RACE, RENIN, GENES, RISK, AND DIABETIC NEPHROPATHY

非裔美国人罹患癌症的风险增加3-6倍 肾病作为糖尿病(DM)的并发症，必不可少 高血压(HTN)，可能还有其他情况。尽管增加了 HTN的频率和严重程度以及限制其发生的社会经济因素 医疗保健可能起到了作用，多项观察表明 更重要的替代因素也参与其中。字段测距 从流行病学和治疗试验到分子生物学和 遗传学研究表明，肾素-血管紧张素系统(RAS)在 通过包括但不限于以下机制的肾病风险 HTN，可能涉及RAS对生长和修复的贡献 增生和肥大。我们的应用程序基于几个 出乎意料的观察。首先，在健康的非裔美国人中，年龄- 调整后的肾脏血浆流量(RPF)显著低于 高加索人，以相同的方案进行评估。此外，尽管有很高的 盐饮食，非裔美国人表现出增强的肾脏血管扩张剂 对血管紧张素转换酶(ACE)抑制的反应 卡托普利增强肾血管对血管紧张素的反应 II(Ang II)。这种模式(这与在 与我们在患者中的初步观察结果类似 DM)提示RAS被激活。第二，在我们的非胰岛素中- 依赖的2型糖尿病患者，我们的初步数据表明 迄今未被识别的反映不适当的RAS异常 激活和自主释放肾素。最令人惊讶的是 2型糖尿病肾组织水平矛盾的RAS活性异常 血浆肾素活性(PRA)极低和肾病患者。 功能性贡献的证据来自血液动力学 在药物阻断RAS期间所做的测量 血管紧张素转换酶抑制剂和血管紧张素转换酶II拮抗剂，以及血管紧张素转换酶II输注期间。在……里面 2型糖尿病，种族是危险的关键决定因素。第三，我们取得了 观察表明，急性高血糖激活了 肾内系统和诱导打击血管紧张素Ⅱ依赖 血管收缩。我们的假设是，风险的增加 肾病代表了遗传易感性之间的相互作用 基于血管紧张素原(AGT)基因频率的增加 有利于肾素系统激活的多态性，这是肥胖的一种行为 和胰岛素抵抗，以放大多态对AGT的影响； 以及高血糖激活肾内系统的肾脏效应 在有利于本地肾内血管紧张素II生产的环境中。我们的 本研究的目标是探索RAS的初步证据 激活解释了许多涉及肾脏风险的2型糖尿病特征， 以及风险方面的种族差异。

African Americans carry a 3-6 fold increased risk of developing nephropathy as a complication of diabetes mellitus (DM), essential hypertension (HTN), and probably other conditions. Although an increased frequency and severity of HTN and socioeconomic factors that limit health care probably contribute, multiple observations indicate that more important alternative factors are also involved. Fields ranging from epidemiology and therapeutic trials to molecular biology and genetics indicate that the renin-angiotensin system (RAS) contributes to the risk of nephropathy via mechanisms that include but go beyond HTN, perhaps involving the contribution of the RAS to growth and repair hyperplasia, and hypertrophy. Our application is based on several unanticipated observations. First, in healthy African Americans, age- adjusted renal plasma flow (RPF) was substantially less than in Caucasians, assessed in an identical protocol. Moreover, despite a high salt diet, African Americans displayed an enhanced renal vasodilator response to angiotensin-converting enzymic (ACE) inhibition with captopril, which enhanced renal vascular responsiveness to angiotensin II (Ang II). This pattern (which clearly differs from that in Caucasians and is similar to our preliminary observations in patients with DM) suggests activation of the RAS. Second, in our non-insulin- dependent Type 2 DM patients, our preliminary data suggest a range of hitherto unrecognized RAS abnormalities reflecting inappropriate activation and autonomous renin release. Most surprising is the paradoxical extreme RAS activation at the renal tissue level Type 2 DM patients with very low plasma renin activity (PRA) and nephropathy. Evidence for a functional contribution comes from hemodynamic measurements made during pharmacological interruption of the RAS with ACE inhibitors and Ang II antagonists, and during Ang II infusion. In Type 2 DM, race is a critical determinant of risk. Third, we have made observations which indicate that acute hyperglycemia activates the intrarenal system and induces striking Ang II-dependent vasoconstriction. Our hypothesis is that the increase in risk of nephropathy represents an interaction between genetic predisposition based on the increased frequency of an angiotensinogen (AGT) gene polymorphism that favors renin system activation, an action of obesity and insulin resistance to amplify the effect of the polymorphism on AGT; and the renal effects of hyperglycemia to activate the intrarenal system in a setting which would favor local intrarenal Ang II production. Our goal in this study is to explore preliminary evidence that RAS activation accounts for many Type 2 DM features involving renal risk, and racial differences in risk.