非胰岛素依赖型糖尿病肾病肾组织中EGF,EGF—R和IGF—1R的…

应用免疫组织化学定量分析的方法，对１２例胰岛素非依赖型糖尿病（ＮＩＤＤＭ）肾病患者肾活检组织中胰岛素样生长因子－１（ＩＧＧＦ－１）受体、表皮生长因子（ＥＧＦ）和表皮生长因子受体（ＥＧＦ－Ｒ）进行了观察，并结合患者的病程、糖尿病肾病分期和肾功能进行了比较。ＮＩＤＤＭ肾病患者肾小管上ＥＧＦ和ＥＧＦ－Ｒ的量明显高于正常人，部分患者肾小球ＥＧＦ也呈阳性反应。正常人和ＮＩＤＤＭ肾病患者肾小管上ＩＧＦ－１受体     

非胰岛素依赖型糖尿病肾组织中凝集素受体含量与分布的研究

应用组织化学及免疫组织化学染色对１０例非胰岛素依赖型糖尿病（ＮＩＤＤＭ）和１０例对照组的尸检肾脏标本的病理形态、凝集素受体含量和分布进行了研究。结果：（１）糖尿病肾小球基底膜（ＧＢＭ）和系膜基质呈弥散和不均匀性增厚。３０％的病例可见肾小球结节性硬化，７０％的病例有肾小球纤维化，在肾小管周围有透明变性的物质沉积。（２）对照组的ＧＢＭ上有蓖麻凝集素（ＲＣＡ）和花生凝集素（ＰＮＡ）受体，肾小管上皮细胞的腔缘对麦胚凝集素（ＷＧＡ）和ＲＣＡ有特异的亲和性。绝大多数ＮＩＤＤＭ的ＧＢＭ无ＲＣＡ表达，对ＷＧＡ的亲和性却明显增加，与对照组比较均有显著性差异。糖尿病ＧＢＭ中ＢＤ半乳糖含量减少，而Ｎ乙酰氨基葡萄糖却异常增多，其糖基的变化均可使ＧＢＭ维持电荷屏障的功能减低，通透性发生改变。两组双花扁豆凝集素（ＤＢＡ）和大豆凝集素（ＳＢＡ）在肾小管的表达无明显差异；荆豆凝集素（ＵＥＡ）和刀豆凝集素（ＣｏｎＡ）在肾组织中均不着色。提示ＮＩＤＤＭ肾小球基底膜中凝集素受体的异常表达，可能是引起糖尿病性肾病的原因之一。     

~（99m）Tc－DTPA肾动态显像测定GFR对糖尿病肾病早期诊断的价值

应用￣（９９ｍ）Ｔｃ－ＤＴＰＡ肾动态显像测定６１例ＮＩＤＤＭ的肾小球滤过率（ＧＦＲ），并与相配对的２０例正常人作比较。结果表明无蛋白尿的糖尿病患者ＧＦＲ，升高率为３５％，且与血糖呈正相关。提示￣（９９ｍ）Ｔｃ－ＤＴＰＡ肾动态显像测定ＧＦＲ可作为糖尿病肾病最早期诊断的检测手段。ＮＩＤＤＭ早期确实存在肾小球高滤状态．ＧＦＲ＞１４０ｍｌ／ｍｉｎ可作为糖尿病肾病发生的预兆指标。     

非胰岛素依赖性糖尿病尿α_1-微球蛋白、THP与肾小管功能的研究

为探讨ＮＩＤＤＭ肾病各期肾小管各节段功能变化，用放射免疫分析法（ＲＩＡ）测定２０例健康对照者及６２例非胰岛素依赖性糖尿病（ＮＩＤＤＭ）患者尿白蛋白排泄率（ＵＡＥＲ），尿α１－微球蛋白（α１－ＭＧ）排泄率（Ｕα１ＥＲ）及尿Ｔａｍｍ－Ｈｏｒｓｆａｌ蛋白（ＴＨＰ）排泄率（ＵＴＨＥＲ）。结果：①Ｕα１ＥＲ均值各组间比较结果：正常白蛋白尿组（ＤＭ－Ⅲ）较健康对照组（Ｃ组）升高无统计学意义（Ｐ＞０．０５），但ＤＭ－Ｉ组中，有９例（３５％）Ｕα１１ＥＲ显著升高（Ｐ＜０．０５）；微量白蛋白尿组（ＤＭ－Ⅱ）较ＤＭ－Ｉ组显著增高（Ｐ＜０．０５）。②ＵＴＨＥＲ最大均值位于大量白蛋白尿组（ＤＭ－Ⅲ）组，较Ｃ组显著降低（Ｐ＜０．０５）；最小均值位于ＤＭ－Ⅱ组与Ｃ组比较ＵＴＨＥＲ无显著性差异（Ｐ＞０．０５）。提示：①ＮＩＤＤＭ微量白蛋白尿期即可伴肾小管功能损伤且部分患者Ｕα１ＥＲ、ＵＴＨＥＲ增高先于ＵＡＥＲ的改变而反映肾脏受累。②ＮＩＤＤＭ肾小管功能损伤既有近曲小管重吸收功能障碍，亦存在髓袢合成、分泌功能异常。③联合检测ＵＡＥＲ、ＵＴＨＥＲ、Ｕα１ＥＲ有助于临床早期、全面判断ＮＩＤＤＭ肾脏病变部位及程度。     

新诊断的NIDDM和IGT患者的早期肾功能改变

本文研究了６３例新诊断的非胰岛素依赖型糖尿病（ＮＩＤＤＭ）患者和１６例糖耐量减低（ＩＧＴ）患者的早期肾功能改变，显示ＮＩＤＤＭ患者早期存在肾小球滤过率（ＧＦＲ）升高，肾脏体积增大和尿白蛋白排泄率（ＵＡＥ）轻度增高；１６例ＩＧＴ患者的ＧＦＲ也高于正常对照组。３４例ＮＩＤＤＭ患者经饮食控制和／或口服降糖药治疗４个月后进行了复查，结果显示：１２例代谢改善者的ＧＦＲ、肾脏体积和ＵＡＥ有不同程度的恢复；２２例代谢无改善者的ＧＦＲ有所升高，肾脏体积和ＵＡＥ则无明显变化。     

Ⅱ型糖尿病合并高血压患者高胰岛素血症和舒血管前列腺素关系的探讨

对２３例非胰岛素依赖型糖尿病（ＮＩＤＤＭ）患者、１８例ＮＩＤＤＭ合并高血压的和平共１８例正常人在糖耐量试验期间血胰岛素、６－酮－前列腺素Ｆ＿（１α）（６－ｋｅｔｏ－ＰＧＦ＿（１α）和前列腺素Ｅ＿２（ＰＧＥ＿２）水平进行了测定。ＮＩＤＤＭ并高血压组基值和糖负荷后血清胰岛素水平显著升高，６－ｋｅｔｏ－ＰＧＦ＿（１α）和ＰＧＥ＿（２）浓度显著下降，尤以胰岛素释放高峰为明显。胰岛素与６－Ｋｅｔｏ－ＰＧＦ＿（１α）浓度呈显著负相关。提示ＮＩＤＤＭ合并高血压可能与高胰岛素血症抑制舒血管前列腺素合成有关。     

葡萄糖转运蛋白基因多态性与糖尿病和糖尿病肾病的关系

目的：探讨葡萄糖转运蛋白（ＧＬＵＴ１）基因多态性与糖尿病及糖尿病肾病（ＤＮ）的关系。 方法：应用ＰＣＲ方法对１３１例Ⅱ型糖尿病（ＮＩＤＤＭ）患者ＧＬＵＴ１基因多态性与ＮＩＤＤＭ及ＤＮ发生之间的关系进行了观察，并结合患者体重指数（ＢＭＩ）和胰岛素敏感指数（ＩＳＩ）进行分析。 结果：①ＮＩＤＤＭ组患者Ｘｂａ Ｉ（＋／－）基因型的发生频率明显高于正常人群（６２％ｖｓ３３％，Ｐ〈０．０１），而Ｘｂａ Ｉ（     

TGF-β1和ECM与糖尿病肾病关系的实验研究

目的 观察高糖条件下大鼠肾小球系膜细胞（ＧＭＣ）分泌细胞外基质（ＥＣＭ）成分中纤粘连蛋白（ＦＮ）、层粘连蛋白（ＬＡＭ）、Ⅱ及Ⅳ型胶原和转化生长因子β（ＴＧＦ－β１）的变化,探讨细胞因子和细胞外基质在糖尿病肾病发病中的作用。方法 采用体外大鼠肾小球系膜细胞培养,用ＥＬＩＳＡ方法测定培养上清液中的ＥＣＭ和ＴＧＦ－β１。结果（１）高糖条件下,ＧＭＣ合成和分泌ＴＧＦ－β１增加。（２）高糖对体外培养的系膜细     

肺癌细胞三种多肽生长因子表达研究

目的探讨肺癌细胞生长因子受体的表达及其与淋巴结转移的关系。方法采用免疫组织化学法对肺癌组织切片中抗表皮生长因子受体（ＥＧＦＲ），血小板源性生长因子受体（ＰＤＧＦＲ）和胰岛素样生长因子１受体（ＩＧＦ１Ｒ）的表达进行检测。结果肺鳞癌ＥＧＦＲ、ＰＤＧＦＲ和ＩＧＦ１Ｒ的阳性率分别为８０％、８５％和７５％；腺癌为８８％、８８％和８１％；小细胞癌为８０％、７０％和８０％；而正常肺组织仅分别为２０％、１０％和２０％（Ｐ＜０．０５）；Ⅲ期肺癌ＥＧＦＲ、ＰＤＧＦＲ和ＩＧＦ１Ｒ的阳性率分别为８８％、８０％、９０％；Ⅱ期肺癌分别为５２％、４３％、５７％（Ｐ＜０．０５）；肺癌细胞三种生长因子受体表达均较正常组织为高。Ⅲ期患者生长因子受体表达明显高于Ⅱ期患者。结论ＥＧＦＲ、ＰＤＧＦＲ及ＩＧＦ１Ｒ的表达与肺癌生长分化、转移等恶性行为密切相关。     

GH,IGF轴与糖尿病视网膜病变

糖尿病视网膜病变（ＤＲ）是糖尿病（ＤＭ）慢性微血管并发症之一，其确切发病机制尚未明。血清生长激素（ＧＨ）水平在ＤＭ患者（尤其胰岛素依赖型糖尿病）中明显升高，并与ＤＲ的发生密切相关。其机理可能是ＧＨ直接作用于视网膜血管，抑或通过胰岛素样生长因子（ＩＧＦ）是介导促进ＤＲ形成。另外也有一些资料提示ＤＭ状态下，视网膜组织局部ＩＧＦ、ＩＧＦ结合蛋白（ＩＧＦＢＰ）及ＩＧＦ受体水平升高，对ＤＲ形成也起着重要作用     

急性肾衰患者尿液和肾组织中表皮生长因子的检测及动态变化的意义

本文应用放射免疫方法首次对6例恢复期急性肾衰(ARF)患者尿中EGF进行了动态观察,并与肾组织中EGF进行了比较。发现随着尿中EGF含量的不断增加,Scr水平逐渐下降,而且肾衰指数和钠滤过分数也里类似的变化。恢复期ARF患者肾组织中EGF含量普遍增加,在伴肾小管上皮细胞再生表现者增加的更为明显,并与尿中EGF的变化平行。以上结果表明,ARF患者尿中EGF含量变化,在一定程度上间接地反映了肾脏中EGF的含量和患者肾小管的修复状态,以及肾功能的恢复情况。     

Structural basis of diabetic nephropathy in microalbuminuric NIDDM patients: a light microscopy study

Summary The objective of the study was to evaluate early structural changes occurring in patients with non-insulin-dependent diabetes mellitus (NIDDM) and microalbuminuria by light microscopy. Basal renal biopsy was performed in patients who were subsequently randomized to different antihypertensive treatments. Fourteen NIDDM patients aged 36–65 years (duration of diabetes 9 ± 7 years) with microalbuminuria (mean urinary albumin excretion 66 ± 49 μg/min) underwent percutaneous renal biopsy. Control biopsies were obtained from five patients of similar age undergoing nephrectomy for renal neoplasia with normal renal function and no history of renal disease. Control and diabetic biopsies were processed by light microscopy and stained with haematoxylin and eosin, periodic acid Schiff, Masson's trichrome and silver methenamine. The percentage of globally sclerotic glomeruli was evaluated. Glomerular volume was determined using perimeter analysis. A semiquantitative assessment (range 0 to 3 +) was made of mesangial sclerosis, interstitial fibrosis, tubular atrophy, arteriosclerosis and arteriolar hyalinosis. Glomerular volume was significantly increased in diabetic as compared to control glomeruli (3.2 ± 8 vs 1.8 ± 7, p < 0.01). Mesangial sclerosis (0.9 vs 0, p < 0.0001) and arteriolar hyalinosis (0.91 vs 0.2, p < 0.022) were significantly higher in diabetic compared to control subjects. No significant differences between diabetic and control subjects were found in the percentage of globally sclerotic glomeruli or in the extent of interstitial fibrosis, tubular atrophy and arteriosclerosis. Thus NIDDM patients with microalbuminuria show histological findings consistent with diabetic nephropathy characterized by glomerular hypertrophy, mesangial sclerosis and arteriolar hyalinosis. However, the renal histological changes are mild and appear less marked than in insulin-dependent diabetic patients. [Diabetologia (1996) 39: 1625–1628].     

Loss of kidney IGF-1 receptors in experimental long-term diabetic rats.

The present study was undertaken to assess the long-term effects of streptozotocin-induced diabetes mellitus on insulin-like growth factor-1 (IGF-1) receptors in rat kidneys. Morphological changes were also evaluated using light and electron microscopy. Using receptor autoradiography the levels of IGF-1 were investigated in rat kidneys diabetic for eight months and controls. Sections from both diabetic and control rats were stained with haematoxylin and eosin for morphological studies. Ultra-thin kidney sections were examined using a transmission electron microscope. IGF-1 receptors were significantly lower in the cortex and the medulla of the diabetic rats compared with controls. Morphological differences between normal and diabetic kidneys were observed in both the cortex and medulla. Glomerular changes and necrosis of the renal cortical and medullary parenchyma were demonstrated in the diabetic rats. Necrosis of cells of the collecting ducts and loops of Henle could explain the loss of IGF-1 receptor concentration in the medulla. Shrinkage of glomeruli and normal proximal convoluted tubules of diabetic kidneys were also observed. Our results also revealed extensive damage to the distal convoluted tubules that have not been reported to possess any insulin-like growth factor-1 receptors. Our results demonstrate a reduction of kidney IGF-1 receptors after long-term diabetes mellitus possibly because of the extensive morphological loss of renal tissue. It could be speculated that early administration of IGF-1 might be useful in longterm diabetes mellitus to prevent the degeneration and/or help regeneration of damaged renal tissue.     

大肠癌组织中表皮生长因子及受体的检测

本文应用免疫组化ABC法检测52例大肠癌和18例正常结肠组织中表皮生长因子（EGF）和表皮生长因子受体（EGF－R）的表达状况。正常组织中EGF阳性率22．2％，EGF－R阳性率16．7％，大肠癌EGF阳性率67．3％，EGF－R阳性率61．5％，二者均明显高于正常对照组织，（P＜0．05）。EGF和EGF－R阳性率与患者年龄，性别及肿瘤部位无明显相关，但随着肿瘤浸润度的加深，EGF与EGF－R的阳性率逐渐增高，有淋巴结转移者二者阳性率高于淋转阴性者，特别是EGF与EGF－R双阳者中有82．6％为进展期大肠癌，另发现低分化大肠癌中EGF和EGF－R阳性率明显低于中高分化癌。本文结果提示：部分大肠癌存在EGF或EGF－R的过度表达；EGF与EGF－R的过度表达与肿瘤润度及淋巴转移有关，其检测可作为诊断肿瘤恶性程度的一项辅助指标，部分正常大肠粘膜组织中也有少量EGF或EGF－R表达。     

2型糖尿病非糖尿病性肾病流行病学及病理变化研究

65例 2型糖尿病患者肾活检发现, 46. 2% (30 /65)有非糖尿病性肾病 (NDRD)。与糖尿病肾病对比,NDRD男性多见、病程短,浮肿、蛋白尿明显,系膜细胞增生及免疫球蛋白沉积显著,病理组织学类型多样,多见的是IgA肾病(占 43. 3% )。     

冬虫夏草防治氨基糖甙急性肾损害的分子生物学机理

本研究采用斑点杂交、免疫组化、放射免疫和~(125)I-mEGF结合试验,分别检测了肾组织EGF前体mRNA表达,肾组织EGF,尿EGF及肾组织EGF受体。发现庆大霉素所致急性肾衰时第四至第12天肾组织EGF前体mRNA表达明显减少,肾皮质、髓质EGF阳性小管上皮细胞数增加。皮质、髓质EGF受体含量分别平均增加7.3～14.6和3.1～4.6倍,但尿EGF排出量并无明显减少,恢复期尿EGF显著增加。冬虫夏草能增加第四天EGF前体mRNA表达,第四至第12天肾皮质EGF含量,第七天尿EGF排出量,而不影响EGF受体数目。该结果表明,冬虫夏草可能通过增加肾组织EGF前体mRNA表达,促进EGF合成,从而促进小管上皮细胞增殖。通过此分子生物学机理加速小管再生修复和急件肾衰的恢复。     

Glomerular expression of thrombospondin-1, transforming growth factor beta and connective tissue growth factor at different stages of diabetic nephropathy and their interdependent roles in mesangial response to diabetic stimuli

Aims/hypothesis We quantified the glomerular expression of thrombospondin-1 (THBS1, also known as TSP-1), transforming growth factor beta 1 (TGFB1, also known as TGF-β1) and connective tissue growth factor (CTGF) at each stage of diabetic nephropathy. We also examined the roles of THBS1 and CTGF in mediating high-glucose- and glycated-albumin-induced synthesis of the matrix protein, fibronectin, by mesangial cells. Methods THBS1, latent and active TGFB1, and CTGF, were detected by immunohistochemistry and in situ hybridisation in biopsies from 19 insulin-dependent diabetic patients with incipient, manifest and advanced diabetic nephropathy, and in 11 control kidneys. Findings were quantified by image analysis. Human mesangial cells were cultured with normal or high glucose, albumin or glycated albumin (Amadori product), +/−THBS1 or CTGF antisense oligonucleotides, or with peptide W, an inhibitor of TGFB1 bioactivation by THBS1. Proteins were measured by western blot analysis or ELISA. Results In glomeruli of normal kidneys, mRNA and protein levels for THBS1, latent-TGFB1 and CTGF were low. They were increased in the incipient stage of diabetic nephropathy, predominantly in mesangial areas, with further increases at later stages of the disease. Little or no active TGFB1 immunostaining was detected prior to manifest diabetic nephropathy. In contrast to high-glucose conditions, increases in fibronectin synthesis that were stimulated by glycated albumin were not dependent on THBS1 activation of latent TGFB1. However, increased fibronectin synthesis in both conditions required CTGF. Conclusions/interpretation Increased glomerular expression of all three factors occurs from the earliest stage of diabetic nephropathy. In contrast to THBS1, CTGF is required for mesangial synthesis of fibronectin stimulated by high glucose or glycated albumin, and is thus a potential therapeutic target. N. A. Wahab and L. Schaefer made an equal contribution to the work reported in this paper     

Three-dimensional architecture of glomerular extracellular matrices in diabetic glomerulosclerosis

The three-dimensional ultrastructural changes of the glomerular extracellular matrices in diabetic glomerulosclerosis were studied in acellular rat and human diabetic glomeruli by scanning electron microscopy. The mesangial matrix appeared as fenestrated septa with oval stomata between the glomerular capillaries in normal control specimens. In diabetic glomerulosclerosis, both in humans and rats, expansion of mesangial matrix and narrowing of the mesangial fenestrae were observed. A thin layer of the mesangial matrix extended into the peripheral glomerular basement membrane (GBM) subendothelially. Thickening of the GBM in diabetic nephropathy might be due to expansion of the mesangial matrix into the peripheral GBM.