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的发病和死亡的最重要原因。最近的临床研究表明，除了重要的心血管风险外，吸烟还是糖尿病患者、高血压患者和肾小球疾病患者慢性肾病 (CKD) 进展的重要风险。吸烟促进慢性肾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发挥作用。我们在此假设尼古丁是一种在香烟烟雾中大量存在的稳定产物，它通过特定的尼古丁受体促进系膜细胞增殖和细胞外基质（ECM）沉积，并导致细胞生长和损伤相关途径的激活，从而加速 CKD 的进展。我们将通过追求以下具体目标 1 来检验这一假设：确定尼古丁暴露作为慢性肾病进展危险因素的作用。该目标的假设是，尼古丁通过增加纤连蛋白和 IV 型胶原蛋白等 ECM 蛋白的沉积，加速盐敏感性高血压动物模型中 CKD 的进展，而肾损伤与肾损伤相关。我们还将确定尼古丁引起的血流动力学变化对这些影响的作用以及尼古丁受体在这些动物肾脏中的分布和表达。我们将采用一种综合方法，利用几种药理阻滞剂，在经过充分验证的盐敏感性高血压模型中评估尼古丁对肾损伤的影响；目标 2：确定 ROS 和 COX-2 衍生的前列腺素对尼古丁肾损伤影响的作用。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盐敏感性高血压肾损伤影响的重要介质。这些研究将在 Dahl 盐敏感大鼠中进行，并结合生物测定、分子生物学和免疫组织化学技术来评估 COX-2 衍生的前列腺素和 ROS 对尼古丁诱导的肾损伤的作用；目标 3：建立响应尼古丁介导细胞增殖和 ECM 沉积的信号转导机制。该目标的假设是，尼古丁激活涉及细胞增殖和基质生成的多种途径，包括 PKC 激活、CRE 和 Src/Raf-1/MAPK/细胞周期蛋白。这些研究将结合最先进的分子生物学技术在人类系膜细胞中进行。公众健康相关性 这些研究将确定尼古丁作为慢性肾病进展危险因素的作用，并确定所涉及的机制。这些研究将揭示可能解释吸烟对肾损伤的有害影响的机制。这些研究将确定尼古丁（香烟烟雾的重要成分）对伴有肾损伤的高血压动物模型的肾损伤的作用。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。