ATP结合元件A1与肾间质泡沫细胞形成、小管间质损害及血清胆固醇的相关性

目的 研究肾小球肾病患者肾间质区域ATP结合元件A1（ABCA1）蛋白的表达及其与泡沫细胞形成、肾小管间质损害、血清胆固醇的相关性。方法 选取诊断明确的Alport综合征患者5例、膜增生性肾小球肾炎（MPGN）患者28例、局灶节段性肾小球硬化（FSGS）患者35例、特发性膜性肾病（IMN）患者36例、IgA肾病（IgAN）患者34例为研究对象。采用免疫组织化学法检测患者肾间质区域（除肾小管）ABCA1蛋白的表达;用直线相关分析其与肾间质区域泡沫细胞相对面积、肾小管间质损害积分、血清胆固醇的相关性。 结果 在各类肾小球疾病患者的肾间质区域中,浸润的单核巨噬细胞、泡沫细胞及肾小管上皮细胞均表达ABCA1蛋白。泡沫细胞浸润者肾间质区域ABCA1蛋白的阳性表达量显著高于无泡沫细胞浸润者（P < 0.05）,但ABCA1的阳性表达量与泡沫细胞相对面积无相关。MPGN、FSGS、IMN患者肾间质区域ABCA1表达量与肾小管间质损害积分呈正相关（P < 0.05）。血清胆固醇与肾间质区域ABCA1蛋白的阳性表达量呈正相关（P < 0.05）。 结论 在各种病理类型的肾小球疾病患者中,血清胆固醇可促进肾间质ABCA1的表达;ABCA1对胞内脂质的转运具有双向作用,其与泡沫细胞形成缺乏肯定关联;ABCA1可能参与了肾小管间质的损害。     

MCP-1在IgA肾病肾组织中的表达与临床病理关系

目的 研究MCP-1在人类IgA肾病肾组织中的表达,进一步了解MCP-1与IgA肾病临床病理关系,并探讨其在IgA肾病进展中的可能作用机制.方法 根据IgA肾病病理半定量评分系统中8个病理指标评分标准,给予IgA肾病组按照病变程度赋予分值,采用SP免疫组织化学方法检测正常对照组和Iga肾病组肾组织中MCP-1的表达,探讨MCP-1与IgA肾病临床病理关系.结果 (1)在正常肾组织中,MCP-1表达较弱,正常对照组与IgA肾病组肾组织中MCP-1表达量均有统计学差异(P＜0.05);(2)IgA肾病肾组织中MCP-1表达量与IgA肾病组织学半定量评分法8个病理指标中破坏肾小球毛细血管袢活动性指数(dGAI)、系膜细胞增生指数(MsHI)、系膜基质增多指数(MsMI)、肾小球慢性病变指数(GCI)、肾间质炎症细胞浸润指数(infI)、肾小管萎缩和肾间质纤维化指数(TCI)等6个指标正相关(P＜0.05),而与内皮细胞增生指数(endol)、小动脉慢性病变指数(VCI)无明显相关性(P＞0.05);IgA肾病肾组织中MCP-1表达量与患者的蛋白尿水平正相关、肌酐清除率水平负相关(P＜0.05),而与患者血尿水平无明显相关性(P＞0.05).结论 在IgA肾病组肾组织中,MCP-1表达量与反映肾小球硬化、肾小管间质纤维化和细胞外基质积聚的病理指标呈正相关,提示其在IgA肾病病情进展中起重要作用.在IgA肾病组肾组织中,MCP-1表达量与蛋白尿呈正相关、肌酐清除率呈负相关,提示其与IgA肾病肾功下降、预后不良有关.     

小球性蛋白尿与肾小管间质损害的相关分析

目的 探讨不同肾小球疾病时蛋白尿程度与小管间质浸润细胞的类型之间相关性，分析其对间质浸润细胞类型的影响和作用。方法对57例原发性肾小球肾炎患者，检测患者24h尿蛋白定量，随即进行肾活检及免疫组织学检测。结果IgA免疫荧光染色阳性的系膜增生性肾炎间质浸润以T细胞为主；急性感染后肾小球肾炎(APGN)则以单核巨噬细胞为主；而在微小病变肾病(MCD)、膜性肾病(MGN)、局灶节段性肾小球硬化(FSGS)、膜增生性肾小球肾炎(MPGN)，淋巴细胞与单核巨噬细胞所占比例无显著性差异。MCD患者蛋白尿定量与间质浸润细胞总数相关，IgA免疫荧光染色阳性的MPGN患者，蛋白尿定量分别与T细胞总数、CD4^ 细胞亚群及单核细胞数量相关；APGN、MGN、FSGS、MPGN(IgA染色阴性)患者，蛋白尿定量与间质浸润细胞总数及细胞亚群无显著相关性。结论蛋白尿可能是引起在IgA免染色阳性的MPGN和MCD患者间质炎症细胞浸润的始动因素之一；在IgA染色阳性的MPGN，蛋白尿引起间质损害的机制主要通过CD4^ 细胞亚群及单核细胞的作用；但在其它原发性肾小球肾炎，蛋白尿不是引起间质炎症细胞浸润的主要因素。     

IgA肾病肾组织中基质金属蛋白酶2和单核细胞趋化因子1的表达

目的探讨基质金属蛋白酶2（MMP-2）和单核细胞趋化因子-1（MCP-1）在IgA肾病肾组织的表达强度及其在该病早期肾损害发病机制中的作用。方法将30例IgA肾病患者经肾脏活体组织检查的。肾组织和1（）例切除肾肿瘤患者正常肾组织,进行MMP-2、MCP-1、Ⅳ型胶原免疫组织化学检测并进行半定量分析,按其组织学改变Lee分级标准和肾小管间质病变程度进行分组和分级,同时检测肾功能、24h尿蛋白定量等临床指标,并与组织学、免疫组织化学检测结果进行相关分析。结果在IgA肾病轻度肾损害阶段,MMP2和MCP-1表达水平显著高于正常对照（P〈0．05）,随着病变级别加重,MMP-2和MCP-1在肾小管间质的表达呈逐渐减少趋势（P〈0．05）,而Ⅳ型胶原在肾小管间质表达随肾损害加重呈逐渐增加趋势（P〈0．01）。Spearman相关分析显示,MMP-2和MCP-1表达水平与肾小管间质炎症细胞浸润程度呈正相关（P〈0．05）,与Ⅳ型胶原表达水平呈负相关（P〈0．05）。结论MMP-2和MCP-1可能参与IgA肾病早期单个核细胞浸润等早期肾损害发病机制。     

儿童IgA肾病肾小管间质损害与其他临床病理指标的关系探讨

目的:探讨在儿童IgA肾病中肾小管间质损害与其他临床及病理指标的关系。方法:回顾性分析2014年01月~2017年09月在我院肾活检确诊的119例原发性IgA肾病患者的资料,对比不同程度及类型的肾小管间质损害与其他临床及病理指标之间的关系。结果:肾间质损害总体程度与年龄、性别、体块指数、肉眼血尿发生率、内皮细胞增生程度、肾小球硬化分值、纤维型新月体的发生没有关系。随着肾间质损害的加重,肾小球系膜细胞及基质增殖程度、细胞型及混合型新月体的发生率、尿蛋白的排出量逐渐增高同时肾小球滤过率逐渐下降。间质炎性细胞浸润与内皮细胞增生及细胞型新月体的发生关系密切,而存在肾小管萎缩和肾间质纤维化的患者更容易出现肾小球硬化。结论:IgA肾病患儿的肾小管间质损害与肾小球病变程度相平行,其与肾小球系膜细胞及基质增生程度、新月体形成、与蛋白尿及肾小球滤过率的改变密切相关。不同的小管间质病理类型与其他病理指标的关系各有区别但与各项临床指标的关系没有差别。     

蛋白尿致肾小管间质纤维化的机制及防治

肾间质纤维化是各种不同病因的慢性肾脏病进展到终末期肾病（ESRD）的共同病变过程。动物实验和临床试验表明，各种肾脏疾病进行性肾功能恶化主要取决于肾间质损伤的严重程度。蛋白尿是肾小球疾病的共同临床表现，长期蛋白尿不仅引起肾小球硬化，而且可以直接导致肾小管间质损伤，后者与肾小球疾病进展的关系更为密切。我们的研究发现，在血压、肾功能均正常且其他各项临床指标相近的条件下，显著蛋白尿IgA肾病患者的肾小球及肾小管间质损害程度更为严重，蛋白尿可作为独立的致病因子，直接造成IgA肾病患者肾小管间质损害。因此，研究肾间质纤维化的分子机制，探索有效的防治措施，对延缓ESRD的进程意义重大。本文重点阐述蛋白尿致肾小管间质损伤的机制及防治现况。     

IgA肾病治疗中的若干问题

IgA肾病（IgA nephropathy）是亚洲，特别是我国常见的原发性肾小球疾病。占全部肾脏活体组织检查（简称：肾活检）患者的30％～40％。它是临床上一组以免疫球蛋白IgA颗粒状或团块状沉积于肾小球系膜区以及毛细血管袢为特征的疾病。其病理改变复杂多样，轻至轻微病变肾小球疾病，重至硬化性肾小球肾炎不等，经常伴有严重的肾小管间质病变。临床表现多种多样，     

转化生长因子β1和结缔组织生长因子在狼疮肾炎肾小管间质中的表达

目的 研究狼疮性肾炎肾小管间质转化生长因子β1（TGF－β1）和结缔组织生长因子（CTGF）的表达特点及其意义。方法 应用免疫组织化学方法比较原发性肾小球肾炎微小病变型（MCD）和狼疮肾炎（LN）肾小管间质中TGF－β1和CTGF的表达及分布以及浸润细胞，α－平滑肌肌动蛋白（SMA）的表达特点。结果 TGF－β1及CTGF可不同程度地表达于LN的肾小球和肾小管间质，且较MCD的表达普遍增高，肾间质TGF－β1表达量与CTGF的表达量之间的相关系数r=0.5316,P=0.023。LN患者肾间质内CD3阳性细胞，CD68阳性细胞，PCNA阳性细胞以及α－SMA的表达明显高于MCD患者。α－SMA的表达程度与肾小管间质纤维化程度存在正相关关系，r=0.436,P=0.032。结论 LN肾间质内TGF－β1和CTGF表达增高，可能与LN肾间质病变及炎性细胞的浸润有关。     

肾小球疾病肾小管-间质损害的研究进展

近年来 ,大量的动物实验及临床病理研究发现 ,肾小球疾病的发展与预后 ,不仅与肾小球疾病本身的损害有关 (肾小球上皮、内皮细胞损伤、系膜细胞增殖、细胞外基质堆积、肾小球硬化等 ) ,更与其肾小管 -间质病变密切相关。换言之 ,肾小管间质病变更密切相关于肾功能损伤和预后。目前 ,肾小管 -间质损害在肾小球病变中的重要性已被越来越多的国内外学者所重视〔1 ,2〕。　　 1　肾小管—间质损害的临床及病理学研究研究证明 ,不同类型肾小球肾炎预后的决定因素是肾小管 -间质损害的有无及严重程度。对膜性肾病的多因素相关分析结果证实 ,肾小管…     

清利解毒活血汤联合西药治疗难治性肾病综合征45例疗效观察

目的探讨中西医结合疗法对难治性肾病综合征（RNS）的疗效。方法对45例有病理资料的RNS患者采用清利解毒活血汤联合泼尼松、环磷酰胺治疗,并对病理类型、系膜细胞及肾小管问质损害程度与疗效的关系进行分析。结果45例RNS完全缓解率48．9％,总有效率84．4％。其中系膜增生性肾炎、IgA肾病、局灶性节段性硬化性肾炎及微小病变肾病疗效较好,膜性肾病及膜增殖性肾炎疗效较差,系膜细胞损害程度及肾小管间质损害程度与疗效密切相关。结论清利解毒活血汤联合泼尼松、环磷酰胺对RNS有较好的疗效,但对膜性肾病、膜增殖肾炎以及系膜细胞损害严重或肾小管间质损害严重患者疗效尚不太理想。     

Differential expression of beta-chemokines MCP-1 and RANTES and their receptors CCR1, CCR2, CCR5 in acute rejection and chronic allograft nephropathy of human renal allografts

BACKGROUND: The beta-chemokines MCP-1 (CCL2) and RANTES (CCL5) have been shown to play important roles in acute renal transplant rejection (AR) and chronic allograft nephropathy (CAN). The potential relationship of expression of these chemokines, their chemokine receptors CCR1, CCR2, CCR5, and the cell populations of inflammatory infiltrate, histological and clinical diagnoses were investigated in biopsies at the time of AR and compared with biopsies of CAN. METHODS: In 24 renal transplant biopsies with AR (n = 15) and CAN (n = 9), the expression of MCP-1 and RANTES, their receptors CCR1, CCR2, and CCR5 and the infiltration with monocytes/macrophages and T cells were studied. RESULTS: As previously described, chemokine and chemokine receptor expression was found mainly in mononuclear cells infiltrating the interstitium and glomeruli. In the tubulointerstitial area and glomeruli the expression of MCP-1, RANTES, and their receptors correlated with an infiltration by monocytes/macrophages. Biopsies with CAN revealed a lower expression of MCP-1, RANTES, CCR1, CCR2 and CCR5 in tubulointerstitial cells, and a significantly lower infiltration with MRP14-positive monocytes/macrophages than biopsies with AR. In AR, MCP-1 and CCR1 showed a lower expression compared to RANTES, CCR2, and CCR5. CONCLUSIONS: The positive correlation between chemokines and chemokine receptors and infiltrating leukocytes during acute rejection, the lower but detectable expression of MCP-1, RANTES, CCR1, CCR2 and CCR5 in CAN, and the differences in the quantity of expression between the different chemokines and chemokine receptors point to a complex regulation of chemokine expression in renal allografts. Since chemokines are not only involved in inflammation but also in tissue regeneration, this could have impact on the development of CAN.     

Gene therapy via blockade of monocyte chemoattractant protein-1 for renal fibrosis

Monocyte chemoattractant protein (MCP)-1, also termed monocyte chemotactic and activating factor (MCAF)/CCL2, plays an important role in progressive organ fibrosis. It was hypothesized that MCP-1, through its cognate receptor, CCR2, regulates the pathogenesis and is therapeutically of importance for renal fibrosis. To achieve this goal, the therapeutic efficacy and efficiency in renal fibrosis induced by a unilateral ureteral obstruction nephropathy model in mice by the blockade of MCP-1/CCR2 signaling was studied. The delivery of N-terminal deletion mutant of the human MCP-1 gene, 7ND, into a skeletal muscle ameliorated renal fibrosis by resulting in decrease in the deposit of type I collagen and in reduced expression of TGF-beta. Concomitantly, gene transfer of 7ND reduced the cell infiltration, most of which were CCR2-positive macrophages, followed by the decrease in MCP-1 expression in the diseased kidneys. These observations suggest that MCP-1 through CCR2 signaling is responsible for Mphi recruitment, which augments downstream events, resulting in renal fibrosis. Moreover, these findings imply that gene therapy against MCP-1/CCR2 signaling via the mutant gene transferred strategy may serve a beneficial therapeutic application for renal fibrosis.     

Effect of the Monocyte Chemoattractant Protein-1/CC Chemokine Receptor 2 System on Nephrin Expression in Streptozotocin-Treated Mice and Human Cultured Podocytes

OBJECTIVE

Monocyte chemoattractant protein-1 (MCP-1), a chemokine binding to the CC chemokine receptor 2 (CCR2) and promoting monocyte infiltration, has been implicated in the pathogenesis of diabetic nephropathy. To assess the potential relevance of the MCP-1/CCR2 system in the pathogenesis of diabetic proteinuria, we studied in vitro if MCP-1 binding to the CCR2 receptor modulates nephrin expression in cultured podocytes. Moreover, we investigated in vivo if glomerular CCR2 expression is altered in kidney biopsies from patients with diabetic nephropathy and whether lack of MCP-1 affects proteinuria and expression of nephrin in experimental diabetes.

RESEARCH DESIGN AND METHODS

Expression of nephrin was assessed in human podocytes exposed to rh-MCP-1 by immunofluorescence and real-time PCR. Glomerular CCR2 expression was studied in 10 kidney sections from patients with overt nephropathy and eight control subjects by immunohistochemistry. Both wild-type and MCP-1 knockout mice were made diabetic with streptozotocin. Ten weeks after the onset of diabetes, albuminuria and expression of nephrin, synaptopodin, and zonula occludens-1 were examined by immunofluorescence and immunoblotting.

RESULTS

In human podocytes, MCP-1 binding to the CCR2 receptor induced a significant reduction in nephrin both mRNA and protein expression via a Rho-dependent mechanism. The MCP-1 receptor, CCR2, was overexpressed in the glomerular podocytes of patients with overt nephropathy. In experimental diabetes, MCP-1 was overexpressed within the glomeruli and the absence of MCP-1 reduced both albuminuria and downregulation of nephrin and synaptopodin.

CONCLUSIONS

These findings suggest that the MCP-1/CCR2 system may be relevant in the pathogenesis of proteinuria in diabetes.Diabetic nephropathy is characterized by increased glomerular permeability to proteins (1). Recently, much attention has been paid to the role of podocyte injury in glomerular diseases, including diabetic nephropathy (2,3), but the precise molecular mechanisms underlying the development of diabetic proteinuria remain unclear.The slit diaphragm, a junction connecting foot processes of neighboring podocytes, represents the major restriction site to protein filtration (4). Mutations of the gene encoding for nephrin, a key component of the slit diaphragm, are responsible for the congenital nephrotic syndrome of the Finnish type (5). Furthermore, a link between a reduction in nephrin expression and proteinuria has been also reported in acquired proteinuric conditions, including diabetic nephropathy (6–8), and studies in patients with incipient diabetic nephropathy have demonstrated that nephrin downregulation occurs in an early stage of the disease (9).A number of factors, including high glucose, advanced glycation end products, and hypertension play a role in the pathogenesis of diabetic nephropathy (10). In addition, monocyte chemoattractant protein-1 (MCP-1), a potent mononuclear cell chemoattractant, is overexpressed within the glomeruli in experimental diabetes (11,12) and has been recently implicated in both functional and structural abnormalities of the diabetic kidney (13).MCP-1 binds to the cognate CC chemokine receptor 2 (CCR2), which is predominantly expressed on monocytes (14), and MCP-1–driven monocyte accrual is considered the predominant mechanism whereby MCP-1 contributes to the glomerular damage. However, the CCR2 receptor has also been shown both in vitro (15,16) and in vivo (17–19) in other cell types besides monocytes, and we have recently demonstrated that both mesangial cells and glomerular podocytes express a functionally active CCR2 receptor (20–22).To assess the potential relevance of the MCP-1/CCR2 system in the pathogenesis of diabetic proteinuria we studied in vitro if MCP-1 binding to the CCR2 receptor modulates nephrin, expression in podocytes. Moreover, we investigated in vivo if glomerular CCR2 expression is altered in kidney biopsies from patients with diabetic nephropathy and whether lack of MCP-1 affects proteinuria and/or expression of nephrin in experimental diabetes.     

异丙酚预先给药对大鼠前脑缺血再灌注时海马单核细胞趋化因子1及其受体表达的影响

目的 探讨异丙酚预先给药对大鼠前脑缺血再灌注时海马单核细胞趋化因子1(MCP1)及其受体(CCR2)表达的影响.方法 健康成年雄性SD大鼠24只,体重250～300g,随机分为3组(n=8):假手术组(S组)仅暴露双侧颈总动脉及股动静脉置管,不夹闭;缺血再灌注组(IR组)采用夹闭双侧颈总动脉10 min合并放血降压再回输法制备前脑缺血再灌注损伤模型;异丙酚预先给药组(P组)脑缺血前即刻股静脉注射异丙酚50 mg/kg.于再灌注6 h时处死大鼠取脑,分离海马神经元,采用RT-PCR法测定MCP-1 mRNA和CCR2mRNA的表达,Western blot法测定MCP-1和CCR2蛋白的表达.结果 IR组和P组海马神经元MCP-1及CCR2表达较S组上调(P＜0.05);P组海马神经元MCP-1及CCR2表达较IR组下调(P＜0.05).结论 异丙酚预先给药可抑制海马神经元MCP-1及CCR2表达,该作用可能会减轻大鼠前脑缺血再灌注损伤.

Abstract：

Objective To investigate the effect of propofol pretreatment on hippocampal monocyte chemotactic protein-1 ( MCP-1 ) and CC-chemokine receptor type 2 (CCR2) expression following forebrain ischemiarepcrfusion (I/R) in rats. Methods Twenty-four male SD rats weighing 250-300 g were randomly divided into 3 groups ( n = 8 each): group Ⅰ control; group Ⅱ I/R and group Ⅲ propofol pretreatment. Cerebral I/R was induced by clamping bilateral common carotid arteries for 10 min combined with hypotension ( MAP was maintained at 35-45 mm Hg) induced by exsanguinations in group Ⅱ and Ⅲ. In group Ⅲ propofol 50 mg/kg was injected into femoral vein immediately before cerebral ischemia. The animals were sacrificed at 6 h of reperfusion. Hippocampal tissue was obtained for detection of MCP-1 mRNA and CCR2 mRNA and their protein expression by RT-PCR and Western blot technique. Results I/R significantly increased the expression of MCP-1 and CCR2 in hippoeampal tissue as compared with control group. Propofol pretreatment significantly attenuated cerebral I/R induced increase in MCP-1 and CCR2 expression. Conclusion Propofol pretreatment can significantly inhibit forebrain I/R-induced hippocampal MCP-1 and CCP2 expression.     

两种病理类型肾病患者尿IgG对人肾小管上皮细胞表达巨噬细胞移动抑制因子的影响

目的 分离纯化表现为肾病综合征(NS)的微小病变型(MCD)及膜性肾病(MN)患者尿IgG，比较它们对人近端小管上皮细胞(HK-2)表达巨噬细胞移动抑制因子(MIF)的影响。方法 采用硫酸铵沉淀&#65380;蛋白G亲和层析纯化尿中IgG，并经SDS-PAGE、Western印迹分析鉴定&#65377;用不同浓度(0&#65380;0.5&#65380;1.0&#65380;2.5&#65380;5.0&#65380;10.0 mg/ml)的上述两种患者的尿IgG分别刺激HK-2细胞6 h，应用RT-PCR检测细胞表达MIF mRNA的变化;应用Western印迹检测细胞中MIF的蛋白水平&#65377; 结果 纯化的尿IgG经SDS-PAGE分析显示其分解为4个片段,以兔抗人IgG抗体进行免疫印迹鉴定，证实这些蛋白条带均为IgG成分&#65377; 两种不同病理类型NS患者的尿IgG均可上调HK-2细胞MIF 的基因及蛋白表达，并呈剂量依赖性&#65377;MN患者的尿IgG 0.1 mg/ml即可明显上调HK-2细胞MIF mRNA和蛋白表达(P < 0.01);而MCD患者的尿IgG需达到2.5 mg/ml才具有显著上调效应&#65377; 结论 呈NS的MCD和MN患者尿IgG可上调HK-2细胞表达MIF&#65377;MN患者尿IgG的作用强于MCD患者,提示这两种不同病理类型患者尿IgG可能存在结构或功能上的差异&#65377;     

Up-regulation of monocyte chemoattractant protein-1 in tubulointerstitial lesions of human diabetic nephropathy

BACKGROUND: We previously described that monocyte chemoattractant protein-1 (MCP-1) plays an important role in progressive glomerular and interstitial damage in inflammatory renal diseases. However, the expression of MCP-1 in diabetic nephropathy remains to be investigated. METHODS: We examined whether locally expressed MCP-1 participates in human diabetic nephropathy via recruiting and activating monocytes/macrophages (Mphi). Urinary and serum MCP-1 levels were measured by enzyme-linked immunosorbent assay in 45 patients with diabetic nephropathy. The presence of MCP-1 in diseased kidneys was determined by immunohistochemical and in situ hybridization analyses. RESULTS: Urinary MCP-1 levels were significantly elevated in patients with diabetic nephrotic syndrome and advanced tubulointerstitial lesions. Moreover, urinary levels of MCP-1 were well correlated with the number of CD68-positive infiltrating cells in the interstitium. In contrast, serum MCP-1 levels remained similar to those of healthy volunteers. Furthermore, we detected the MCP-1-positive cells in the interstitium of diabetic nephropathy via both immunohistochemical and in situ hybridization analyses. CONCLUSION: These observations suggest that locally produced MCP-1 may be involved in the development of advanced diabetic nephropathy, especially in the formation of tubulointerstitial lesions possibly through Mphi recruitment and activation. Moreover, up-regulation of MCP-1 may be a common pathway involved in the progressive tubulointerstitial damage in diabetic nephropathy as well as inflammatory renal diseases.     

Expression of IL-8 during reperfusion of renal allografts is dependent on ischemic time

BACKGROUND: Ischemia/reperfusion injury is an inherent consequence of solid organ transplantation that increases tissue inflammation and negatively impacts organ transplant function and survival. This study investigated the expression levels of chemokine and chemokine receptor genes in living versus cadaver donor renal allografts before and after reperfusion. METHODS: This study involved 39 renal transplant patients (19 cadaveric and 20 living donor). The ischemia biopsy was taken just before graft declamping and the reperfusion biopsy 30 min after declamping. Whole-cell RNA was isolated and chemokine (IL-8, CCL2/MCP-1, CXCL10/IP-10 and CCL5/RANTES) and chemokine receptor (CCR2 and CCR5) expression was tested by quantitative PCR. RESULTS: Just prior to declamping, ischemic cadaveric donor grafts had higher expression of CXCL10/IP-10 but not IL-8 or CCL2/MCP-1 than living donor grafts. IL-8 expression increased 50% from ischemia to reperfusion in living donor grafts but increased more than 13-fold during reperfusion of cadaver donor grafts. Increased total ischemia time induced greater IL-8 expression during reperfusion. MCP-1 expression also increased during reperfusion of living and cadaver donor grafts but differences were not observed between the two groups of grafts. RANTES, CCR2, and CCR5 expression did not change in ischemic vs. reperfusion biopsies. CONCLUSIONS: The expression of chemokines directing neutrophil and macrophage recruitment increases during reperfusion of living and cadaveric donor renal allografts. Expression levels of IL-8 correlate with the ischemic time imposed on the renal graft. Early tissue injury may be attenuated by strategies antagonizing chemokines directing the recruitment of neutrophils and macrophages into kidney grafts.     

Increased urinary excretion of monocyte chemoattractant protein-1 in proteinuric renal diseases

Monocyte chemoattractant protein-1 (MCP-1) is a chemokine that is produced mainly by tubular epithelial cells in kidney and contributes to renal interstitial inflammation and fibrosis. More recently, we have demonstrated that urinary MCP-1 excretion is increased in proportion to the degree of albuminuria (proteinuria) and positively correlated with urinary N-acetylglucosaminidase (NAG) levels in type 2 diabetic patients. Based on these findings, we have suggested that heavy proteinuria, itself, probably aggravates renal tubular damage and accelerates the disease progression in diabetic nephropathy by increasing the MCP-1 expression in renal tubuli. In the present study, to evaluate whether urinary MCP-1 excretion is increased in the proteinuric states not only in diabetic nephropathy but also in other renal diseases, we examined urinary MCP-1 levels in IgA nephropathy patients with macroalbuminuria (IgAN group; n = 6), and compared the results with the data obtained from type 2 diabetic patients with overt diabetic nephropathy (DN group; n = 23) and those without diabetic nephropathy (non-DN group; n = 27). Urinary MCP-1 excretion levels in non-DN, DN, IgAN groups were 157.2 (52.8-378.5), 346.1 (147.0-1276.7), and 274.4 (162.2-994.5) ng/g creatinine, median (range), respectively. Expectedly, urinary MCP-1 and NAG excretion levels in DN and IgAN groups were significantly elevated as compared with non-DN group. Therefore, we suggest that MCP-1 expression in renal tubuli is enhanced in proteinuric states,irrespective of the types of renal disease, and that increased MCP-1 expression probably contributes to renal tubular damage in proteinuric states.