Grant: Operating Grant

Statement of the health problem: Obesity and diabetes mellitus are growing health care problems, and both are risk factors for heart disease and stroke. Diabetic nephropathy further increases cardiovascular risk, and recent studies show that diabetic nephropathy is rising along with the number of new cases of diabetes. Objective: Diabetic nephropathy is a consequence of the effects of high glucose concentrations on kidney cells including activation of the renin angiotensin system (RAS). The objective of the current proposal is to better understand how obesity contributes to the onset and progression of diabetic nephropathy. Studies will test the hypothesis that changes in proteins produced by fat cells influence the susceptibility of the kidney to high glucose-induced and RAS-induced kidney injury. We expect to establish that the kidney is an unexpected but important target tissue for the fat-derived protein, adiponectin. Blood levels of adiponectin decline with obesity, and we believe that adiponectin protects the kidney from injury. Our preliminary data shows that adiponectin can lessen the response of kidney cells to high glucose and activation of the RAS, and that loss of the gene for adiponectin is associated with increased diabetic kidney injury in mice. Experimental Plan: In order to test our hypothesis that adiponectin protects the kidney from the harmful effects of glucose and activation of the RAS, we will study cultured kidney cells from the kidney, and determine if adiponectin can reduce the response of these cells to glucose and the RAS. The cellular studies will provide the basis for examining the effect of deletion of the genes for adiponectin on the onset and progression of diabetic nephropathy and kidney injury due to activation of the RAS in mice. We will then determine if treatment with adiponectin will lessen diabetic nephropathy and kidney injury due to activation of the RAS in mice.