足细胞相关蛋白与足细胞相关肾病研究进展

近年来对足细胞分子结构的深入研究，有助于足细胞相关肾病认识、诊断和分型。足细胞损伤常导致裂孔膜和足细胞结构的变化，基因突变或外界因素常通过四组途径改变足突细胞功能：①裂孔膜形成；②足细胞与肾小球基底膜的附着；③actin细胞骨架；④足细胞顶膜区。本文综述上述四组蛋白与肾脏疾病发生的最新进展。     

足细胞相关蛋白与足细胞相关肾病研究进展

近年来对足细胞分子结构的深入研究 ,有助于足细胞相关肾病认识、诊断和分型。足细胞损伤常导致裂孔膜和足细胞结构的变化 ,基因突变或外界因素常通过四组途径改变足突细胞功能 :①裂孔膜形成 ;②足细胞与肾小球基底膜的附着 ;③actin细胞骨架 ;④足细胞顶膜区。本文综述上述四组蛋白与肾脏疾病发生的最新进展     

肾脏疾病中细胞周期调控研究进展

细胞周期的调控是肾脏疾病发病机制研究的一个新领域。本文综述了细胞周期调控蛋白在不同肾脏疾病中的表达和作用     

细胞周期抑制蛋白p21与肾脏疾病

肾脏细胞增殖与凋亡异常在肾脏疾病中具有重要意义，其调控最终发生在细胞周期水平上，细胞周期抑制蛋白p21属于负向细胞周期调控蛋白，与多种肾脏疾病中细胞增殖和凋亡异常有关，可能影响肾脏疾病进展，对此深入研究可为肾脏疾病的防治提供新的启示。     

细胞周期抑制蛋白p21与肾脏疾病

肾脏细胞增殖与凋亡异常在肾脏疾病中具有重要意义 ,其调控最终发生在细胞周期水平上 ,细胞周期抑制蛋白p2 1属于负向细胞周期调控蛋白 ,与多种肾脏疾病中细胞增殖和凋亡异常有关 ,可能影响肾脏疾病进展 ,对此深入研究可为肾脏疾病的防治提供新的启示     

胃癌组织中细胞周期蛋白D1和细胞周期蛋白质依赖激酶6的表达与预后的关系

目的检测细胞周期蛋白D1(cyclin D1)和细胞周期蛋白质依赖激酶6(CDK6)在胃癌组织中的表达情况,分析其表达与胃癌的临床病理因素和预后之间的关系。方法用Western blot 法测定48例胃癌组织及其邻近的正常胃黏膜中cyclinD1和CDK6的表达量。结果 Cyclin D1在 58％的胃癌组织中呈异常高表达,且其表达与胃癌的浸润深度、淋巴转移和TNM分期相关。CDK6 的表达水平在69％的胃癌组织中异常升高,并与组织学分类、淋巴转移和TNM分期相关。未发现 cyclin D1和CDK6在胃癌组织中的表达存在线性相关关系。包括cyclin D1和CDK6过表达在内的多个因素与胃癌患者的5年生存率相关,但只有TNM分期和CDK6是患者预后的独立影响因素。结论 Cyclin D1和CDK6的异常高表达有可能在胃癌的发生、发展过程中发挥重要作用。     

细胞周期素E及细胞周期素依赖性激酶2在胃癌组织中的表达及意义

目的探讨胃癌组织中细胞周期素E(cyclinE)及细胞周期素依赖性激酶2(CDK     

肾脏疾病中细胞周期调控研究进展

细胞周期的调控是肾脏疾病发病机制研究的一个新领域。本文综述了细胞周期调控蛋白在不同肾脏疾病中的表达和作用。     

细胞周期调控蛋白的研究进展及其在增殖性肾炎研究中…

细胞生长周期是由一系列细胞内在的蛋来调控，这些蛋白包手细胞周期素，细胞 期素依赖的蛋白激酶和蛋白激酶抑制因子。本文综述了细胞周期控蛋白的研究动态，以及有关的增殖性疾病研究中应用现况和前景。     

Cell-cycle regulatory proteins in podocyte cell in idiopathic nephrotic syndrome of childhood

BACKGROUND: The podocyte cell is believed to play an important role in idiopathic nephrotic syndrome (INS) of childhood. In adults with cellular and collapsing focal segmental glomerulosclerosis (FSGS), the expression of cell-cycle regulatory proteins such as p27, p57, and cyclin D is decreased and expression of cyclin A, Ki-67, and p21 is observed in podocyte cells suggestive of a dysregulated podocyte phenotype. We investigated for alterations in the expression of cyclin kinase inhibitors, p27, p57, p21, and cyclins D and A in the podocyte cell of children with INS. METHODS: Forty-two kidney biopsies were investigated; 14 with minimal-change disease (MCD), seven with diffuse mesangial hypercellularity (DMH), 12 with FSGS, four with Alport syndrome (AS), and five normal biopsies. The sections were examined by immunohistochemistry using dual staining method. Podocyte cells were first identified by Wilm's tumor-1 staining after which expressions of cell-cycle regulatory proteins were analyzed. A quantitative analysis was performed for the proportion of podocyte cells that expressed each cell cycle regulatory protein. RESULTS: On light microscopy, all podocyte cells expressed p27, while p57 and p21 expression was seen in a portion of podocyte cells in normal kidney biopsies. Cyclin D was expressed in a small percent of podocyte cells though the expression was more marked in mesangial and endothelial cells. Cyclin A expression was not seen in normal biopsies. The mean expression of p27 decreased significantly in order from normal (100%), MCD (45.9%), DMH (22.4%), and FSGS (16.7%), and the difference between MCD and FSGS was significant. p21 was significantly and equally reduced in MCD (2.3%), DMH (0%), and FSGS (0.7%) compared to normal (66.6%). There was no significant difference in expression of p57, cyclin D and cyclin A in the podocyte cells between normal and children with INS. Children with AS showed a significant decrease in p27 and p21 expression, while the expression of p57, cyclin D and cyclin A were unchanged from normal, thus demonstrating a pattern similar to INS. CONCLUSION: The podocyte cell in children with INS down-regulates expression of cyclin kinase inhibitors such as p21 and p27, but not p57, but does not up-regulate cyclin D and cyclin A that are needed to overcome the G1/S transition and move the cell forward in the cell cycle process. Thus, the podocyte cell remains trapped in the G1 arrest phase. In children with INS or AS, the dysregulated podocyte phenotype is different than the one described in adults with cellular or collapsing FSGS.     

细胞周期调节蛋白在肾小球足细胞损伤中的作用

蛋白尿是肾脏疾病常见的临床表现之一,也是进展至肾衰竭的独立危险因素.肾小球滤过屏障结构或功能异常是蛋白尿发生的重要原因.     

Cell-cycle regulatory proteins in the podocyte in collapsing glomerulopathy in children

Podocyte is a terminally committed cell in G1 arrest of cell cycle, and is unable to overcome G1/S transition phase in children with minimal change disease (MCD) and classic focal segmental glomerulosclerosis (FSGS), in contrast to dysregulated proliferative phenotype of idiopathic collapsing glomerulopathy (CGN) in adults. Forty-two kidney biopsies, MCD (14), FSGS (12), CGN (4), and normal (CON) (12), were evaluated by immunohistochemistry using dual staining for expression of p27, p21, and p57, and cyclins D and A, in podocytes of children with CGN. On light microscopy, all podocytes expressed p27, whereas p21 and p57 expression was seen in a portion of podocytes in normal kidney biopsies. Cyclin D was expressed in a small percentage of podocytes. Cyclin A expression was absent in normal biopsies. The staining for p27 decreased significantly, in order, from normal (100%) to MCD (45.8%) to CGN (24.2%) to FSGS (16.6%). p21 staining was significantly decreased from normal (69.8%) to CGN (15.5%) to MCD (2.2%) to FSGS (0.6%), and the difference between CGN and MCD and FSGS was also significant. There was no significant difference in staining of p57. Cyclin D staining was significantly increased in CGN (26.8%) compared to normal (7.2%), MCD (1.6%), and FSGS (0.0%), and the difference between CGN and MCD and FSGS was also significant. De novo cyclin A staining was only observed in children with CGN. Thus, p27 and p21 but not p57 was decreased in CGN, as in FSGS when compared to normal. Both cyclins D and A staining were increased in CGN. The staining pattern in CGN would suggest that podocyte is able to overcome G1/S transition phase, and has a proliferative phenotype. We propose, based on the significant contrast observed in podocytes injury response between CGN (proliferative) and classic FSGS (non-proliferative), that CGN not be considered as a morphological variant of FSGS.     

Cell cycle regulatory proteins in glomerular disease

Evidence is accumulating that directly responsible for the rate of progression of glomerular disease are specific positive (cyclins and cyclin-dependent kinases) and negative (cyclin-kinase inhibitors) cell cycle regulatory proteins. The challenge for nephrologists is to determine which ones are expressed in renal disease and their precise role in glomerular cell proliferation, hypertrophy and differentiation. Ultimately the goal is to find ever more appropriate therapeutic strategies to arrest or prevent progressive renal disease.     

细胞周期调控蛋白在人类肾小球肾炎中肾小管及间质细胞的表达及其意义

目的 观察人类肾小球肾炎时肾小管－间质细胞的细胞周期调控蛋白的表达情况。方法 采用免疫组织化学技术，检测19例肾小球肾炎患者肾穿刺标本中细胞周期正性调控蛋白周期素D1（cyclin D1)，周期素A（cyclin A0，细胞周期负性调控蛋白p21^CIP1（p21)和增殖细胞核抗原（PCNA）的表达。结果 在人类肾小球肾炎中肾小管上皮细胞及间质细胞均见cyclin D1,cyclin A及p21的表达，并与PCNA呈正相关。小管的阳性表达以间质病变I级和Ⅱ级组显著，间质阳性细胞数与小管间质病变程度及患者尿NAG活性呈显著正相关。结论 人类肾小球肾炎时，细胞周期调控蛋白参与肾小管上皮细胞及间质细胞的增殖，参与肾间质纤维化的发展。     

Cell cycle regulatory proteins in glomerular disease.

The growth response of resident glomerular cells is determined by the underlying disease. Thus glomerular cells can proliferate, fail to proliferate, hypertrophy or apoptose. Cell growth is controlled by cell cycle regulatory proteins, and cell proliferation requires that cyclin-dependent kinases (CDK) be activated by partner cyclins. Inhibiting CDK2 reduces mesangial cell proliferation. Mesangial cell proliferation also requires that levels of specific cyclin kinase inhibitors (CKI) decrease. In contrast, the visceral glomerular epithelial cells' inability to proliferate may be due to increased levels of CKI. Moreover it is becoming increasingly clear that mesangial cell hypertrophy in diabetes requires increased CKI expression. Finally, apoptosis, which is often linked to proliferation, may also be due to the increased activity of CDK2. Thus, identifying specific cell cycle regulatory proteins following injury may provide future targets for therapy in glomerular disease.     

Distinct structural forms of type I collagen modulate cell cycle regulatory proteins in mesangial cells

BACKGROUND: Extracellular matrix molecules profoundly regulate cell behavior, including proliferation. In glomerulonephritis, type I collagen accumulates in the mesangium and is constantly structurally modified and degraded during the course of the disease. METHODS: We studied how two structurally distinct forms of type I collagen, monomer versus polymerized fibrils, affect cell proliferation, mitogen-activated protein kinase (MAPK) activation, and expression of G1-phase regulatory proteins in cultured rat mesangial cells (MCs). To analyze the possible involvement of collagen-binding integrins in type I collagen-derived growth signals further, distribution patterns of integrin chains were examined by immunocytochemistry. RESULTS: Polymerized type I collagen completely prevented the increase of DNA synthesis and cell replication induced by 5% fetal calf serum (FCS) or 25 ng/mL platelet-derived growth factor (PDGF) in MCs on monomer type I collagen. Protein expression of cyclins D1 and E was markedly down-regulated in MCs plated on polymerized type I collagen for eight hours in 5% FCS, as compared with MCs on monomer type I collagen. Incubation with 5% FCS reduced expression of the cdk-inhibitor protein p27Kip1 on monomer but not on polymerized type I collagen. Moreover, polymerized type I collagen markedly reduced cyclin E-associated kinase activity in the presence of 5% FCS. Polymerized type I collagen diminished the PDGF-induced phosphorylation and nuclear translocation of p42/p44 MAPK, but did not affect phosphorylation of PDGF beta-receptors. In MCs plated on monomer type I collagen, alpha1, alpha2, and beta1 integrin chains were recruited into focal contacts. However, on polymerized type I collagen, alpha2 and beta1, but not alpha1, integrin chains were condensed into focal contacts. CONCLUSIONS: The growth-inhibitory effect of polymerized type I collagen is characterized by rapid changes of expression and/or activation of MAPK and G1-phase regulators and could result from the lack of alpha1beta1 integrin signaling in MCs on polymerized type I collagen. Conceivably, deposition of polymerized type I collagen might reflect a reparative response to control MC replication in glomerular inflammation.     

Abnormalities of apoptotic and cell cycle regulatory proteins in distinct histopathologic components of benign prostatic hyperplasia

INTRODUCTION: Benign prostatic hyperplasia (BPH) is a slowly progressive abnormal glandular enlargement with heterogeneous morphology. Disruption of apoptotic pathways has been suggested as an important regulatory mechanism in this common and significantly morbid disease. METHODS: Prostatic tissue from 20 patients with BPH and no prior or subsequent prostatic carcinoma was obtained by transurethral prostatectomy (TURP) at the University of California Davis. Apoptotic regulatory proteins: BCL2, BAX and p27 were analyzed by immunohistochemistry and evaluated for expression in four distinct histologic patterns: hyperplastic epithelium, nodules, dilated glands and atrophic/inflammatory glands. RESULTS: Particularly striking was the decreased expression of BAX and an abnormal BCL2 : BAX ratio within all nodules relative to expression in other epithelial patterns. p27 expression was decreased in 35% of the hyperplastic epithelial areas and 10% of the nodules. DISCUSSION: Overall, abnormal expression of BCL2, BAX and/or p27 was identified in the hyperplastic epithelium of 19 (90%) of specimens and all 12 (100%) of the hyperplastic nodules. The high frequency of abnormalities in apoptosis regulatory genes, suggests that alteration of apoptotic pathways is important for the development of this condition.     

The role of cell cycle proteins in Glomerular disease

Although initially identified and characterized as regulators of the cell cycle and hence proliferation, an extended role for cell cycle proteins has been appreciated more recently in a number of physiologic and pathologic processes, including development, differentiation, hypertrophy, and apoptosis. Their precise contribution to the cellular response to injury appears to be dependent on both the cell type and the nature of the initiating injury. The glomerulus offers a remarkable situation in which to study the cell cycle proteins, as each of the 3 major resident cell types (the mesangial cell, podocyte, and glomerular endothelial cell) has a specific pattern of cell cycle protein expression when quiescent and responds uniquely after injury. Defining their roles may lead to potential therapeutic strategies in glomerular disease.