Anemia and diabetic nephropathy

Anemia has recently been recognized as a frequent complication of diabetic nephropathy, appearing earlier than in nondiabetic renal disease and amplifying the risks of cardiovascular and microvascular complications. A major cause is an inappropriate erythropoietin response to anemia, often accompanied by iron de.-ciency and therapy with angiotensin-converting enzyme inhibitors and angiotensin receptor blockers.     

Lipids and diabetic nephropathy

Although several factors may mediate the development and progression of diabetic nephropathy, hyperlipidemia is now considered an independent and major determinant of progression of renal disease in diabetes. The following discussion focuses on the experimental evidence that incriminates hyperlipidemia as a pathogenic factor for diabetic nephropathy and the potential mechanisms that may mediate renal injury from hyperlipidemia, as well as the clinical studies involving therapeutic interventions for hyperlipidemia and their impact on progression of diabetic renal disease.     

巨噬细胞与糖尿病肾病

糖尿病肾病是一种慢性炎性疾病,而巨噬细胞是重要的炎性细胞,在糖尿病肾病的发生、发展中起重要作用.血液中的单核细胞在选择素、细胞间黏附分子-1(ICAM-1)、血管细胞黏附分子-1(VCAM-1)、单核细胞趋化蛋白-1(MCP-1)及骨桥蛋白等细胞黏附分子或趋化因子作用下经历滚动、黏附、迁移等过程,浸润于肾组织而分化成巨噬细胞,体内持续高血糖等因素使其活化,释放转化生长因子-β(TGF-β)、肿瘤坏死因子-α(TNF-α)、白细胞介素(IL)-1、IL-6、IL-18等细胞因子,促进肾小球系膜细胞分泌细胞外基质及成纤维细胞增殖,引起系膜细胞外基质沉淀、肾小球硬化及间质纤维化等肾损伤,从而促进糖尿病肾病的发展.调控巨噬细胞的浸润与活化可能是防治糖尿病肾病的新途径.     

表观遗传学与糖尿病肾病

表观遗传调控主要包括DNA甲基化、组蛋白修饰和微小RNA(miRNA)等.糖尿病肾病(DN)是糖尿病主要的慢性并发症之一.一些特定基因的启动子区甲基化水平异常,组蛋白乙酰化与去乙酰化及miRNA等都参与了DN的发生、发展.对表观遗传学与DN关系的研究,可为进一步认识和治疗DN提供一种新的途径.     

Inflammation and diabetic nephropathy

Diabetic nephropathy has become the main cause of renal failure, but unfortunately the intimate mechanisms leading to the development and progression of renal injury are not yet fully known. Activated innate immunity and inflammation are relevant factors in the pathogenesis of diabetes. Moreover, different inflammatory molecules, including chemokines, adhesion molecules, and proinflammatory cytokines, may be critical factors in the development of microvascular diabetic complications, including nephropathy. This new pathogenic perspective leads to important therapeutic considerations, with new pathogenic pathways becoming important therapeutic targets that can be translated into clinical treatments for diabetic nephropathy.     

Proteomics and diabetic nephropathy

Diabetes mellitus is acknowledged to be a group of metabolic diseases and heterogeneous in natural history, pathogenesis, response to treatment, and disease progression and remission. Diabetic nephropathy (DN) accounts for approximately 40% of all newly diagnosed cases of endstage renal disease. The complexity of diabetes and its complications requires a broad-based, unbiased, scientific approach such as proteomics. Recently, proteomics (the systematic analysis of protein identity, quantity, and function) has been applied to the study of DN. Proteomic investigations into diabetic kidney disease have identified new mechanisms of diabetic renal pathology, as well as potential urinary markers of DN. Other current proteomic advances in understanding DN include identifying the role of advanced glycation end products in decreased mitochondrial respiration and also the rapid development of mass spectrometric methods for protein and peptide markers of DN development and markers to pharmacologic therapies. Proteomic analysis has only recently been applied to the study of DN, yet it has shown substantial potential.     

水通道蛋白与糖尿病肾病

水通道蛋白即存在于细胞膜上的特异性水转运孔道,目前发现的水通道蛋白已有11种。有研究证明,在糖尿病中水通道蛋白-1,2,3的表达是上调的,这有助于防止糖尿病时机体溶质和水的进一步丢失。有学者认为糖尿病肾病中尿排泄水通道蛋白-2减少,这可能与集合管细胞对血管加压素应答的细胞信号转导途径受损有关,而且在糖尿病酮症酸中毒患者治疗期间,可以通过尿排泄水通道蛋白-2来估计循环血容量的恢复情况。     

C-C亚族趋化因子与糖尿病肾病

C—C亚族趋化因子大部分由激活的T细胞和单核细胞产生,主要包括单核细胞趋化蛋白（MCP）-1和正常T细胞活化后表达和分泌的调节蛋白（RANTES）。MCP-1和RANTES是单核／巨噬细胞的特异性趋化因子,在糖尿病肾病（DN）肾组织中表达增加。高水平的C—C趋化因子通过与其受体结合介导单核／巨噬细胞在肾组织的募集和分化,导致肾小球系膜细胞增生,细胞外基质积聚及肾小管纤维化。阻止C—C趋化因子表达将有可能为治疗DN开辟一条新的途径。     

Epac-Rap1与糖尿病肾病

Epac-Rap1通路是蛋白激酶A经典通路以外cAMP重要的效应通路,它在肾脏中的广泛表达,能够增强肾脏血管内皮细胞的屏障功能,影响细胞的连接、黏附和迁移,对肾脏的生理活动起到不可或缺的作用.近年研究表明,Epac-Rap1信号通路激活下游信号级联系统,通过促进细胞肥大、介导肾间质纤维化、上调炎性反应细胞因子的表达,促进糖尿病肾病的病理生理改变.相关研究为理解糖尿病肾病状态下Epac-Rap1通路的作用拓宽了视野,有助于发现分子水平治疗糖尿病肾病的新靶点.     

新的脂肪细胞因子与糖尿病肾病

Chemerin、visfatin、vaspin、视黄醇结合蛋白 4(RBP4 )是近几年新发现的脂肪细胞因子,它们参与体内物质和能量代谢、肥胖、胰岛素抵抗等病理生理过程. 目前许多研究发现,它们与糖尿病肾病关系密切,直接或间接参与了糖尿病肾病的病理生理过程.对这几种因子的深入研究将为糖尿病肾病的防治提供新的预测指标及治疗靶点.     

肾小管上皮细胞表型转化与糖尿病肾病

肾小管病变及肾间质纤维化在糖尿病肾病中的重要作用逐渐被认识,其中肾小管上皮细胞向间充质细胞转化(EMT)可能是其发挥作用的关键环节,与肾间质纤维化的程度相平行。在糖尿病肾病中引发EMT的因素主要有高血糖、晚期糖基化终末产物、蛋白尿、血管紧张素Ⅱ、结缔组织生长因子等。     

NADPH氧化酶与糖尿病肾病

还原型烟酰胺腺嘌呤二核苷酸磷酸(NADPH)氧化酶是许多非吞噬细胞中活性氧簇(ROS)产生的主要来源。生理情况下,NADPH氧化酶处于低表达与低活性状态,但在细胞因子、高糖、高脂等作用下,它能被激活,产生更高水平的ROS。ROS作为氧化应激的中心环节,参与糖尿病肾病病理生理过程。NADPH氧化酶通过其产生的ROS,可改变肾脏血液动力学、影响细胞外基质的重构、激活细胞内信号转导等,促进糖尿病肾病的发生、发展。调节酶复合物的活性以减弱肾脏的氧化应激,有望成为延缓肾功能损害的有效治疗措施。     

Haptoglobin phenotype and diabetic nephropathy

Abstract Aims/hypothesis. To determine if the haptoglobin 2 allele is associated with an increased risk for the development of diabetic nephropathy. Methods. This study included 110 consecutive normotensive subjects with Type I (insulin-dependent) diabetes mellitus and Type II (non-insulin-dependent) diabetes mellitus seen in two outpatient clinics in Israel. Diabetes duration was greater than 10 years for Type I diabetes and more than 5 years for Type II diabetic subjects. Microalbuminuria was defined as urinary protein excretion of 30 to 300 mg/24 h, and macroalbuminuria was defined as urinary protein excretion of greater than 300 mg/24 h. Serum was taken from subjects for haptoglobin typing by gel electrophoresis. Results. Of the participating subjects 54 had Type I and 56 had Type II diabetes. None (0/18) of the subjects homozygous for the haptoglobin 1 allele (1–1) showed any sign of diabetic nephropathy, as compared with 34 % (19/55) of subjects homozygous for the haptoglobin 2 allele (2–2) and 27 % (10/37) of heterozygous subjects (2–1) (p < 0.04). Of the subjects 29 showed macroalbuminuria. The risk of developing macroalbuminuria was found to be greater in subjects with two haptoglobin 2 alleles (22 %) (12/55) as compared with one haptoglobin 2 allele (8 %) (3/37) or no haptoglobin 2 alleles (0 %) (0/18) (p < 0.03). Conclusion/interpretation. By showing a graded risk relation to the number of haptoglobin 2 alleles in Type I and Type II diabetic subjects, these studies further support our hypothesis that the haptoglobin phenotype is a major susceptibility gene for the development of diabetic nephropathy. [Diabetologia (2001) 44: 602–604] Received in revised from: 5 January 2001     

Antihypertensive drugs and diabetic nephropathy

Diabetic nephropathy is the most common cause of endstage renal disease in the United States. Hypertension is a major risk factor that predisposes individuals with diabetes to the development of renal disease and is very common in patients with diabetes. The benefit of blood pressure control on the rate of progression of diabetic nephropathy is being increasingly demonstrated in both type 1 and type 2 diabetic patients. Angiotensin converting enzyme inhibitors have proven renoprotective benefits in human studies, but the results of studies with calcium channel blockers are somewhat inconclusive. The other classes of antihypertensives also may have certain indications in the population of patients with diabetic nephropathy. In this paper we will critically review current strategies for the treatment of hypertension in patients with established diabetic nephropathy.     

尿液蛋白质组学与糖尿病肾病

蛋白质组学是系统研究细胞或组织全套蛋白质生物学信息的科学,其中尿液蛋白质组学以其独特的优点广泛应用于基础和临床研究领域.糖尿病肾病是糖尿病最常见且危害巨大的并发症之一,许多学者运用尿液蛋白质组学分析方法对糖尿病肾病进行研究,发现了一些与糖尿病肾病相关的生物学标志及可能的发生机制,展示了尿液蛋白质组学技术在糖尿病肾病早期诊断、动态监测病情及发现新的治疗靶点方面的前景.