神经生长因子在2型糖尿病大鼠肾组织中的表达及意义

目的建立2型糖尿病大鼠模型,观察神经生长因子（NGF）在该大鼠肾组织中的表达及单核／巨噬细胞（CD68）的浸润情况。方法应用高糖高脂饮食加小剂量链脲佐菌素（STZ）制备2型糖尿病大鼠模型。采用免疫组化技术检测各组肾组织中NGF及CD68的表达水平。结果①高糖高脂可成功诱导胰岛素抵抗,小量STZ可使血糖升高,达到糖尿病标准。2型糖尿病大鼠模型制备成功后,继续喂养6周,血肌酐（SCr）、尿素氮（BUN）、内生肌酐清除率（Ccr）、尿白蛋白排泄率（UAE）、肾重／体重增加等特征,肾组织出现明显基底膜增厚、系膜区扩张等病理学改变。②糖尿病组大鼠肾组织中NGF、CD68表达较正常组明显增加。且NGF、CD68二者数量呈正相关。结论①糖尿病模型建立后6周,已出现糖尿病肾病早期改变。②NGF可能通过介导炎症反应参与糖尿病肾脏损害过程,且此炎症反应至少部分与单核／巨噬细胞的增殖活化及浸润有关。     

厄贝沙坦对2型糖尿病大鼠肾组织中核因子-κB的调节

目的 建立2型糖尿病大鼠模型。观察血管紧张素Ⅱ(Ang Ⅱ)受体拮抗剂厄贝沙坦对该模型大鼠肾组织中核因子-κB(NF-κB)活化的影响。方法 应用高糖高脂饮食加小剂量链脲佐菌素(STZ)制备2型糖尿病大鼠模型。采用免疫组织化学技术检测各组肾小球中NFκB及单核/巨噬细胞(ED-1)的表达水平。结果 (1)高糖高脂饮食加低剂量STZ使大鼠血糖升高(22.48±6.54 vs 4.71±0.34,P<0.01),并出现胰岛素抵抗。继续喂养6周后,模型成功动物具有血胰岛素不低,内生肌酐清除率、尿微量白蛋白、肾重/体重增加等特征。(2)糖尿病组大鼠肾组织中NF-κB、ED-1表达较对照组明显增加。厄贝沙坦治疗6周后,NF-κB活性降低(5.10±1.80 vs 8.45±1.09,P<0.01),单核/巨噬细胞浸润减轻,肾功能指标及组织病理学损害得以改善。结论 (1)通过饮食加小剂量STZ的方法,成功复制了2型糖尿病大鼠模型。该模型在6周后已出现糖尿病肾病的早期改变。(2)上述大鼠肾组织中NF-κB活性增加,厄贝沙坦的肾脏保护作用至少部分与减少肾组织中激活的NF-κB表达,减轻肾组织中单核/巨噬细胞浸润有关。     

霉酚酸酯对糖尿病大鼠肾组织RANTES与ED-1表达的影响

目的：建立链脲佐菌素（STZ）诱导的糖尿病大鼠模型并用霉酚酸酯（MMF）干预，动态观察细胞因子（RANTEs）、单核／巨噬细胞表面特异性标志抗原（ED-1）、Ⅳ型胶原（Col Ⅳ）在肾组织中的表达，探讨MMF能否通过抑制肾组织炎症反应达到保护肾脏的作用。方法：36只雄性SD大鼠随机分为正常对照组、糖尿病模型组和MMF治疗组，于实验第4周、14周末每组分别处死6只大鼠，处死前留取24h尿进行24h尿蛋白定量，处死后免疫组织化学染色观察RANTES、ED-1、Col Ⅳ在肾组织中的表达。结果：（1）正常肾组织RANTES有少量表达，模型组的表达均显著增高，MMF组各时间点与相应模型组比较均显著降低；（2）正常肾组织ED-1有少量表达，模型组的表达均显著增高，MMF组各时间点与相应模型组比均显著降低。结论：MMF可能是通过下调RANTES在肾组织中的表达、减少单核／巨噬细胞在肾组织中的浸润．在旱期抑制肾组织炎症反应．进而对肾脏具有一定的保护作用．     

霉酚酸酯对2型糖尿病大鼠肾脏单核细胞趋化蛋白-1表达的影响

目的:探讨霉酚酸酯对2型糖尿病大鼠肾脏单核细胞趋化蛋白-1(monocyte chemoattractant protein-1,MCP-1)表达的影响.方法:将实验动物分为正常对照组、糖尿病组及霉酚酸酯治疗组.霉酚酸酯治疗组给予霉酚酸酯(my cophenolate mofetil,MMF;15 mg·kg-1·d-1)治疗.13周后检测各组大鼠尿白蛋白排泄率、内生肌酐清除率、血糖、血脂、血胰岛素;HE 及PAS 染色观察肾脏病理改变;用免疫组化方法检测肾组织中MCP-1及单核/巨噬细胞(ED-1)的表达.结果:MMF可以减少2型糖尿病大鼠24 h尿蛋白排泄率及内生肌酐清除率,使大鼠肾脏组织中MCP-1和ED-1的表达降低,并改变肾脏病理结构.结论:霉酚酸酯对2型糖尿病大鼠肾脏有部分保护作用,其机制可能通过部分下调2型糖尿病大鼠肾脏MCP-1的表达来实现的.     

霉酚酸酯对糖尿病肾组织炎性因子表达的抑制作用

目的探讨霉酚酸酯（MMF）在糖尿病肾组织中发挥抗炎作用及其机制。方法MMF治疗2型糖尿病大鼠，观察肾组织单核／巨噬细胞浸润，及转录因子（NF）-KBp65、神经生长因子表达的变化；不同浓度的霉酚酸干预高糖环境下培养的肾小球系膜细胞，测定细胞间粘附分子（ICAM）-1、单核细胞趋化蛋白（MCP）-1及神经生长因子（NGF）表达的变化。结果MMF治疗能显著改善糖尿病大鼠肾功能，伴肾小球NF-KBp65活性明显下降，NGF表达水平明显降低，单核／巨噬细胞浸润显著减轻。霉酚酸对高糖诱导的肾小球系膜细胞ICAM-1、MCP-1和NGF高表达有显著的抑制作用。结论MMF很可能通过降低NF-KB活性，间接抑制炎性因子表达、炎症细胞浸润。霉酚酸对高糖环境下肾小球系膜细胞ICAM-1、MCP-1和NGF的高表达有显著抑制作用。     

塞来昔布对2型糖尿病大鼠肾脏结缔组织生长因子表达的影响

目的:探讨塞来昔布对2型糖尿病大鼠肾脏结缔组织生长因子(CTGF)表达的影响.方法:36只大鼠分成对照组及模型组,模型组通过采用4周高糖高脂饮食配合链脲佐菌素(STZ)诱导的方法来制备类似2型糖尿病的动物模型,然后随机将大鼠分成糖尿病组及治疗组,给药8周后观察血肌酐、血胰岛素、尿微量白蛋白、血糖的变化;HE及PAS染色观察肾脏病理改变;免疫组化方法检测肾组织中CTGF的表达.结果:塞来昔布可以减少2型糖尿病大鼠尿蛋白排泄率及血肌酐;使大鼠肾脏组织中CTGF的表达降低,并使肾脏病理改变好转.结论:塞来昔布对2型糖尿病大鼠肾脏有保护作用,其机制可能部分是通过下调2型糖尿病大鼠肾脏CTGF的表达来实现的.     

霉酚酸酯对糖尿病大鼠肾组织单核细胞趋化蛋白-1与细胞间黏附分子-1表达的影响

糖尿病肾病(DN)肾内单核细胞趋化蛋白-1(MCP-1)、细胞间黏附分子-1(ICAM-1)表达上调,单核/巨噬细胞浸润等炎症机制越来越受到重视犤1犦。本研究探讨霉酚酸酯(MMF)对糖尿病(DM)肾组织MCP-1、ED-1、ICAM-1表达的影响,旨在为DN的抗炎治疗提供实验依据。一、材料和方法1.糖尿病模型建立及分组:30只雄性昆明种SD大鼠(安医大实验动物中心提供),行右肾切除术和腹腔注射单剂量STZ65mg/kg。随机分3组:对照组(C);模型组(DM);MMF给药组(DM MMF),每组10只。MMF10mg·kg-1·d-1灌胃。整个实验期间不用胰岛素。2.指标检测:术后8周末测尿…     

霉酚酸酯对糖尿病大鼠肾组织T细胞浸润的影响

目的 探讨霉酚酸酯(MMF)对链脲佐菌素(STZ)诱导的糖尿病大鼠T淋巴细胞在肾脏组织浸润的影响.方法 30只雄性Wistar大鼠(鼠龄2～3个月),随机分为正常对照组、糖尿病模型组和MMF治疗组[15mg·(kg·d)-1].观察16周后,检测大鼠血糖(BG)、血尿素氮(BUN)、血肌酐(Scr)、肾肥大指数(肾重KW/体重BW)和24h尿蛋白定量(24Upro).用流式细胞仪方法检测肾组织中CD3+、CD4+T淋巴细胞以及细胞因子TNF-α、IFN-y的含量,免疫组化法测肾组织中CD4+、CD8+T细胞的表达.结果 与对照组相比,糖尿病(DM)组大鼠BG、BUN、Scr、Kw/Bw、24Upro等指标均显著升高,差异有统计学意义(P＜0.01).通过流式细胞仪检测,糖尿病大鼠肾脏内CD3+、CD4+T细胞以及由CD4+T细胞产生IFN-γ、TNF-α均显著上调(P＜0.01),通过免疫组化肾脏内CD4+、CD8+T细胞均显著升高(P＜0.01).除血糖、肾肥大指数外,治疗组上述指标均比糖尿病组低,差异有统计学意义(P＜0.05).结论 霉酚酸酯通过抑制T淋巴细胞在糖尿病大鼠肾脏组织中的浸润从而下调炎症因子的表达发挥肾脏保护作用.     

他克莫司对糖尿病早期大鼠肾组织巨噬细胞浸润、增殖及活化的影响

目的 研究他克莫司( FK506)对糖尿病早期大鼠肾组织巨噬细胞浸润、增殖及活化的影响及探讨其肾脏保护作用机制.方法 链脲菌素(STZ)腹腔一次性注射建立大鼠糖尿病模型.按数字随机法分为对照组、模型组、他克莫司(0.5、1.0 mg·kg-1·d-1)治疗组,4周后观察大鼠肾质量指数(肾质量/体质量,KWI)、尿白蛋白排泄率(UAER)、肌酐清除率(Ccr)及肾组织病理形态学变化.应用免疫组化单染及双染方法检测肾组织内巨噬细胞表面标志抗原ED-1、增殖细胞核抗原(PCNA)及诱生性一氧化氮合酶(iNOS)的表达.结果 他克莫司1.0组大鼠KWI低于模型组(P＜0.05).他克莫司0.5组与1.0组大鼠UAER水平与肾小球平均体积低于模型组(P＜0.05).他克莫司1.0组肾小管间质损伤指数也明显低于模型组(P＜0.01).免疫组化显示模型组大鼠肾组织ED-1+、PCNA+及iNOS+巨噬细胞数显著高于对照组(P＜0.01);他克莫司0.5与1.0组ED-1+的巨噬细胞数与模型组差异无统计学意义;PCNA+及iNOS+的巨噬细胞数则显著低于模型组(P＜0.01).结论 他克莫司可改善糖尿病早期大鼠肾损害,其机制可能部分与抑制肾组织中巨噬细胞的增殖及活化有关.     

祛痰通络汤对糖尿病大鼠肾组织内质网应激相关分子GRP78和CHOP表达的影响

目的:观察祛痰通络汤对糖尿病大鼠肾组织中内质网应激相关分子GRP78和CHOP表达的影响。方法:高糖高脂饲料联合腹腔注射STZ制备糖尿病模型,随机分为4组,分别为正常对照组、模型组、祛痰通络汤组、四苯基丁酸组,治疗8周。观察各组24 h尿蛋白定量、肾脏病理学变化;免疫组化和western-blot检测肾组织内质网应激相关蛋白GRP78,CHOP的表达。结果:祛痰通络汤降低尿蛋白,减轻病理改变;模型组肾组织的GRP78、CHOP表达明显升高(P0.05),祛痰通络汤组GRP78、CHOP表达明显低于模型组(P0.05)。结论:糖尿病大鼠肾脏中GRP78、CHOP表达明显增强,祛痰通络汤降低内质网应激,可能是其肾脏保护作用的重要机制。     

2型糖尿病肾病大鼠模型的建立

目的：建立2型糖尿病肾病（DIN）大鼠模型。方法：雌性SD大鼠接受单侧肾切除手术2周后，给予高糖高脂饮食（常规饲料加20％蔗糖、10％猪油、2．5％胆固醇）喂养4周，再加用小剂量链脲佐菌素（蜘亿，30mg／kg）腹腔注射，分别检测1周、7周后各组大鼠血糖、胰岛素、血压、血脂、尿蛋白、肾功能等指标，并于7周后进行组织形态学观察。结果：单侧肾切除大鼠给予高糖高脂饮食和低剂量STZ观察7周后，模型成功动物具有高血糖、高血脂、高血压、胰岛素抵抗等特点，并出现DN相应的形态及功能改变。结论：通过单侧肾切除后，饮食加小剂量蜘亿的方法，可成功制备2型DN大鼠模型。     

2型糖尿病肾病中晚期病变大鼠模型的研究

目的：探索一种与人类2型糖尿病肾病（DN）中晚期病变类似的大鼠模型。方法：Wistar大鼠18只,随机分为假手术组和模型组。模型组大鼠行右侧肾切除术并以高脂饲料喂养12周后,进行腹腔葡萄糖耐量实验（IPGTT）及胰岛素耐量实验（ITT）,再以30 mg/kg的剂量腹腔注射链脲佐菌素（STZ）,持续观察24周。每4周检测体重,血糖和24 h尿蛋白水平。实验结束时取血检测血清总蛋白、白蛋白、总胆固醇、三酰甘油、尿素氮和肌酐水平,取肾组织观察病理形态学变化并进行半定量评分。结果：与假手术组相比,模型组大鼠IPGTT及ITT葡萄糖曲线下面积显著增加,动物血糖、胆固醇、三酰甘油、尿素氮及肌酐水平显著升高,白蛋白水平显著降低。模型组肾小球硬化指数与肾小管间质纤维化指数显著高于假手术组,表现出弥漫性肾小球硬化及重度的肾小管间质纤维化。结论：单侧肾切除合并高糖高脂饮食加小剂量STZ腹腔注射可以造成与人类2型DN中晚期病变类似的大鼠模型,其造模方法简单可靠,适合于DN的药效学研究。     

2-(8-hydroxy-6-methoxy-1-oxo-1h-2-benzopyran-3-yl) propionic acid, an inhibitor of angiogenesis, ameliorates renal alterations in obese type 2 diabetic mice

One of the mechanisms involved in the progression of diabetic nephropathy, the most common cause of end-stage renal failure, is angiogenic phenomenon associated with the increase of angiogenic factors such as vascular endothelial growth factor (VEGF)-A and angiopoietin (Ang)-2, an antagonist of Ang-1. In the present study, we examined the therapeutic efficacy of 2-(8-hydroxy-6-methoxy-1-oxo-1H-2-benzopyran-3-yl) propionic acid (NM-3), a small molecule isocoumarin with antiangiogenic activity, using diabetic db/db mice, a model of obese type 2 diabetes. Increases in kidney weight, glomerular volume, creatinine clearance, urinary albumin excretion, total mesangial fraction, glomerular type IV collagen, glomerular endothelial area (CD31(+)), and monocyte/macrophage accumulation (F4/80(+)) observed in control db/db mice were significantly suppressed by daily intraperitoneal injection of NM-3 (100 mg/kg, for 8 weeks). Increases in renal expression of VEGF-A, Ang-2, fibrogenic factor transforming growth factor (TGF)-beta1, and chemokine monocyte chemoattractant protein-1 but not tumor necrosis factor-alpha were also inhibited by NM-3 in db/db mice. Furthermore, decreases of nephrin mRNA and protein levels in db/db mice were recovered by NM-3. In addition, treatment of db/db mice with NM-3 did not affect body weight, blood glucose, serum insulin, or food consumption. NM-3 significantly suppressed the increase of VEGF induced by high glucose in cultured podocytes and also suppressed the increase of VEGF and TGF-beta induced by high glucose in cultured mesangial cells. Taken together, these results demonstrate the potential use of NM-3 as a novel therapeutic agent for renal alterations in type 2 diabetes.     

Mycophenolate mofetil prevents the development of glomerular injury in experimental diabetes

BACKGROUND: Experimental and clinical evidence suggests that inflammation plays a role in the pathogenesis of diabetic nephropathy, in addition to, or in concert with, the associated hemodynamic and metabolic changes. The present study assessed the effects of chronic anti-inflammatory therapy in experimental diabetic nephropathy. METHODS: Adult male Munich-Wistar rats were made diabetic with streptozotocin after uninephrectomy, kept moderately hyperglycemic by daily injections of NPH insulin and distributed among three groups: C, non-diabetic rats; DM, rats made diabetic and treated with insulin as described earlier; and DM+MMF, diabetic rats receiving insulin and treated with mycophenolate mofetil (MMF), 10 mg/kg once daily by gavage. Renal hemodynamic studies were performed 6 to 8 weeks after induction of diabetes. Additional rats were followed during 8 months, at the end of which renal morphological studies were performed. RESULTS: After 6 to 8 weeks, diabetic rats exhibited marked glomerular hyperfiltration and hypertension. Diabetic rats developed progressive albuminuria and exhibited widespread glomerulosclerotic lesions associated with macrophage infiltration at 8 months. Treatment with MMF had no effect on blood pressure, glomerular dynamics or blood glucose levels, but did prevent albuminuria, glomerular macrophage infiltration and glomerulosclerosis. Thus, the renoprotective effect of MMF was not associated with a metabolic or renal hemodynamic effect, and must have derived from its well-known anti-inflammatory properties, which include restriction of lymphocyte and macrophage proliferation and limitation of the expression of adhesion molecules. CONCLUSIONS: These findings are consistent with the notion that inflammatory events are central to the pathogenesis of diabetic nephropathy and suggest that MMF may help prevent the progression of diabetic nephropathy.     

Macrophages in mouse type 2 diabetic nephropathy: correlation with diabetic state and progressive renal injury

BACKGROUND: Macrophage-mediated renal injury has been implicated in progressive forms of glomerulonephritis; however, a role for macrophages in type 2 diabetic nephropathy, the major cause of end-stage renal failure, has not been established. Therefore, we examined whether macrophages may promote the progression of type 2 diabetic nephropathy in db/db mice. METHODS: The incidence of renal injury was examined in db/db mice with varying blood sugar and lipid levels at 8 months of age. The association of renal injury with the accumulation of kidney macrophages was analyzed in normal db/+ and diabetic db/db mice at 2, 4, 6, and 8 months of age. RESULTS: In db/db mice, albuminuria and increased plasma creatinine correlated with elevated blood glucose and hemoglobin A1c (HbA1c) levels but not with obesity or hyperlipidemia. Progressive diabetic nephropathy in db/db mice was associated with increased kidney macrophages. Macrophage accumulation and macrophage activation in db/db mice correlated with hyperglycemia, HbA1c levels, albuminuria, elevated plasma creatinine, glomerular and tubular damage, renal fibrosis, and kidney expression of macrophage chemokines [monocyte chemoattractant protein-1 (MCP-1), osteopontin, migration inhibitory factor (MIF), monocyte-colony-stimulating factor (M-CSF)]. The accrual and activation of glomerular macrophages also correlated with increased glomerular IgG and C3 deposition, which was itself dependent on hyperglycemia. CONCLUSION: Kidney macrophage accumulation is associated with the progression of type 2 diabetic nephropathy in db/db mice. Macrophage accumulation and activation in diabetic db/db kidneys is associated with prolonged hyperglycemia, glomerular immune complex deposition, and increased kidney chemokine production, and raises the possibility of specific therapies for targeting macrophage-mediated injury in diabetic nephropathy.     

霉酚酸酯对糖尿病大鼠肾脏基质金属蛋白酶9、转化生长因子β1表达的影响

目的 探讨霉酚酸酯（MMF）对糖尿病（DM）大鼠肾脏的保护作用及其机制。 方法 将实验动物分为正常对照组、DM组及MMF治疗组。MMF组给予MMF(15 mg/kg,口服,1次/d) 治疗。8 周后检测各组大鼠尿蛋白量（24 h）、内生肌酐清除率（Ccr）、血糖;HE染色观察肾脏病理改变;免疫组化及RT-PCR法检测肾组织中基质金属蛋白酶9（MMP-9）、转化生长因子β1（TGF-β1）的表达。 结果 DM组大鼠血糖[（22.18±3.36） mmol/L比（6.40±0.87）mmol/L]、尿蛋白量（24 h）[（26.80±0.82） mg比（6.64±1.42） mg]、Ccr[（0.220±0.380） ml/min比（0.098±0.015） ml/min]显著高于对照组（P ＜ 0.05）。MMF组的尿蛋白量（24 h）[（16.17±1.15） mg]、Ccr[（0.220±0.380） ml/min比（0.207±0.377） ml/min]均显著低于DM组（P ＜ 0.05）。与DM组比较,MMF组肾小球肿大、系膜细胞增生显著减轻。肾组织中MMP-9在对照组表达较多,主要在肾小球系膜细胞胞质内及肾小管上皮细胞,DM组表达较弱,MMF组介于两组之间,组间差异均有统计学意义（P < 0.05）。TGF-β1在正常对照组大鼠肾组织有少量表达,在DM组表达较强,在MMF组介于两组之间,组间差异亦均有统计学意义（P < 0.05）。 结论 MMF可降低DM大鼠尿蛋白排泄、Ccr,减轻早期肾小球肥大,此作用可能与MMF上调肾组织中MMP-9表达、下调TGF-β1的表达、减少系膜外基质的沉积有关。     

依那普利联合霉酚酸酯对大鼠糖尿病肾脏协同保护作用及机制

目的 探讨依那普利联合霉酚酸酯(MMF)对大鼠糖尿病肾脏协同保护作用及其机制&#65377; 方法 建立STZ诱导的大鼠单侧肾切除糖尿病模型, 随机分5组:对照组&#65380; 模型组&#65380;依那普利组&#65380; MMF组及依那普利与MMF联合给药组&#65377;8周后观察尿白蛋白排泄率(AER)&#65380; 肾组织病理及丙二醛(MDA)含量与超氧化物歧化酶(SOD)&#65380; 过氧化氢酶(CAT)&#65380; 谷胱苷肽过氧化物酶(GSH-PX)活性变化&#65377;免疫组化或Western 印迹检测肾组织ED-1&#65380;ICAM-1与TGF-β1蛋白表达&#65377;结果 (1) 各给药组均可抑制糖尿病大鼠AER增加及肾小球病理损害(P < 0.05, 0.01); 联合给药组可明显减轻糖尿病肾小管间质损伤指数(P < 0.05)&#65377;(2)对糖尿病肾组织MDA含量增加及SOD&#65380; CAT与GSH-PX活性降低的改善作用,联合组优于单给药组(P < 0.05, P < 0.01)&#65377;(3)模型组肾小球与肾小管间质ED-1阳性细胞数与ICAM-1表达明显高于对照组(P < 0.01); 各给药组ED-1阳性细胞数明显低于模型组(P < 0.05, P < 0.01); 依那普利给药组肾组织ICAM-1表达与模型组相比差异无统计学意义, MMF与联合组ICAM-1表达明显低于模型组(P < 0.05)&#65377; (4)Western印迹显示糖尿病肾组织TGF-β1表达较对照组增加1.79倍,各给药组肾组织TGF-β1表达较模型组分别下降39.72%,44.80%与55.09%&#65377;结论 依那普利与MMF联合给药对糖尿病肾脏保护作用优于单种药物治疗,其机制部分与其对肾组织氧化应激增加&#65380;炎症细胞浸润及TGFβ1表达有协同抑制作用有关&#65377;     

Macrophages in streptozotocin-induced diabetic nephropathy: potential role in renal fibrosis.

BACKGROUND: Renal fibrosis is central to the progression of diabetic nephropathy; however, the mechanisms responsible for fibroblast and matrix accumulation in this disease are only partially understood. Macrophages accumulate in diabetic kidneys, but it is unknown whether macrophages contribute to renal fibrosis. Therefore, we examined whether macrophage accumulation is associated with the progression of renal injury and fibrosis in type 1 diabetic nephropathy and whether macrophages exposed to the diabetic milieu could promote fibroblast proliferation. METHODS: Kidney macrophages, renal injury and fibrosis were analysed in diabetic C57BL/6J mice at 2, 8, 12 and 18 weeks after streptozotocin injection. Isolated rat bone marrow macrophages were stimulated with diabetic rat serum or carboxymethyllysine (CML)-bovine serum albumin (BSA) to determine whether macrophage-conditioned medium could promote the proliferation of rat renal (NRK-49F) fibroblasts. RESULTS: Progressive injury and fibrosis in diabetic nephropathy was associated with increased numbers of kidney macrophages. Macrophage accumulation in diabetic mice correlated with hyperglycaemia (blood glucose, HbA1c levels), renal injury (albuminuria, plasma creatinine), histological damage and renal fibrosis (myofibroblasts, collagen IV). Culture supernatant derived from bone marrow macrophages incubated with diabetic rat serum or CML-BSA induced proliferation of fibroblasts, which was inhibited by pre-treating fibroblasts with interleukin-1 (IL-1) receptor antagonist or the platelet-derived growth factor (PDGF) receptor kinase inhibitor, STI-571. CONCLUSION: Kidney macrophage accumulation is associated with the progression of renal injury and fibrosis in streptozotocin-induced mouse diabetic nephropathy. Elements of the diabetic milieu can stimulate macrophages to promote fibroblast proliferation via IL-1- and PDGF-dependent pathways which may enhance renal fibrosis.