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.
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.
