些原发性局灶节段性肾小球硬化（FSGS）患者中所见的细胞病变，其特征为覆盖硬化或塌陷肾小球小叶的细胞增殖。FSGS细胞病变中足细胞增殖所涉及的细胞周期机制尚不清楚。

方法

我们通过免疫组织化学和免疫电子显微镜检查了12例具有FSGS细胞病变的肾活检标本以及6例未检测到异常的肾活检标本中细胞周期蛋白D1、细胞周期蛋白E、细胞周期蛋白A、细胞周期蛋白B1、细胞周期蛋白依赖性激酶（CDK）2、CDK4、诸如p21WAF1/CIP1（p21）、p27kip1（p27）和p57kip2（p57）等CDK抑制剂以及威尔姆斯瘤蛋白-1（WT-1）的表达模式。通过原位杂交进一步评估细胞周期蛋白D1、细胞周期蛋白E、p21、p27和p57的信使核糖核酸（mRNA）表达模式。

结果

在对照组中，细胞周期蛋白A、细胞周期蛋白B1、CDK2、CDK4和p21的免疫染色几乎难以察觉，但在肾小球上皮细胞（GECs）中观察到细胞周期蛋白D1、细胞周期蛋白E、p27和p57的阳性信号。在FSGS的细胞病变中，细胞周期蛋白E、细胞周期蛋白A、细胞周期蛋白B1、CDK2和p21的阳性信号出现在GEC细胞核中，而未检测到WT-1、p27、p57和细胞周期蛋白D1。免疫电子显微镜显示，与对照组相比，在细胞病变的GEC细胞核中，细胞周期蛋白E、CDK2和p21特异性金颗粒显著增加，而细胞周期蛋白D和p57特异性颗粒缺失。原位杂交研究显示，在形成FSGS细胞病变的GECs中存在细胞周期蛋白D1、细胞周期蛋白E、p21、p27和p57 mRNA的特异性信号。