血管内皮生长因子和糖尿病肾病

糖尿病肾病时血管内皮生长因子 (VEGF)在肾脏局部、血浆和尿液中的发生变化。VEGF参与糖尿病肾病的发生与进展。抑制VEGF及其受体可能是一条新的糖尿病治疗途径。     

糖尿病大鼠骨折后血管内皮生长因子的变化

目的 观察糖尿病大鼠骨折后血管内皮细胞生长因子（VEGF）的变化。方法 70只清洁雄性Wistar大鼠随机分为对照组和链脲佐菌素（stz）诱导的速发型糖尿病组，线锯锯断两组大鼠左胫骨后复位外固定。于骨折后1、2、3、4、6、8周取静脉血保留血清；大鼠左下肢X线片观察骨折愈合情况；取骨折断端组织行HE染色光镜观察、免疫组织化学检测VEGF；酶联免疫吸附分析法（EHsa）检测血清VEGF。结果 糖尿病组4周可以看见纤维骨痂，8周才有较多骨性骨痂出现，较对照组明显滞后；HE染色镜下观察糖尿病组骨形成滞后；3周VEGF免疫组织化学灰度值两组间差异有统计学意义，（实验组142．8±3．8；对照组128．0±5．5，P〈0．01）；两组血清中VEGF差异元统计学意义（P〉0．05）。结论 糖尿病大鼠骨折后血清中VEGF未减少，局部组织VEGF含量低是导致糖尿病大鼠骨折愈合差的原因之一。     

血管内皮生长因子及其受体与糖尿病肾病

糖尿病肾病（diabetic nephropathy,DN）发病率逐年增加,在欧美国家已成为终末期肾病（end stage renal disease,ESRD）和透析的首要病因,预计在不久的将来,在中国DN会迅速超过肾小球肾炎而成为ESRD的第1位病因。DN病因复杂,有基因多态性、代谢紊乱、免疫紊乱、血流动力学异常、炎症等参与。     

血管内皮生长因子及其受体对糖尿病肾病大鼠微血管病变的作用

目的：探讨血管内皮生长因子（VEGF）及其受体（VEGFR2）在糖尿病肾病（DN）大鼠肾微血管病变发病中的作用。方法：将正常Wistar大鼠12只随机分为正常对照组、糖尿病肾病组。糖尿病肾病组用STZ诱导建立DN模型,大鼠自由进食、饮水。于第4周和第8周各组分别处死大鼠6只。测定血生化及24h尿蛋白定量,以正常肾小球为对照,采用特异性抗体和免疫组织化学方法,观察大鼠肾小球VEGF、VEGFR2、TM-1的分布及其强度变化,并结合肾脏病理进行分析。应用RT-PCR技术测定VEGF和VEGFR2mRNA的表达。结果：（1）糖尿病肾病组第4周,8周时,尿白蛋白排泄率,血糖,血脂升高,均高于正常对照组（P〈0.01）,肾组织光镜,出现早期糖尿病肾病典型的病理改变过程。（2）免疫组化显示糖尿病组4周、8周时肾脏VEGF、VEGFR2及TM-1表达均较正常对照组上调（P〈0.01）,VEGF与TM-1呈正相关（4周时r=0.947,P〈0.001;8周时r=0.923,P〈0.001）;RT-PCR检测结果显示糖尿病肾病组第8周时VEGF-mRNA和VEGFR2-mRNA表达均较正常对照组升高（P〈0.05）,第8周时VEGF-mRNA和VEGFR2-mRNA表达较第4周时增高（P〈0.05）。结论：糖尿病肾病大鼠肾小球VEGF、VEGFR2、TM-1表达增强,与糖尿病肾脏新生血管生成有关。     

血管内皮生长因子基因多态性与糖尿病肾病的相关性研究

目的 探讨血管内皮生长因子(VEGF)-634G／C基因多态性与糖尿病肾病(DN)的关系。方法 运用PCR-限制性多态性片段长度(RFLP)技术检测98例健康对照者和216例2型糖尿病患者[其中DN患者104例，单纯2型糖尿病(DM)患者112例]的基因型，比较各组的基因型和等位基因频率。结果 (1)CC基因型者血清VEGFT水平高于CG及GG型者；(2)DN组CC基因型和C等位基因频率显著高于DM组和正常对照组；(3)与GG型和CG型组相比，CC型组DN的发生率明显上升；(4)Logistic回归分析显示VEGF、VEGF基因多态性、收缩压(SBP)、HbA1c、LDL-C、体重指数(BMI)是DN的危险因素。结论 VEGF-63gG／C多态性与2型DM伴发肾病的发生有关，C等位基因可能是DN的易感基因。     

生长激素-胰岛素样生长因子轴与糖尿病肾病

生长激素(GH)和胰岛素样生长因子(IGF)轴在糖尿病肾病发病过程中有一定的作用。应用生长抑素类药物可明显改善肾脏病变。     

生长激素-胰岛素样生长因子轴与糖尿病肾病

生长激素(GH)和胰岛素样生长因子(IGF)轴在糖尿病肾病发病过程中有一定的作用。应用生长抑素类药物可明显改善肾脏病变。     

早期糖尿病肾病血管内皮机能不全的特点

伴临床肾病的糖尿病病人死于心血管并发症是不伴肾病的40倍。糖尿病肾病患者常有高血压、脂质和脂蛋白异常,血浆纤维蛋白原增高及大量吸烟等心血管危险因子,但尚不足以解释因心血管病变引起的死亡率大副度上升。作者曾报道,伴早期、临床肾病的糖尿病病人有血管内皮机能不全,表现在尿白蛋白排泄率增高,血浆VW因子(Von Willehrand)升高。本文进一步研究伴不同程度蛋白尿病人血管内皮细胞释放组织纤溶酶原激活物(tPA)的能力。本研究将40例胰岛素依赖犁糖尿病男性病人在年龄、糖尿病病程匹配的情况下,按蛋白尿程度分为三组:第一组19例,尿白蛋白排泄正常(<30mg     

血管内皮生长因子在阿霉素肾病大鼠中的表达及其意义

血管内皮生长因子(VEGF)具有增加血管通透性和促进新生血管形成的作用。但病理状态下它的生物学功能及在肾小球疾病发生发展中的作用尚不明确。我们观察了阿霉素肾病(ADR)大鼠血清、肾组织VEGF的表达及与尿蛋白的关系,以探讨VEGF在ADR发病中的意义。 一、材料与方法 1.实验动物与分组:SD雄性健康大鼠30只,体重180-220 g,随机分为3组:(1)A组:正常对照组(n=10),大鼠     

胃癌血清中血管内皮生长因子和一氧化氮水平的变化及其意义

我们采用酶联免疫吸附测定(ELISA)法与分光光度法分别检测血管内皮生长因子 (VEGF)和一氧化氮 (NO)在胃癌、慢性胃炎患者以及健康人血清中的表达水平 ,探讨它们与胃癌的关系及其临床意义。一、对象和方法1.对象 :2 0 0 2年 1月～ 2 0 0 3年 4月在我院行手术治疗的胃癌住院患者 5 7例 ,均术后病理学证实。其中男 3 9例 ,女 18例 ,年龄 3 2～ 74岁 ,平均 5 3 .8岁。患者术前均未经放疗或化疗。慢性胃炎患者 (均经胃镜胃粘膜活检确诊为慢性活动性胃炎 ) 45例 ,另有健康献血人员3 0例 ,作为正常对照组。胃癌患者均在术前空腹留取外周静脉血…     

Blockade of serotonin 2A receptor improves glomerular endothelial function in rats with streptozotocin-induced diabetic nephropathy

Background Serotonin (5-HT) is involved in vascular inflammation and atherosclerogenesis. Serum 5-HT concentrations are elevated in diabetes, and 5-HT is involved in diabetic vasculopathies. Sarpogrelate hydrochloride, a 5-HT2A receptor antagonist, has renoprotective effects, but its effect in diabetic nephropathy is not elucidated. The aim of this study was to examine the effects of sarpogrelate on endothelial dysfunction in rats with streptozotocin (STZ)-induced diabetes. Methods Rats with STZ-induced diabetes were either untreated or treated with sarpogrelate (30 mg/kg P.O.) for 8 weeks. At the end of the experiment, we measured urinary albumin excretion, serum adiponectin concentration and platelet-derived microparticles. Intraglomerular coagulation was detected by immunostaining for platelets. Production of renal reactive oxygen species (ROS) and nitric oxide (NO) was investigated by confocal laser microscopy and used as an index of glomerular endothelial dysfunction. Results Diabetic nephropathy was associated with enhanced production of ROS and diminished bioavailable NO in the glomeruli. Treatment with sarpogrelate improved ROS/NO imbalance in glomeruli, suppressed platelet aggregation in glomeruli, reduced platelet-derived microparticles, increased serum adiponectin level and reduced the level of albuminuria, compared with non-treated diabetic rats. Conclusions Our results indicate that sarpogrelate improves endothelial function in rats with STZ-induced diabetes through a reduction of glomerular platelet activation and an increase in serum adiponectin concentrations and suggest that sarpogrelate is potentially useful for the treatment of diabetic nephropathy.     

氯沙坦钾对糖尿病肾病大鼠血浆一氧化氮和肝细胞生长因子水平的影响

本研究旨在观察氯沙坦钾对糖尿病肾病(DN)大鼠血浆一氧化氮(NO)和肝细胞生长因子(HGF)水平的影响, 从而探讨氯沙坦钾对DN的肾脏保护作用机制.     

Inducible nitric oxide synthase-derived nitric oxide promotes glomerular angiogenesis via upregulation of vascular endothelial growth factor receptors

The vascular endothelial growth factor (VEGF) system is of major importance for glomerular endothelial repair in glomerulonephritis (GN) and is significantly affected by nitric oxide (NO) release. For investigating whether glomerular upregulation of inducible NO synthase (iNOS) in GN might affect VEGF-mediated repair, a selective iNOS inhibitor, L-N6-(1-iminoethyl)-lysin (L-NIL), was administered to rats with anti-Thy 1.1 GN from day -2 until day 5 after GN induction. Compared with untreated nephritic rats, L-NIL-treated nephritic rats showed similar mean arterial BP, significantly decreased de novo peak nitrate production, and increased albuminuria on day 6. This was preceded by a significant decrease of glomerular endothelial cell proliferation and endothelial area on day 2 in L-NIL-treated nephritic rats. Upregulation of glomerular VEGF mRNA and protein expression, in particular of the VEGF(164) splicing variant, occurred similarly in L-NIL-treated and untreated nephritic rats on days 2 and 7. However, the upregulation of glomerular VEGF receptor 1 and 2 mRNA expression on day 2 was reduced by 77 and 67%, respectively, in L-NIL-treated nephritic rats as compared with untreated nephritic rats. In parallel, glomerular VEGF(165) binding was reduced by 34% in L-NIL-treated nephritic rats on day 2. Glomerular upregulation of the VEGF(164) co-receptor neuropilin-1 mRNA in nephritic rats was reduced by L-NIL treatment only on day 7. Healthy untreated or L-NIL-treated controls showed no significant differences in any parameter analyzed. In conclusion, impaired repair of glomerular endothelium and downregulation of glomerular VEGF receptor expression was observed after selective iNOS inhibition in experimental GN. These data identify iNOS-derived NO production as the first in vivo regulator of the glomerular VEGF system and as an important mechanism promoting glomerular healing.     

Uncoupling of vascular endothelial growth factor with nitric oxide as a mechanism for diabetic vasculopathy

The role of VEGF in vascular disease is complicated. Vascular endothelial growth factor (VEGF) expression can be deleterious in diabetic vasculopathy, especially in kidney and retina. In contrast, VEGF seems to be renoprotective in nondiabetic renal disease. VEGF exerts it biologic effects in association with nitric oxide (NO), yet it is known that NO bioavailability is reduced in diabetes. Thus, it was hypothesized that this diverse biologic effect of VEGF on diabetic vasculopathy is due to uncoupling of VEGF with NO. VEGF stimulated NO production in a dose-dependent manner in bovine aortic endothelial cells (BAEC), and this was inhibited by either high glucose or Nomega-nitro-l-arginine methyl ester (L-NAME) treatment. Endothelial NO synthase phosphorylation by VEGF was also inhibited by high glucose. It is interesting that both high glucose and L-NAME enhanced the proliferative response of endothelial cells, which was prevented by an NO donor. Furthermore, high glucose as well as L-NAME stimulated VEGF and kinase-insert domain receptor (KDR) (VEGF receptor 2) mRNA expression in BAEC. These data suggest that the uncoupling of VEGF with NO enhances endothelial cell proliferation via the KDR pathway. Compatible with these findings, a KDR antagonist blocked this response. In addition, a VEGF mutant, which binds only KDR, induced extracellular signal-regulated kinase (ERK) activation, and inhibition of ERK completely blocked endothelial cell proliferation under this condition, suggesting a role of the KDR-ERK1/2 pathway on endothelial cell proliferation. In conclusion, high glucose causes an uncoupling of VEGF with NO, which enhances endothelial cell proliferation via activation of the KDR-ERK1/2 pathway. These results may provide new insights into the understanding of the mechanism of diabetic vascular disease.     

Regression of advanced diabetic nephropathy by hepatocyte growth factor gene therapy in rats

Diabetic nephropathy is the main cause of end-stage renal disease requiring dialysis in developed countries. In this study, we demonstrated the therapeutic effect of hepatocyte growth factor (HGF) on advanced rather than early diabetic nephropathy using a rat model of streptozotocin-induced diabetes. Early diabetic nephropathy (16 weeks after induction of diabetes) was characterized by albuminuria, hyperfiltration, and glomerular hypertrophy, whereas advanced diabetic nephropathy showed prominent transforming growth factor (TGF)-beta1 upregulation, mesangial expansion, and glomerulosclerosis. An SP1017-formulated human HGF (hHGF) plasmid was administered by intramuscular injection combined with electroporation over a 30-day follow-up in rats with early and advanced diabetic nephropathy. hHGF gene therapy upregulated endogenous rat HGF in the diabetic kidney (rat HGF by RT-PCR was threefold higher than in diabetic rats without therapy). hHGF gene therapy did not improve functional or morphologic abnormalities in early diabetic nephropathy. hHGF gene therapy reduced albuminuria and induced strong regression of mesangial expansion and glomerulosclerosis in advanced diabetic nephropathy. These findings were associated with suppression of renal TGF-beta1 and mesangial connective tissue growth factor (CTGF) upregulation, inhibition of renal tissue inhibitor of metalloproteinase (TIMP)-1 expression, and reduction of renal interstitial myofibroblasts. In conclusion, our results suggest that hHGF gene therapy may be considered as an innovative therapeutic strategy to treat advanced diabetic nephropathy.     

血管内皮细胞生长因子和内抑素失衡在2型糖尿病肾病中的作用

目的探讨血管内皮细胞生长因子（VEGF）和内抑素在2型糖尿病肾病（DN）中的作用。方法对30例2型糖尿病无肾病和30例2型DN患者，采用ELISA法检测血清中VEGF和内抑素的浓度变化进行了观察，30例健康成人作为正常对照，并结合临床进行了分析。结果2型糖尿病无肾病和2型DN患者血中VEGF和内抑素的表达与正常人相比均有明显差异（P〈0．05，P〈0．01），2型DN患者血中VEGF和内抑素浓度的增加与蛋白尿、肾功能及视网膜病变程度密切相关。而与高血压、高血脂及糖化血红蛋白水平之间无统计学意义。结论2型糖尿病无肾病和2型DN患者血中VEGF和内抑素的表达动态的逐渐增加，其增加与2型DN患者的蛋白尿形成、肾功能和糖尿病视网膜病变改变关系密切，VEGF和内抑素参与了2型DN患者血管增生的肾脏病变和功能紊乱发生的作用。     

血管内皮细胞生长因子水平及其基因多态性与2型糖尿病肾病的关系

研究表明,血管内皮细胞生长因子(VEGF)介导了糖尿病。肾病(DN)患者肾小球内皮细胞损伤和功能紊乱,VEGF基因突变会影响VEGF的水平。我们观察2型DN及2型糖尿病(DM)患者血浆VEGF水平与VEGF基因多态性的变化,并研究其与2型DN的关系。     

C-peptide and islet transplantation improve glomerular filtration barrier in diabetic nephropathy rats

ObjectivesIslet transplantation has been proved to be effective in delaying early stage of DN. This study was established to observe the mechanism of islet transplantation on early diabetic nephropathy (DN).MethodThe diabetes mellitus (DM) rat model was established by an injection of a single-dose streptozotocin. According to the treatment, the rats were randomly divided into 4 groups: the untreated DN rats (DN group); the C-peptide treated rats (CP group); the islet transplanted rats (IT group); the normal control rats (NC group). Renal function and structure of glomerular filtration barrier (GFB) were evaluated by urinalysis and histopathological examination, respectively. The renal fibrotic factors, TGF- β1 and CTGF, as well as the anti-renal fibrosis factor HGF were assessed by immunohistochemical staining and western blotting methods.ResultsAfter C-peptide treatment and islet transplantation, the GFB structure was obviously improved. The blood glucose significantly decreased in the IT group. The 24h urine protein and glomerular basement membrane thickness decreased, the pathological changes of podocytes improved, TGF- β1 and CTGF decreased and HGF increased in the CP group and the IT group compared with that in the DN group (P < 0.05), especially in the IT group.ConclusionIslet transplantation could ameliorate the structure of GFB of early DN in a rat model, and the treatment effect was partly attributed to the restoration of C-peptide concentration. Suppressing the fibrosis system can be the potential mechanism of islet transplantation, which is independent of blood glucose control.