糖尿病大鼠肾组织中核因子-kB调控单核细胞趋化蛋白-1表达作用的研究

糖尿病肾病(DN)是糖尿病(DM)最常见的慢性并发症之一,发病机制十分复杂，至今仍未完全阐明。被多数学者认可的病因有：高糖一蛋白激酶C(PKC)途径、蛋白质的非酶糖化一晚期糖化终产物(AGEs)途径、醛糖还原酶(AR)-多元醇途径、氧化应激(oxidativestress，OS)途径一，以及局部肾素血管紧张素系统(RAS)等。     

贝那普利联合缬沙坦治疗糖尿病肾病蛋白尿的疗效观察

我国成人糖尿病患病率为11.6％,仅25.8％的患者接受治疗,其中仅39.7％的患者血糖控制良好[1].由于大部分糖尿病患者治疗不正规,导致糖尿病肾病（DN）发生率逐年增高,且成为终末期肾病的主要原因[2].因此,及时有效地阻断DN进一步发展具有重要意义.近来研究结果表明[3],肾素-血管紧张素（RAS）系统在DN的发生发展中起着重要作用,阻断RAS系统可延缓DN的进行性加重[4].我们对应用贝那普利联合缬沙坦治疗糖尿病肾病蛋白尿的临床疗效进行观察.     

析因设计评价血管紧张素转换酶抑制剂与血管紧张素Ⅱ1型受体拮抗剂单用及联用治疗不同分期糖尿病肾病的效果

糖尿病肾病(DN)的早期干预可望逆转肾功能.肾素-血管紧张素系统(RAS)参与了DN的发生发展,血管紧张素转换酶抑制剂(ACEI)和血管紧张素Ⅱ(AngⅡ)1型受体拮抗剂(ARB)分别阻断RAS的不同环节发挥肾功能保护作用.本研究采用2×3析因设计分别观察DN不同分期以及RAS单纯阻断和双重阻断的干预效果.     

肾素-血管紧张素系统与糖尿病肾病

肾素-血管紧张素系统（renin—angiotensin system，RAS）在调节机体血压、维持内环境稳定等发面发挥重要作用。过去30年中大量的基础和临床试验均表明RAS过度激活是糖尿病肾病（diabeticDie—phropathy，DN）等肾脏疾病发生发展的重要机制之一，抑制RAS成为DN治疗的一个有效途径。随着肾素抑制剂、肾素／肾素原．肾素／肾素原受体轴、血管紧张素转化酶2（ACE2）-Ang1～7-Mas轴等RAS新成员的发现，RAS原有的一些概念正在不断更新和完善，本文着重介绍了RAS与DN有关最新进展。     

肾素抑制剂研究新进展

近年来大量研究证实,抑制肾素血管紧张素系统(renin angiotensin system, RAS)对治疗心血管疾病、肾脏疾病及糖尿病并发症等具有良好的效果.众所周知,经典的RAS通过以下途径激活:血管紧张素原在肾素作用下生成无活性的十肽:血管紧张素Ⅰ,后者经血管紧张素转换酶(ACE)催化形成具有活性的八肽:血管紧张素Ⅱ,过度激活RAS产生的血管紧张素Ⅱ将主要通过血管紧张素Ⅱ受体1型(AT1R)产生高血压及靶器官损害.     

胰高血糖素与2型糖尿病及其肾病的关系

胰高血糖素是调控糖代谢平衡的重要激素之一,血清胰高血糖素的异常升高与2型糖尿病的起始和进展相关.糖尿病肾病是糖尿病常见的微血管并发症之一,胰高血糖素及其受体信号系统可能在它的发生、发展中发挥重要作用.其可能机制是通过cAMP、一氧化氮和前列腺素等诱导肾小球高滤过,通过增加DNA和蛋白质的合成诱导系膜细胞的增生、肥大,并可与肾素-血管紧张素系统(RAS)相互作用,最终引起肾小球损伤.胰高血糖素及其受体可作为治疗2型糖尿病及其肾脏并发症的靶点.     

血管紧张素转化酶基因多态性与糖尿病血管并发症

肾素 -血管紧张素系统 (RAS)是心血管主要的调节系统 ,血管紧张素转化酶 (ACE)基因存在I/D多态性 ,该序列决定了血清中ACE的水平。ACEI/D多态性与糖尿病患者缺血性心脏病的发生存在相关性 ,与视网膜病变的发生无关 ,而ACEI/D多态性与糖尿病肾病、血管性疾病的相关性尚存在争论。因此 ,明确ACE多态性与糖尿病的关系尚需进行更大规模的人群前瞻性研究。     

脂肪组织局部肾素-血管紧张素系统的调节及其在糖尿病中的作用

脂肪组织局部存在肾素-血管紧张素系统(RAS)中几乎所有的组分,这些组分不仅构成局部RAS,而且是循环中RAS各成分的重要来源.多种因素包括肥胖、胰岛素等均可以影响脂肪组织中RAS各成分的表达.脂肪组织局部RAS活性增加,可作用于脂肪细胞,抑制脂肪细胞分化及脂质代谢,并影响脂肪细胞因子分泌,同时血管紧张素可作用于周围组织,通过加重炎性反应和氧化应激等途径,导致胰岛素抵抗,参与糖尿病的病理过程.     

Chymase与糖尿病心肌病变

Chymase是一种糜蛋白酶样丝氨酸蛋白酶,人类心脏中Chymase具有生成血管紧张素Ⅱ(AngⅡ)的生物学活性.研究发现,在冠状动脉粥样硬化、心室肥厚、心肌纤维化等病理状态下,Chymase的表达和活性明显增高.糖尿病心肌病变表现为循环和心脏局部肾素-血管紧张素系统(RAS)的过度激活,Chymase可能通过促进AngⅡ生成、诱发炎症反应、调节胶原代谢等途径参与糖尿病心肌病变的发生和发展,抑制Chymase的表达或活性对糖尿病心肌病变可能具有治疗价值.     

局部肾素-血管紧张素系统与糖尿病肾病

RAS在糖尿病肾病(DN)发生发展中的作用是确切的,特别是肾脏局部的RAS.肾脏存在RAS的所有成分,包括:肾素(renin)、血管紧张素原(angiotensinogen、AGT)、血管紧张素Ⅰ(AngⅠ)、血管紧张素Ⅱ(AngⅡ)、ACE、血管紧张素Ⅱ1型(ATl)受体.本文将会探讨DN时此系统各个成份的变化.     

Microalbuminuria in type 1 and type 2 diabetes mellitus: evidence with angiotensin converting enzyme inhibitors and angiotensin II receptor blockers for treating early and preventing clinical nephropathy

A cumulative incidence of diabetic nephropathy of 25% to 40% has been documented after duration of diabetes of at least 25 years in both type 1 and type 2 diabetic patients. Diabetic nephropathy has become the leading cause (25%-44%) of end-stage renal failure in Europe, the United States, and Japan. Until the early 1980s, no renoprotective treatment was available for use in diabetic nephropathy. Death occurred on average 5 to 7 years after the onset of persistent proteinuria. The two main treatment strategies for prevention of diabetic nephropathy are improved glycemic control and blood pressure lowering, particularly using drugs blocking the reninangiotensin system. Megatrials and meta-analyses have clearly demonstrated the beneficial effect of both the above-mentioned treatment modalities. Secondary prevention, that is, treatment modalities applied to diabetic patients at high risk for developing diabetic nephropathy (eg, those with microalbuminuria) has been documented, applying angiotensin converting enzyme inhibitors and angiotensin II receptor blockade. The renoprotective effects of these drugs are independent of their beneficial reduction in blood pressure.     

Renin-angiotensin system in diabetic nephropathy

The importance of the renin angiotensin system (RAS) in the development and progression of the diabetic nephropathy is confirmed with the recent demonstration that the development of nephropathy in the diabetic patients can be avoided by blockers of the RAS. For that reason, the promotion of preventive programs for the detection of microalbuminuria, from the early phases of the diabetes is needed. Control of blood pressure, of glucose and lipids are needed. If microalbuminuria is present, the administration of a blocker of RAS, even in the presence of normal blood pressure can prevent the progression to diabetic nephropathy. The main objective to prevent the development and progression of nephropathy in the diabetic patients, as well as the cardiovascular risk, is a strict control of the PA.     

Do agents that block the RAS truly offer renoprotective effects in early stage, nonproteinuric nephropathy?

Clinical practice guidelines from many professional societies endorse renin-angiotensin system (RAS) antagonists as first-line antihypertensive agents in diabetes and chronic kidney disease, largely based on putative renoprotective properties that may be blood pressure (BP) independent. To evaluate the relevance of these recommendations to early stage, nonproteinuric nephropathy, studies of primary and secondary prevention of kidney disease were reviewed. Primary prevention studies were reviewed only for diabetic populations. Secondary prevention studies included hypertensive and normotensive, and diabetic and nondiabetic patients with microalbuminuria or low glomerular filtration rate. Overall, use of RAS antagonists as first-line agents does not appear to be as important as control of BP. To achieve protective levels of BP, multiple antihypertensive agents are usually required. Long-term studies with clinically relevant outcomes (death and loss of kidney function) are needed to clarify whether specific agents provide benefits beyond that of BP control in early stage, nonproteinuric nephropathy.     

Of the renin-angiotensin system and reactive oxygen species Type 2 diabetes and angiotensin II inhibition

Rates of type 2 diabetes mellitus are increasing worldwide at an explosive rate. This "epidemic" is largely driven by a concomitant obesity epidemic, which is seen not only in affluent countries, but in industrializing countries as well, concomitant with the rapid change toward Western life-style patterns worldwide. Recent clinical trials such as Heart Outcomes Prevention Evaluation (HOPE), Losartan Intervention for Endpoint reduction (LIFE), and Study of Cognition and Prognosis in the Elderly (SCOPE) have indicated that blocking the renin-angiotensin system (RAS) may reduce the risk of developing type 2 diabetes mellitus. This effect may be explained by a variety of diabetogenic factors, which seem to be moderated by angiotensin II, such as free fatty acids (FFA) and the phenomena of adipocyte differentiation, as well as inflammation and oxidative damage. Insulin resistance, usually present in cases of impaired glucose tolerance, is the major identifiable defect in subjects at risk for type 2 diabetes. Elevated FFA levels result in reduced activation of phosphoinositol-3 kinase, an enzyme that is essential for normal insulin-stimulated glucose uptake. This reduction is potentiated by angiotensin II and consequently insulin-stimulated glucose uptake is improved by RAS inhibition. Furthermore, blockade of the angiotensin II AT(1)-receptor has been shown to stimulate the differentiation of adipocytes that store FFAs, which leads to reduced plasma FFA levels and decreased insulin resistance. There are also data suggesting that AT(1)-receptor blockade reduces inflammatory activation and the production of reactive oxygen species (ROS), a major factor in the pathophysiology of diabetes and a major cardiovascular risk factor. Both proinflammatory molecules and ROS increase the risk of insulin resistance and atherogenesis. It is thought that FFAs and hyperglycemia increase ROS production and oxidative stress, leading to the activation of signaling molecules such as nuclear factor kappa-B and other mediators of stress-sensitive pathways, which increases insulin resistance and will lead to beta-cell dysfunction and diabetic complications during the longer term. Inhibiting the RAS seems to have an effect on several steps in this cascade. There is an obvious need for large-scale clinical trials specifically designed to assess the protective benefits of blocking the RAS in individuals at risk of developing type 2 diabetes. Two such trials on the prevention of type 2 diabetes are ongoing, the Diabetes Reduction Assessment with Ramipril and Rosiglitazone Medications (DREAM) study and the more ambitious Nateglinide and Valsartan in Impaired Glucose Tolerance Outcomes Research (NAVIGATOR) trial, which is also assessing prevention of cardiovascular events.     

Treatment of diabetic nephropathy in its early stages

Diabetic nephropathy is one of the most frequent causes of end-stage renal disease (ESRD), and, in recent years, the number of diabetic patients entering renal replacement therapy has dramatically increased. The magnitude of the problem has led to numerous efforts to identify preventive and therapeutic strategies. In normoalbuminuric patients, optimal glycemic control (HbA(1c) lower than 7.5%) plays a fundamental role in the primary prevention of ESRD [weighted mean relative risk reduction (RRR) approximately 37% for metabolic control versus trivial renoprotection for intensive anti-hypertensive therapy or ACE-inhibitors (ACE-I)]. In the microalbuminuric stage, strict glycemic control probably reduces the incidence of overt nephropathy (weighted mean RRR approximately 50%), while blood pressure levels below 130/80 mmHg are recommended according to the average blood pressure levels obtained in various studies. In normotensive patients, ACE-I markedly reduce the development of overt nephropathy almost regardless of blood pressure levels; in hypertensive patients, ACE-I are less clearly active (weighted mean RRR approximately 23% versus other drugs), whereas angiotensin-receptor blockers (ARB) appear strikingly renoprotective. Once overt proteinuria appears, it is uncertain whether glycemic control affects the progression of nephropathy. In type 1 diabetes, various anti-hypertensive treatments, mainly ACE-I, are effective in slowing down the progression of nephropathy; in type 2 diabetes, two recent studies demonstrate that ARB are superior to conventional therapy or calcium channel blockers (CCB). In clinical practice, pharmacological tools are not always used to the best benefit of the patients. Therefore, clinicians and patients need to be educated regarding the renoprotection of drugs inhibiting the renin-angiotensin system (RAS) and the overwhelming importance of achieving target blood pressure.     

Association of the renin-angiotensin system gene polymorphism with nephropathy in type II diabetes

Diabetic nephropathy is the most frequent cause of end-stage renal failure. One of the crucial factors in a development of renal and cardiovascular complications of diabetes is genetic predisposition. The genes of the renin-angiotensin system are important group of candidate genes involved in pathogenesis of chronic renal diseases. The purpose of our study was the evaluation of a possible role of genetic polymorphisms of some of the RAS system genes in the nephropathy in type 2 diabetes. The study was performed in 117 patients with diabetic nephropathy, compared with 200 healthy subjects as a control group. The following polymorphisms: insertion/deletion (I/D) of the angiotensin-converting enzyme gene (ACE), M235T of the angiotensinogen gene (AGT) and A1166C of the angiotensin II type 1 receptor gene (AT1R) were evaluated by polymerase chain reaction (PCR). No statistically significant differences between groups were found in the allele frequency and genotype distribution for ACE and AGT polymorphisms. The results for the AT1R gene polymorphism revealed significant differences in allele and genotype frequencies. The homozygous CC genotype was more frequent in patients with diabetic nephropathy than in control group. Both genotypes with the C allele (AC + CC) were found in 56% of patients compared to 38% in control group. These results suggest increased susceptibility to diabetic nephropathy in individuals carrying the CC genotype. Therefore, the A1166C polymorphism of the AT1R gene could be a potential genetic marker for increased susceptibility to renal complications in type 2 diabetes.     

Ace inhibition and cardiovascular mortality and morbidity in essential hypertension: The end of the search or a need for further investigations?

Scientific evidence currently available supports the concept that renin-angiotensin blockade with angiotensin converting enzyme inhibitors as a first-line treatment exhibits in arterial hypertension beneficial effects in the prevention of mortality and morbidity comparable to those achieved with diuretics and β-blockers. In addition, the renin-angiotensin blockade has also proved to be beneficial in the secondary prevention of several complications of hypertensive disease such as after myocardial infarction and congestive heart failure, as well as in the prevention of the incidence of type 2 diabetes, and the progression of diabetic and nondiabetic nephropathy. In this later regard, recent evidence with angiotensin II receptor antagonists in reducing the progression of nephropathy in type 2 diabetes strongly confirms that antagonism of the renin-angiotensin system is an effective approach to cardiovascular and renal disease. Finally, the renin-angiotensin blockade in high-risk patients may reduce cardiovascular mortality independently of the effect on blood pressure (BP). The effect of other antihypertensive drugs on cardiovascular risk in patients with high-normal BP should be investigated to establish whether they exhibit a comparable effect or whether there is a class-related benefit of drugs blocking the renin-angiotensin system. Such a strategy could also be encouraged to design future interventional studies with the newer classes of compounds (angiotensin II AT₁-receptor antagonists, vasopeptidase inhibitors, endothelin antagonists), which would have the additional potential advantage of providing information more easily transferable to large-scale clinical practice.     

Nephropathy in type 2 diabetes

End-stage renal failure (ESRF) in diabetic patients, mostly type 2, has become the most frequent cause of renal replacement therapy in western Europe. The majority of patients with type 2 diabetes and renal failure suffer from diabetic glomerulosclerosis, but nondiabetic renal disease and atypical presentations, e.g. as irreversible acute renal failure or ischaemic nephropathy, play an increasingly important role. Known risk factors for the onset of diabetic nephropathy include (1) genetic predisposition (indicated by a history of hypertension and cardiovascular events in first-degree relatives), (2) quality of glycaemic control, (3) level of blood pressure, and (4) smoking. At the time when type 2 diabetes is diagnosed, an abnormal blood pressure profile is found in approximately 80%. In patients with established diabetic nephropathy, hypertension is the most important factor which promotes progression, and this is susceptible to intervention. Although less data are available for type 2 diabetes (compared with type 1 diabetes), ACE inhibitors appear to be the antihypertensive agent of first choice, but monotherapy is rarely sufficient to achieve the blood pressure goal. Although, at least in principle, diabetic nephropathy is a preventable condition, currently only a minority of type 2 diabetic patients in western Europe receives adequate medical treatment to prevent onset or progression of diabetic nephropathy. Consequently, novel approaches to patient management and interdisciplinary interaction are necessary to fulfil the postulate of the St Vincent declaration concerning prevention of diabetic complications.     

Antiproteinuric effect of RAS blockade: New mechanisms

Experimental and clinical studies have shown that blockade of the renin-angiotensin system (RAS) is effective in reducing proteinuria in conditions such as diabetes by reducing systemic and intraglomerular hydrostatic pressure. However, increasing evidence suggests that nonhemodynamic effects, such as preservation of the podocyte slit diaphragm structure and function, may also mediate the antiproteinuric effects of RAS blockade. In this review, we analyze in detail the evidence for known and novel mechanisms considered to play important roles in mediating the antiproteinuric effect of RAS blockers, with a particular focus on diabetic nephropathy.     

Polymorphisms in the gene encoding angiotensin I converting enzyme 2 and diabetic nephropathy

Aims/hypothesis Substantial evidence exists for the involvement of the renin–angiotensin system (RAS) in diabetic nephropathy. Angiotensin I converting enzyme 2 (ACE2), a new component of the RAS, has been implicated in kidney disease, hypertension and cardiac function. Based on this, the aim of the present study was to evaluate whether variations in ACE2 are associated with diabetic nephropathy.Materials and methods We used a cross-sectional, case–control study design to investigate 823 Finnish type 1 diabetic patients (365 with and 458 without nephropathy). Five single-nucleotide polymorphisms (SNPs) were genotyped using TaqMan technology. Haplotypes were estimated using PHASE software, and haplotype frequency differences were analysed using a ²-test-based tool.Results None of the ACE2 polymorphisms was associated with diabetic nephropathy, and this finding was supported by the haplotype analysis. The ACE2 polymorphisms were not associated with blood pressure, BMI or HbA₁c.Conclusions/interpretation In Finnish type 1 diabetic patients, ACE2 polymorphisms are not associated with diabetic nephropathy or any studied risk factor for this complication. Further studies are necessary to assess a minor effect of ACE2.Electronic Supplementary Material Supplementary material is available for this article at .