贝那普利对糖尿病肾病大鼠MCP-1的影响

本研究证实糖尿病肾病(DN)大鼠的肾小球上有明显单核/巨噬细胞浸润，但机制尚不清楚。单核细胞趋化蛋白(MCP-1)是针对单核细胞的趋化因子，可能在DN的发生中起重要作用。     

单核细胞趋化蛋白-1与糖尿病肾病

单核细胞趋化蛋白-1(MCP-1)是一种对单核细胞具有特异趋化功能的细胞因子,参与单核/巨噬细胞的浸润,在糖尿病肾病(DN)的发生发展中起重要作用。而螺内酯、血管紧张素转换酶抑制剂或血管紧张素Ⅱ受体阻滞剂、噻唑烷二酮类、免疫调节剂麦考酚酸莫酯(MMF)、维生素E及他汀类均能使MCP-1水平下降,延缓DN的发生发展。     

单核细胞趋化蛋白—1和糖尿病肾病

糖尿病肾病（DN）往往存在着血糖、血脂的代谢紊乱及某些细胞因子（白介素－1、肿瘤坏死因子－α）和血管紧张素Ⅱ水平的升高，这些改变均可使体内单核细胞趋化因子－1（MCP－1）水平上升。MCP-1一种对单核细胞有强烈趋化作用的细胞因子，它的增多使肾小球中单核浸润，导致细胞外基质在肾小球和肾小管中堆积。因此MCP-1在DN的发生、发展中起重要作用。     

单核细胞趋化蛋白-1在糖尿病肾病发病中的作用

糖尿病肾病(DN)是严重影响糖尿病(DM)患者生存和生活质量的慢性并发症之一。细胞外基质(ECM)在肾小球、肾小管聚集导致的肾小球坏死及肾间质纤维化是其特征性病理改变Ⅲ，DN确切的发病机制尚未完全明了。近年来的研究资料显示，DN的发生可能和单核细胞／巨噬细胞(M0／Mφ)在肾组织的广泛浸润有关，而单核细胞趋化蛋白一     

单核细胞趋化蛋白-1和糖尿病肾病

糖尿病肾病 (DN)往往存在着血糖、血脂的代谢紊乱及某些细胞因子 (白介素 1、肿瘤坏死因子 α)和血管紧张素Ⅱ水平的升高 ,这些改变均可使体内单核细胞趋化因子 1(MCP 1)水平上升。MCP 1是一种对单核细胞有强烈趋化作用的细胞因子 ,它的增多使肾小球中单核细胞浸润 ,导致细胞外基质在肾小球和肾小管中堆积。因此MCP 1在DN的发生、发展中起重要作用。     

MCP-1及其基因多态性与糖尿病肾病的关系

糖尿病肾病（DN）的发病机制比较复杂,至今尚未完全阐明,可能与遗传易感性、糖代谢紊乱、细胞因子、炎症机制等多种因素有关[1]。近年研究发现,DN可能和单核巨噬细胞在肾组织的广泛浸润有关。而单核细胞趋化蛋白-1（MCP-1）是单核巨噬细胞特异性趋化因子,是单核巨噬细胞聚集活化的主要因素[2]。本文结合文献就MCP-1及其基因多态性（SNP）与DN的关系作一综述。     

单核细胞趋化蛋白1和糖尿病肾病的关系探讨

已报道许多细胞因子参与糖尿病肾病 (ＤＮ)的发生、发展 ,单核细胞趋化蛋白 1(ｍｏｎｏｃｙｔｅｃｈｅｍｏａｔｔｒａｃｔａｎｔｐｒｏｔｅｉｎ 1,ＭＣＰ 1)为其中之一。ＭＣＰ 1的增多使肾小球中单核 /巨噬细胞浸润 ,导致细胞外基质 (ＥＣＭ)在肾小球和肾小管中堆积 ,从而参与ＤＮ的发生、发展。本实验检测不同时期的糖尿病(ＤＭ)患者血、尿ＭＣＰ 1的水平 ,以探讨ＭＣＰ 1和ＤＮ的关系。一、对象和方法1.对象 :2型ＤＭ患者 31例 ,系我院内分泌科住院患者。均符合 1997年美国糖尿病协会 (ＡＤＡ)的诊断标准。排除心、肝疾病 ,排除泌尿系感…     

C-C亚族趋化因子与糖尿病肾病

C—C亚族趋化因子大部分由激活的T细胞和单核细胞产生,主要包括单核细胞趋化蛋白（MCP）-1和正常T细胞活化后表达和分泌的调节蛋白（RANTES）。MCP-1和RANTES是单核／巨噬细胞的特异性趋化因子,在糖尿病肾病（DN）肾组织中表达增加。高水平的C—C趋化因子通过与其受体结合介导单核／巨噬细胞在肾组织的募集和分化,导致肾小球系膜细胞增生,细胞外基质积聚及肾小管纤维化。阻止C—C趋化因子表达将有可能为治疗DN开辟一条新的途径。     

巨噬细胞与糖尿病肾病

糖尿病肾病是一种慢性炎性疾病,而巨噬细胞是重要的炎性细胞,在糖尿病肾病的发生、发展中起重要作用.血液中的单核细胞在选择素、细胞间黏附分子-1(ICAM-1)、血管细胞黏附分子-1(VCAM-1)、单核细胞趋化蛋白-1(MCP-1)及骨桥蛋白等细胞黏附分子或趋化因子作用下经历滚动、黏附、迁移等过程,浸润于肾组织而分化成巨噬细胞,体内持续高血糖等因素使其活化,释放转化生长因子-β(TGF-β)、肿瘤坏死因子-α(TNF-α)、白细胞介素(IL)-1、IL-6、IL-18等细胞因子,促进肾小球系膜细胞分泌细胞外基质及成纤维细胞增殖,引起系膜细胞外基质沉淀、肾小球硬化及间质纤维化等肾损伤,从而促进糖尿病肾病的发展.调控巨噬细胞的浸润与活化可能是防治糖尿病肾病的新途径.     

单核细胞趋化蛋白-1与肺部疾病关系的研究进展

<正>单核细胞趋化蛋白-1(monocyte chemoattractant protein-1,MCP-1)是一种具有趋化效应的细胞因子,因氨基酸序列N端最早出现的两个半胱氨酸排列相邻而属于趋化因子CC亚家族,主要趋化单核/巨噬细胞、淋巴细胞等炎性细胞向病变部位聚集并被激活产生各种细胞因子,导致炎症产生与发展。主要由巨噬细胞、内皮细胞、单核细胞、树突细胞、上皮细胞等分泌,在促炎反应、血管重塑、肿瘤形成和转移、组织     

Monocyte chemoattractant protein 1 mediates retinal detachment-induced photoreceptor apoptosis

Photoreceptor apoptosis is a major cause of visual loss in retinal detachment (RD) and several other visual disorders, but the underlying mechanisms remain elusive. Recently, increased expression of monocyte chemoattractant protein 1 (MCP-1) was reported in vitreous humor samples of patients with RD and diabetic retinopathy as well as in the brain tissues of patients with neurodegenerative diseases, including Alzheimer's disease and multiple sclerosis. Here we report that MCP-1 plays a critical role in mediating photoreceptor apoptosis in an experimental model of RD. RD led to increased MCP-1 expression in the Müller glia and increased CD11b+ macrophage/microglia in the detached retina. An MCP-1 blocking antibody greatly reduced macrophage/microglia infiltration and RD-induced photoreceptor apoptosis. Confirming these results, MCP-1 gene-deficient mice showed significantly reduced macrophage/microglia infiltration after RD and very little photoreceptor apoptosis. In primary retinal mixed cultures, MCP-1 was cytotoxic for recoverin+ photoreceptors, and this toxicity was eliminated through immunodepleting macrophage/microglia from the culture. In vivo, deletion of the gene encoding CD11b/CD18 nearly eliminated macrophage/microglia infiltration to the retina after RD and the loss of photoreceptors. Thus, MCP-1 expression and subsequent macrophage/microglia infiltration and activation are critical for RD-induced photoreceptor apoptosis. This pathway may be an important therapeutic target for preventing photoreceptor apoptosis in RD and other CNS diseases that share a common etiology.     

Monocyte chemoattractant protein-1 (MCP-1) 2518G/A gene polymorphism in Turkish type 2 diabetes patients with nephropathy

Tissue macrophage accumulation is thought to induce insulin resistance during obesity and stimulate the progression of diabetic nephropathy (DN). The objective of this study was to investigate genotypic and allelic frequencies of monocyte chemoattractant protein-1 (MCP-1) gene polymorphism in the healthy and patients with and without DN. The MCP-1 genotypes were determined in 43 patients with nephropathy and 43 without nephropathy and a control group of 105 healthy individuals. The genotype MCP-1 (-2518G/A) distribution did differ between the control group and the type 2 diabetic patients (P?=?0.004). The frequency of the polymorphic G allele was also no similar for the group with type 2 diabetes as for the control group with 20.9 and 32.4%, respectively (P?=?0.012). The AA genotype and A allele at MCP-1 -2518 was an independent risk factor for the progression of type 2 diabetes. In conclusion, MCP-1 AA genotype and A allele may play a specific role(s) in determining diabetic susceptibility, but do not seem to be important in the clinical manifestations of DN.     

Preventive effect of cerivastatin on diabetic nephropathy through suppression of glomerular macrophage recruitment in a rat model

AIMS/HYPOTHESIS: We investigated the effect of cerivastatin, a statin, on the development of diabetic nephropathy in spontaneously hypertensive rats (SHR) with streptozotocin-induced diabetes. METHODS: Diabetic SHR were given standard chow or chow containing cerivastatin at a dose of 0.1 mg/kg or 1.0 mg/kg for 12 weeks. Effects of cerivastatin on urinary albumin excretion, mesangial expansion, glomerular macrophage infiltration, and the number of anionic sites on the glomerular basement membrane (GBM) were assessed. RESULTS: Cerivastatin did not affect the blood glucose concentration, blood pressure or serum cholesterol concentration in diabetic SHR. However, cerivastatin treatment caused a dose-dependent decrease of albuminuria and hyperfiltration. At 1.0 mg/kg, cerivastatin inhibited the diabetes-induced expansion of mesangial and tuft areas on histological examination of the kidneys, as well as the loss of anionic sites from the GBM evaluated with polyetyleneimine and the intraglomerular infiltration of ED1-positive macrophages evaluated by immunohistochemistry. Whole-kidney expression of mRNA for MCP-1 and TGF-beta, estimated by the real-time quantitative RT-PCR, was increased (both 2.6-fold) in untreated diabetic SHR at 12 weeks. Cerivastatin treatment (1.0 mg/kg) inhibited the up-regulated expression of MCP-1 and TGF-beta mRNA (decreased to 48% and 34%, respectively) in diabetic SHR. CONCLUSION/INTERPRETATION: In this hypertensive model of diabetic nephropathy, cerivastatin decreased albuminuria through suppression of glomerular hyperfiltration, mesangial expansion, and the loss of charge barrier independently of a cholesterol-lowering effect. These preventive effects could be at least partly due to inhibition of macrophage recruitment and activation, and inhibition of TGF-beta overexpression.     

Expression of monocyte chemoattractant protein 1 mRNA in human idiopathic pulmonary fibrosis.

Macrophages are thought to play an important role in the pathologic changes associated with idiopathic pulmonary fibrosis (IPF). The mechanisms for increased monocyte/macrophage recruitment in IPF are unknown. Monocyte chemoattractant protein 1 (MCP-1) is the predominant monocyte chemoattractant secreted by a variety of different cell types in culture. We examined the expression of MCP-1 mRNA and its protein product in vivo in IPF and non-IPF lung specimens by in situ hybridization and immunocytochemistry. The cell types expressing MCP-1 in vivo were identified by immunostaining with specific antibodies. We demonstrated the expression of MCP-1 mRNA in pulmonary epithelial cells, in monocytes/macrophages, and in vascular endothelial and smooth muscle cells. Lung epithelial cells in patients with IPF strongly expressed MCP-1 mRNA and its protein product. In contrast, epithelial cells in non-IPF specimens did not express MCP-1 mRNA. Macrophages and vascular endothelial and smooth muscle cells were shown to express MCP-1 in both IPF and non-IPF lung specimens. These findings provide a basis for the understanding of the in vivo physiologic processes that mediate monocyte/macrophage recruitment and infiltration in the lung interstitium and the pathologic state contributing to an increased alveolar monocyte/macrophage population and inflammation in IPF.     

p38丝裂原活化蛋白激酶对HBZY-1系膜细胞株表达NF-κB和MCP-1的调控

目的 探讨p38丝裂原活化蛋白激酶(p38 mitogen-activated protein kinase, p38MAPK)与NF-κB、单核细胞趋化蛋白1(monocyte chemoattractant protein-1, MCP-1)之间的关系,从而研究p38MAPK和NF-κB、MCP-1在糖尿病肾病中的作用机制.方法 分别以高葡萄糖、高胰岛素、H2O2和糖基化终产物孵育大鼠肾小球系膜细胞株HBZY-1;先以p38MAPK特异抑制剂SB203580预处理细胞株HBZY-1,再给予上述4种因素孵育细胞株HBZY-1,观察其p38MAPK和NF-κB、MCP-1的表达.结果 高葡萄糖、高胰岛素、H2O2和糖基化终产物均可独立激活p38MAPK,使其磷酸化表达量增加,NF-κB、MCP-1表达也明显增加;SB203580预处理后,NF-κB、MCP-1表达被显著抑制.结论 p38MAPK可能通过激活NF-κB、MCP-1而诱导糖尿病时肾脏的损害,p38MAPK和NF-κB、MCP-1在糖尿病肾病的发生发展过程中可能起重要作用.     

不同尿白蛋白水平的糖尿病患者单核细胞趋化蛋白-1和尿N-乙酰β-D-氨基葡萄糖苷酶的含量变化及其临床意义

目的观察不同尿白蛋白水平的糖尿病患者单核细胞趋化蛋白1(MCP1)和尿N乙酰βD氨基葡萄糖苷酶(NAG)的含量变化及其临床意义。方法将60例糖尿病患者按尿白蛋白排泄率(UAER)的不同分为正常白蛋白尿组、微量白蛋白尿组和大量白蛋白尿组3组。分别测定血清和尿MCP1的含量、尿NAG含量以及血肌酐(Scr)、糖化血红蛋白(GHbAlc),进行组间比较,并与对照组比较,同时做尿MCP1与GHbAlc、UAER、NAG的相关分析。结果尿MCP1含量及NAG含量在所有患者中均升高,明显高于对照组,且大量白蛋白尿组升高最明显,其升高程度与尿白蛋白排泄率增高程度一致,即随糖尿病肾病加重而逐渐升高。而血清MCP1水平较低,与对照组比较无显著性差异;尿MCP1与GHbAlc、UAER、NAG呈正相关关系。结论尿中MCP1升高与糖尿病肾病的发生发展有密切关系,尤其与肾小管间质损伤有更密切的关系。     

Monocyte chemoattractant protein-1 has prosclerotic effects both in a mouse model of experimental diabetes and in vitro in human mesangial cells

Aims/hypothesis Diabetic nephropathy is characterised by mesangial extracellular matrix accumulation. Monocyte chemoattractant protein-1 (MCP-1), a chemokine promoting monocyte infiltration, is upregulated in the diabetic glomerulus. We performed in vitro and in vivo studies to examine whether MCP-1 may have prosclerotic actions in the setting of diabetes, presumably via its receptor, chemokine (C-C motif) receptor 2 (CCR2), which has been described in mesangial cells. Methods Human mesangial cells were exposed to recombinant human (rh)-MCP-1 (100 ng/ml) for 12, 24 and 48 h and to rh-MCP-1 (10, 100 and 200 ng/ml) for 24 h. Fibronectin, collagen IV and transforming growth factor, beta 1 (TGF-β1) protein levels were measured by ELISA and pericellular polymeric fibronectin levels by western blotting. The intracellular mechanisms were investigated using specific inhibitors for CCR2, nuclear factor kappa B (NF-κB), p38 mitogen-activated protein kinase and protein kinase C, and an anti-TGF-β1 blocking antibody. In both non-diabetic and streptozotocin-induced diabetic mice that were deficient or not in MCP-1, glomerular fibronectin accumulation was examined by immunohistochemistry, while cortical Tgf-β1 (also known as Tgfb1) and fibronectin mRNA and protein levels were examined by real-time PCR and western blotting. Results In mesangial cells, MCP-1 binding to CCR2 induced a 2.5-fold increase in fibronectin protein levels at 24 h followed by a rise in pericellular fibronectin, whereas no changes were seen in collagen IV production. MCP-1-induced fibronectin production was TGF-β1- and NF-κB-dependent. In diabetic mice, loss of MCP-1 diminished glomerular fibronectin protein production and both renal cortical Tgf-β1 and fibronectin mRNA and protein levels. Conclusions/interpretation Our in vitro and in vivo findings indicate a role for the MCP-1/CCR2 system in fibronectin deposition in the diabetic glomerulus, providing a new therapeutic target for diabetic nephropathy.     

Addition of angiotensin II type 1 receptor blocker to CCR2 antagonist markedly attenuates crescentic glomerulonephritis

The monocyte chemoattractant protein-1 (MCP-1)/CC-chemokine receptor 2 (CCR2) pathway plays a critical role in the development of antiglomerular basement membrane (anti-GBM) nephritis. We recently showed angiotensin II (Ang II) infusion in rats activated MCP-1 and transforming growth factor-β1 (TGF-β1), which in turn induced macrophage infiltration of renal tissues. This study was performed to demonstrate that combination therapy with a CCR2 antagonist (CA) and an Ang II type 1 receptor blocker (ARB) ameliorated renal injury in the anti-GBM nephritis model. An anti-GBM nephritis rat model developed progressive proteinuria and glomerular crescent formation, accompanied by increased macrophage infiltration and glomerular expression of MCP-1, angiotensinogen, Ang II, and TGF-β1. Treatment with CA alone or ARB alone moderately ameliorated kidney injury; however, the combination treatment with CA and ARB dramatically prevented proteinuria and markedly reduced glomerular crescent formation. The combination treatment also suppressed the induction of macrophage infiltration, MCP-1, angiotensinogen, Ang II, and TGF-β1 and reversed the fibrotic change in the glomeruli. Next, primary cultured glomerular mesangial cells (MCs) stimulated by Ang II showed significant increases in MCP-1 and TGF-β1 expression. Furthermore, cocultured model consisting of MCs, parietal epithelial cells, and macrophages showed an increase in Ang II-induced cell proliferation and collagen secretion. ARB treatment attenuated these augmentations. These data suggest that Ang II enhances glomerular crescent formation of anti-GBM nephritis. Moreover, our results demonstrate that inhibition of the MCP-1/CCR2 pathway with a combination of ARB effectively reduces renal injury in anti-GBM nephritis.