Nicotine and Chronic Kidney Disease

尼古丁与慢性肾脏病

• 批准号: 7524184
• 负责人: EDGAR A JAIMES
• 金额: $ 56.74万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-20 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7524184
• 关键词: Affect; Angiotensin II; Animal Model; Animals; Arts; Atherosclerosis; Biological Assay; Blood Vessels; Cell Proliferation; Chronic Kidney Failure; Clinical; Clinical Research; Collagen Type IV; Cyclins; Dahl Hypertensive Rats; Data; Deposition; Diabetes Mellitus; Dialysis procedure; End stage renal failure; Extracellular Matrix; Extracellular Matrix Proteins; Fibronectins; Goals; Growth; Human; Hypertension; Immunohistochemistry; In Vitro; Incidence; Individual; Injury; Kidney; Lung diseases; Mediating; Mediator of activation protein; Modeling; Molecular Biology; Molecular Biology Techniques; Morbidity - disease rate; National Health and Nutrition Examination Survey; Neuraxis; Nicotine; Outcome; Pathogenesis; Pathway interactions; Patients; Play; Population; Prevalence; Preventive; Process; Production; Property; Prostaglandin-Endoperoxide Synthase; Prostaglandins; Proteinuria; Public Health; Pulmonary Hypertension; Reactive Oxygen Species; Renal glomerular disease; Research; Risk; Risk Factors; Role; Signal Transduction; Smoke; Smoker; Source; Techniques; Testing; Therapeutic; Tissues; Tobacco; United States; Vascular Endothelium; Vascular Smooth Muscle; Work; base; cancer type; cardiovascular risk factor; cell growth; cigarette smoking; cigarette smoking; cost; cyclooxygenase 2; diabetic; experience; hemodynamics; in vivo; lung vascular injury; mesangial cell; mortality; non-diabetic; novel strategies; prevent; public health relevance; receptor; response; salt sensitive; vasculogenesis

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.

描述（由申请人提供）：在美国，吸烟已被确定为可预防发病率和死亡率的最重要原因，这表明，除了是重要的心血管风险外，吸烟还成为糖尿病患者和肾小球疾病患者的慢性肾脏病（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。尼古丁已被提议作为香烟烟雾中的化合物，可能在吸烟者的血管和肺损伤的发病机理中起作用。我们在这里假设尼古丁是一种稳定的烟烟，在香烟烟雾中以大量烟雾存在，可以通过特定的尼古丁受体促进肾小球细胞增殖和细胞外基质（ECM）沉积来加速CKD的进展，并导致涉及细胞生长和损伤的途径激活。我们将通过追求以下特定目的1：确定尼古丁暴露是慢性肾脏疾病进展中的危险因素的作用来检验这一假设。该目标的假设是，尼古丁在盐敏感高血压动物模型中加速了CKD的进展，这通过增加ECM蛋白（例如纤连蛋白质和IV型胶原蛋白）的沉积而与肾损伤相关。我们还将确定尼古丁引起的血液动力学变化对这些作用的作用以及尼古丁受体在这些动物肾脏中的分布和表达。我们将利用几种药理阻滞剂使用一种全面的方法来评估尼古丁对盐敏感高血压模型的肾脏损伤的影响；目标2：确定ROS和COX-2衍生的前列腺素对尼古丁在肾损伤中的影响的作用。该目标的假设是，活性氧（ROS）和COX-2衍生的前列腺素是尼古丁诱导的肾脏损伤在盐敏感高血压中的影响的重要介体。这些研究将在DAHL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结合，以评估Cox-2衍生的前列腺素和ROS在尼古丁诱导的肾损伤方面的作用；目标3：建立介导细胞增殖和ECM沉积的信号转导机制，以响应尼古丁。该目标的假设是尼古丁激活了与细胞增殖和基质产生有关的几种途径，包括PKC激活，CRE和SRC/RAF-1/MAPK/Cyclins。这些研究将在人类的细胞细胞中，利用艺术分子生物学技术的结合。公共卫生相关性这些研究将决定尼古丁作为慢性肾脏疾病进展的危险因素的作用，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脏损伤的有害影响的机制。这些研究将确定尼古丁是香烟烟雾的重要组成部分，在伴有肾脏损伤的高血压动物模型中肾脏损伤。我们将使用各种最先进的技术来评估尼古丁诱导肾脏损伤的机制。