Nicotine and Chronic Kidney Disease

描述（由申请人提供）：在美国，吸烟已被确定为可预防的发病率和死亡率的最重要原因。最近的临床研究表明，吸烟除了是一个重要的心血管风险外，也是糖尿病、高血压和肾小球疾病患者慢性肾脏疾病（CKD）进展的重要风险。吸烟促进慢性肾脏疾病进展的机制尚未阐明。尼古丁被认为是香烟烟雾中的一种化合物，可能在吸烟者血管和肺损伤的发病机制中起作用。我们在此假设尼古丁是香烟烟雾中大量存在的稳定产物，通过特定尼古丁受体促进系膜细胞增殖和细胞外基质（ECM）沉积，并导致参与细胞生长和损伤的途径激活，从而加速CKD的进展。我们将通过以下具体目标来验证这一假设：1 .确定尼古丁暴露在慢性肾脏疾病进展中的风险因素。这一目的的假设是，尼古丁通过增加ECM蛋白（如纤维连接蛋白和IV型胶原）的沉积，加速了与肾损伤相关的盐敏感性高血压动物模型中CKD的进展。我们还将确定尼古丁引起的血流动力学变化在这些影响中的作用以及这些动物肾脏中尼古丁受体的分布和表达。我们将采用一种综合的方法，利用几种药物阻滞剂来评估尼古丁对盐敏感性高血压模型中肾损伤的影响；目的2：确定ROS和COX-2衍生前列腺素在尼古丁肾损伤中的作用。这一目的的假设是活性氧（ROS）和COX-2衍生的前列腺素是盐敏感性高血压患者尼古丁诱导肾损伤的重要介质。这些研究将在达尔盐敏感大鼠中进行，并利用生物测定、分子生物学和免疫组织化学技术的组合来评估COX-2衍生的前列腺素和ROS在尼古丁诱导的肾损伤中的作用；目的3：建立尼古丁对细胞增殖和ECM沉积的信号转导机制。这一目标的假设是尼古丁激活了参与细胞增殖和基质产生的几种途径，包括PKC激活、cre和Src/Raf-1/MAPK/细胞周期蛋白。这些研究将在人类系膜细胞中进行，利用最先进的分子生物学技术的组合。这些研究将确定尼古丁作为慢性肾脏疾病进展中的危险因素的作用，并将确定所涉及的机制。这些研究将揭示可能解释吸烟对肾损伤有害影响的机制。这些研究将确定尼古丁（香烟烟雾的重要成分）在伴有肾损伤的高血压动物模型中对肾损伤的作用。我们将使用各种最先进的技术来评估尼古丁诱导肾损伤的机制。

DESCRIPTION (provided by applicant): Cigarette smoking has been identified as the most important cause of preventable morbidity and mortality in the U.S. Recent clinical studies suggest that in addition to being an important cardiovascular risk, cigarette smoking is also an important risk for the progression of chronic kidney disease (CKD) in diabetics, hypertensives and patients with glomerular diseases. The mechanisms by which cigarette smoking promotes the progression of chronic kidney disease have not been elucidated. Nicotine has been proposed as a compound in cigarette smoke that may play a role in the pathogenesis of vascular and lung injury in smokers. We herein hypothesize that nicotine, a stable product present in large amounts in cigarette smoke, accelerates the progression of CKD by promoting mesangial cell proliferation and extracellular matrix (ECM) deposition via specific nicotine receptors and resulting in the activation of pathways involved in cell growth and injury. We will test this hypothesis by pursuing the following specific Aim 1: To identify the role of nicotine exposure as a risk factor in the progression of chronic kidney disease. The hypothesis for this aim is that nicotine accelerates the progression of CKD in animal model of salt sensitive hypertension that is associated with renal injury by increasing the deposition of ECM proteins such as fibronectin and type IV collagen. We will also determine the role of nicotine induced hemodynamic changes on these effects and the distribution and expression of nicotine receptors in the kidneys of these animals. We will use a comprehensive approach utilizing several pharmacologic blockers to assess the effects of nicotine on renal injury in a well validated model of salt sensitive hypertension; Aim 2: To identify the role of ROS and COX-2 derived prostaglandins on the effects of nicotine in renal injury. The hypothesis for this aim that reactive oxygen species (ROS) and COX-2 derived prostaglandins are important mediators of the effects of nicotine induced renal injury in salt sensitive hypertension. These studies will be performed in Dahl salt sensitive rats and utilizing a combination of bioassays, molecular biology and immunohistochemistry techniques to assess the role of COX-2 derived prostaglandins and ROS on nicotine induced renal injury; Aim 3: To establish the signal transduction mechanisms mediating cell proliferation and ECM deposition in response to nicotine. The hypothesis for this aim is that nicotine activates several pathways involved in cell proliferation and matrix production including PKC activation, CREs, and Src/Raf-1/MAPK/cyclins. These studies will be performed in human mesangial cells utilizing a combination of state of the art molecular biology techniques. PUBLIC HEALTH RELEVANCE These studies will determine the role of nicotine as a risk factor in the progression of chronic kidney disease and will identify the mechanisms involved. These studies will unveil mechanisms that may explain the deleterious effects of cigarette smoking on renal injury. These studies will determine the role of nicotine, an important component of cigarette smoke, on kidney damage in an animal model of high blood pressure that is accompanied by kidney injury. We will use a variety of state of the art techniques to assess the mechanisms by which nicotine induces renal injury.