雌激素与糖尿病肾病

雌激素可通过调节血管紧张素(ANG)-Ⅱ受体亚型间的比例、促进ANG-Ⅱ向舒血管的ANG-(1-7)的转化等,抑制肾内高表达的ANG-Ⅱ对糖尿病肾病(DN)发生、发展的促成作用;维持肾脏正常功能必需的一氧化氮(NO)的合成和功能,抑制过量NO的生成,调节NO系统在DN不同阶段病理生理过程中的作用;并通过对基质金属蛋白酶、转化生长因子-β作用的调节,影响细胞外基质代谢等机制而发挥肾保护作用。     

雌激素与糖尿病肾病

雌激素可通过调节血管紧张素(ANG)-Ⅱ受体亚型间的比例、促进ANG-Ⅱ向舒血管的ANG-(1-7)的转化等，抑制肾内高表达的ANG-Ⅱ对糖尿病肾病(DN)发生、发展的促成作用；维持肾脏正常功能必需的一氧化氮(NO)的合成和功能，抑制过量NO的生成，调节NO系统在DN不同阶段病理生理过程中的作用；并通过对基质金属蛋白酶、转化生长因子-β作用的调节，影响细胞外基质代谢等机制而发挥肾保护作用。     

结缔组织生长因子:糖尿病肾病治疗的新靶点

结缔组织生长因子(CTGF)作为转化生长因子(TGF)-β下游的调节因子参与了糖尿病肾病(DN)的发生发展,成为DN治疗研究的新靶点.其中高血糖、糖基化终末产物(AGEs)、肾素血管紧张素醛固酮系统(RAAS)等均可刺激.肾组织产生CTGF,引起肾纤维化.因此,通过控制上述因素抑制CT-GF的表达及特异地阻断CTGF将延缓DN的发展.     

转化生长因子β在糖尿病肾病发生中的作用

糖尿病肾病(DN)是糖尿病(DM)患者常见和特异的微血管并发症,其发病机制尚未完全明确,转化生长因子(TGF)-β特别是TGF-β1在DN的发病中发挥了重要作用,阻断TGF-β1的过度表达、抑制或降低其生物活性,有可能成为一种新的预防和治疗DN的有效措施.本文就TGF-β的生物学特性、在DN发生中的作用及目前所作的相关研究做一简单综述.     

色素上皮衍生因子与糖尿病肾病

色素上皮衍生因子(PEDF)是丝氨酸蛋白酶抑制剂超家族成员之一,其主要生物学作用是营养神经、神经元保护、抗氧化应激、抗炎性反应、抑制新生血管形成等.越来越多的研究显示,PEDF在糖尿病肾病中可发挥独特的保护作用,如减少肾小球细胞外基质生成、预防肾脏纤维化,并通过抑制肾脏炎性反应和氧化应激反应而抑制肾小球毛细血管内皮细胞增生、调节血管的渗透性,从而减少尿蛋白的生成.因此,PEDF有望成为糖尿病肾病的一个治疗靶点.     

高糖环境下VEGF与PEDF在GMC中表达及rAAV-AS基因的干预作用

目的 探讨高糖对大鼠肾小球系膜细胞(GMC)色素上皮细胞衍生因子(PEDF) 和血管内皮生长因子(VEGF)表达影响以及腺相关病毒介导血管抑素(rAAV-AS)基因的干预作用.方法 将培养的大鼠GMC株分为6组,高糖作为刺激因素,rAAV-AS 作为干预因素.分别设低糖组、高糖组、高糖加腺相关病毒(rAAV)组及高糖加rAAV-AS 治疗组.用免疫细胞化学及ELISA法测定各组系膜细胞PEDF 以及VEGF蛋白表达.结果 高糖可下调GMC中PEDF蛋白的表达,上调GMC中VEGF蛋白的表达.rAAV-AS可逆转高糖导致GMC的VEGF蛋白表达的增加及PEDF蛋白表达的降低.结论 rAAV-AS可以一定程度改善高糖诱导的VEGF和PEDF表达失衡而发挥对糖尿病肾病(DN)的保护作用.     

色素上皮衍生因子抑制糖基化终产物介导人肾小球系膜细胞糖基化终产物受体表达的研究

目的 观察色素上皮衍生因子（PEDF）、晚期糖基化终产物受体（RAGE）的表达及重组PEDF对RAGE表达的抑制作用,探讨PEDF与DN的关系及对DN的保护作用. 方法 采用糖化小牛血清白蛋白（AGE-BSA）体外诱导人肾小球系膜细胞（HRMCs）,Western blot及RT-PCR法分别检测RAGE、PEDF蛋白和mRNA表达. 结果 （1） AGE-BSA（100～400 mg/L）呈浓度梯度减少HRMCsPEDF表达（P＜0.01）,升高RAGE表达（P＜0.01）;（2）重组PEDF蛋白（5～40 nmol/L）呈浓度依赖性抑制AGE-BSA介导RAGE蛋白在HRMCs的表达（P＜0.05）. 结论 AGEs通过降低PEDF表达,增加RAGE表达参与DN的发生,PEDF可能通过抑制AGE-RAGE轴对DN发挥保护作用.     

Vasohibin-1与糖尿病肾病

Vasohibin-1 (VASH-1)是一种以负反馈机制调节血管生成的内皮源性分泌蛋白.它能够以负反馈作用机制抑制血管内皮生长因子的作用,参与多种抗血管生成作用.作为机体的自我防御因子,VASH-1能够维持血管内皮的完整性,从而起到抵御糖尿病微血管并发症的作用.近年研究表明,VASH-1对肾小球内皮细胞和系膜细胞具有缓解微血管损害、调节炎性反应、延缓肾间质纤维化等重要功能,对糖尿病肾病具有重要的保护作用,可能成为糖尿病肾病早期治疗的一个新靶点.     

TGF-β1诱导的上皮-间充质转化与糖尿病肾病

糖尿病肾病(DN)肾间质纤维化的初始环节之一是肾小管上皮-间充质转化(EMT),而转化生长因子-β1(TGF-β1)是EMT发生的重要诱导因子.了解DN中肾小管上皮细胞EMT的发生及过程,探讨Smad7、C-肽、TGF-β1抗体、组蛋白去乙酰化酶抑制剂和血管紧张素受体抑制剂在DN中的作用,将为DN治疗提供新的思路.     

苦参碱对糖尿病大鼠肾脏的保护作用

目的 探讨苦参碱对糖尿病(DM)大鼠肾脏的保护作用及机制.方法 采用单侧肾切除、腹腔注射链脲佐菌素诱导糖尿病肾病(DN)大鼠模型,并设立正常对照(NC)组;DN对照(DN)组,苦参碱治疗组(MT)(100 mg·kg~(-1)·d~(-1)),腹腔给药8 w后处死所有大鼠,检测苦参碱对DM大鼠肾功能的影响,病理切片HE染色,观察肾脏病理改变,免疫组化检测肾组织转化生长因子β1(TGF-β1)的表达水平.结果 与NC组大鼠比较,DN组大鼠尿蛋白排泄量增多,肾小球体积增加,血尿素氮(BUN)和肌酐(Cr)升高,肾组织TGF-β1表达上调(P<0.01).苦参碱明显减少DN大鼠尿蛋白排泄量,降低血清BUN、Cr水平(P<0.05,P<0.01),肾小球体积明显改善,肾组织TGF-β1表达明显下调(P<0.05,P<0.01).结论 苦参碱显著改善抑制肾脏TGF-β1表达,改善肾小球肥大,减轻蛋白尿,对DM大鼠肾损害具有保护作用.     

促血管生成素-1对糖尿病大鼠肾脏色素上皮衍生因子和血小板反应蛋白-1基因表达的影响

目的 观察色素上皮衍生因子（PEDF）、血小板反应蛋白-1（TSP-1）在糖尿病大鼠肾脏的表达变化,探讨促血管生成素-1（Ang-1）对上述因子的影响. 方法 将雄性SD大鼠分正常对照（NC）组、DN组、空载处理（BV）组、Ang-1处理（AV）组.采用STZ腹腔注射诱导大鼠DN模型.成模8周后尾静脉注射Ang-1腺病毒载体.多时点检测24 hUAlb和肾组织PEDF、TSP-1蛋白及mRNA表达水平.结果 DN、BV、AV组24 hUAlb均升高,其中AV组于20周后降低（P＜0.05）.DN、BV、AV组肾组织PEDF蛋白及mRNA表达下调,TSP-1表达上调（P＜0.05）,其中AV组12周后肾组织PEDF和TSP-1mRNA及蛋白表达变化较DN、BV组改善明显（P＜0.05）. 结论 糖尿病大鼠肾脏PEDF、TSP-1异常表达参与DN发生发展,给予Ang-1可改善糖尿病大鼠肾脏PEDF、TSP-1异常表达.     

Identification of the antivasopermeability effect of pigment epithelium-derived factor and its active site

Vascular permeability plays a key role in a wide array of life-threatening and sight-threatening diseases. Vascular endothelial growth factor can increase vascular permeability. Using a model system for nonproliferative diabetic retinopathy, we found that pigment epithelium-derived factor (PEDF) effectively abated vascular endothelial growth factor-induced vascular permeability. A 44-amino acid region of PEDF was sufficient to confer the antivasopermeability activity. Additionally, we identified four amino acids (glutamate-101, isoleucine-103, leucine-112, and serine-115) critical for this activity. PEDF, or a derivative, could potentially abate or restore vision loss from diabetic macular edema. Furthermore, PEDF may represent a superior therapeutic approach to sepsis-associated hypotension, nephrotic syndrome, and other sight-threatening and life-threatening diseases resulting from excessive vascular permeability.     

Diabetic nephropathy and long-term treatment effects of rosiglitazone and enalapril in obese ZSF1 rats

Diabetic nephropathy (DN) is a major cause of end-stage renal disease. Yet the pathogenic mechanisms underlying the development of DN are not fully defined, partially due to lack of suitable models that mimic the complex pathogenesis of renal disease in diabetic patients. In this study, we describe early and late renal manifestations of DN and renal responses to long-term treatments with rosiglitazone or high-dose enalapril in ZSF1 rats, a model of metabolic syndrome, diabetes, and chronic renal disease. At 8 weeks of age, obese ZSF1 rats developed metabolic syndrome and diabetes (hyperglycemia, glucosuria, hyperlipidemia, and hypertension) and early signs of renal disease (proteinuria, glomerular collagen IV deposition, tubulointerstitial inflammation, and renal hypertrophy). By 32 weeks of age, animals developed renal histopathology consistent with DN, including mesangial expansion, glomerulosclerosis, tubulointerstitial inflammation and fibrosis, tubular dilation and atrophy, and arteriolar thickening. Rosiglitazone markedly increased body weight but reduced food intake, improved glucose control, and attenuated hyperlipidemia and liver and kidney injury. In contrast, rosiglitazone markedly increased cardiac hypertrophy via a blood pressure-independent mechanism. High-dose enalapril did not improve glucose homeostasis, but normalized blood pressure, and nearly prevented diabetic renal injury. The ZSF1 model thus detects the clinical observations seen with rosiglitazone and enalapril in terms of primary and secondary endpoints of cardiac and renal effects. This and previous reports indicate that the obese ZSF1 rat meets currently accepted criteria for progressive experimental diabetic renal disease in rodents, suggesting that this may be the best available rat model for simulation of human DN.     

Down-regulation of angiogenic inhibitors: a potential pathogenic mechanism for diabetic complications

Diabetic retinopathy (DR) and diabetic nephropathy (DN) are the most common microvascular complications of diabetes. DR is a leading cause of blindness, and DN is a major cause of end-stage renal diseases. Diabetic macular edema (DME) resulting from increased vascular permeability in the retina and retinal neovascularization (NV) represent two major pathological changes in DR and are the primary causes of vision loss in diabetic patients. Previous studies have shown that angiogenic factors such as vascular endothelial growth factor (VEGF) play a key role in the development of DME and retinal NV. Studies in recent years have demonstrated that a number of endogenous angiogenic inhibitors are present in the normal retina and counter act the effect of VEGF in the regulation of angiogenesis and vascular permeability. Decreased levels of angiogenic inhibitors in the vitreous and retina have been found in diabetic patients and diabetic animal models. The decreased levels of angiogenic inhibitors shift the balance between angiogenic factors and angiogenic inhibitors and consequently, lead to the development of DME and retinal NV. Recently, we have found that these angiogenic inhibitors are expressed at high levels in the normal kidney and are down-regulated in diabetes. Moreover, these inhibitors inhibit the activity of VEGF and TGF-beta, two major pathogenic factors of DN. Therefore, decreased levels of these angiogenic inhibitors in diabetes may be associated with pathologies of DN. This review will summarize recent progress in these fields and therapeutic approaches to use angiogenic inhibitors for the treatment of diabetic complications.     

Insulin resistance in diabetic nephropathy — cause or consequence?

Insulin resistance (IR) is associated with multiple risk factors for cardiovascular disease. Many studies have shown that IR is present in chronic renal failure (CRF), and recent evidence suggests that IR can also occur in the early stages of renal disease. Patients with diabetic nephropathy (DN) have an increase in cardiovascular mortality, and since IR may be a contributing factor, this emphasizes the importance of a detailed understanding of the mechanisms linking IR and renal dysfunction at different stages of DN. IR can be detected early on in DN, e.g. at the stage of microalbuminuria (MA) and this could indicate a common genetic trait for IR and DN. As DN progresses further, IR is aggravated and it may, in addition to other factors, possibly accelerate the decline in renal function toward end-stage renal disease (ESRD). Several potentially modifiable mechanisms including circulating hormones, neuroendocrine pathways and chronic inflammation, are said to contribute to the worsening of IR. In ESRD, uremic toxins are of major importance.In this review article, we address the association between different stages of DN and IR and attempt to summarize major findings on potential mechanisms linking DN and IR. We conclude that IR is a consequence, and potentially also a cause of DN. In addition, there are probably genetic and environmental background factors that predispose to both IR and DN.     

CTGF在糖尿病肾病发病机制中的作用及意义

糖尿病肾病(DN)状态下,高糖环境、血循环机械应力、肾素-血管紧张素-醛固酮系统等多种因素可上调结缔组织生长因子(CTGF)的表达。上调的CTGF可通过自身或联合其他细胞因子促进肾脏细胞有丝分裂、调节细胞周期的限制点、促进细胞外基质合成增加和降解减少,导致细胞外基质沉积,从而导致肾脏肥大、肾小球硬化以及肾小管纤维化,介导DN的发生与发展。CTGF是DN发病中的关键细胞因子。因此,以其为特异性靶标可能给DN的治疗带来新希望。     

Pigment epithelium-derived factor inhibits TNF-alpha-induced interleukin-6 expression in endothelial cells by suppressing NADPH oxidase-mediated reactive oxygen species generation

Pigment epithelium-derived factor (PEDF) has recently been shown to be involved in the pathogenesis of proliferative diabetic retinopathy. Atherosclerosis is an inflammatory-fibroproliferative disease as well. Oxidative stress plays a major role in retinopathy and atherosclerosis. Accordingly, we investigated effects of PEDF on reactive oxygen species (ROS) generation, NF-kappaB activation and interleukin (IL)-6 expression in TNF-alpha-exposed HUVEC. TNF-alpha significantly increased intracellular ROS generation, which was completely blocked by PEDF or diphenylene iodonium, an inhibitor of NADPH oxidase. Further, PEDF completely prevented the TNF-alpha-induced increase in NADPH oxidase activity. PEDF or an antioxidant, N-acetylcysteine, significantly inhibited the TNF-alpha-induced NF-kappaB activation. PEDF inhibited TNF-alpha-induced expression of IL-6 at both mRNA and protein levels. Moreover, TNF-alpha downregulated PEDF mRNA levels. Ligand blot analysis revealed that HUVEC possessed a membrane protein with binding affinity for PEDF. The results demonstrated that PEDF inhibited TNF-alpha-induced NF-kappaB activation and subsequent IL-6 overexpression in HUVEC by suppressing NADPH oxidase-mediated ROS generation. Our present study suggests that PEDF may play an important role in the development and progression of atherosclerosis.     

检测2型糖尿病患者血浆同型半胱氨酸水平的临床意义探讨

目的 探讨2型糖尿病(DM)患者血浆同型半胱氨酸(HCY)水平及意义。方法 用化学发光法对55例肾功正常的2型DM患者[DM组,其中无肾病38例、早期糖尿病肾病17例(DN)例]及51例健康人(对照组)的血浆HCY水平进行测定比较,同时分析血浆HCY与DM患者年龄、病程、血压、血浆叶酸(Fol)、维生素B12、总胆固醇(CH)、肌酐(SCr)及尿白蛋白排泄率(UAER)之间的相关性。结果 DM组血浆HCY水平均较对照组明显升高(P<0.01),合并早期肾病者血浆HCY水平较无肾病者明显升高(P<0.05);DM患者血浆HCY水平与UAER及SCr呈显著正相关(P<0.05),与其他因素间无明显相关性。结论 糖尿病患者尤其是合并肾脏损害者血浆HCY明显升高,高HCY血症可能是DN发生发展的危险因素之一。     

Diabetic renal disease in African Americans

Diabetic nephropathy (DN) is the No. 1 cause of end-stage renal disease in the United States and is highly prevalent in African Americans. Almost all DN in African Americans is caused by type 2 diabetes. Glycemic control and control of blood pressure are essential to prolong renal survival and to protect against cardiovascular events. Among African Americans, diabetic nephropathy seems to affect women more than men, which may be related to increased rates of obesity and diabetes in African American women. In addition to gender, the development of albuminuria, family history, and possibly birth weight are factors that predict progression of renal disease in African Americans with DN. The impact of glycemic control, appropriate antihypertensives, and the optimal level of blood pressure control in African Americans with advanced DN require further study. This article will review the clinical characteristics, risk factors, predictors of disease progression, and treatment of diabetic nephropathy in African Americans.