Adenosine 2A Receptor Agonist in Diabetic Nephropathy

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DESCRIPTION (provided by applicant): Activation of inflammatory pathways within the kidney tissue is one of the pathogenic mechanisms in the development of diabetic nephropathy. Activation of adenosine A2A receptors (A2ARs) reduces inflammation. In animal models of acute renal injury, administration of ATL146e, a selective A2AR agonist, reduces inflammation and protects tissue. A2A agonists also reduce inflammation and proteinuria and prevented histological changes in an animal model of diabetic nephropathy. Currently, this compound is being used in phase I human studies. We hypothesized that ATL146e given to proteinuric diabetic subjects will reduce inflammation. Our specific aims are to compare the effects of intravenous ATL146e and ACE inhibitor, enalprilat, on, 1. urinary concentration of inflammatory cytokines and growth factors, 2. total, cortical and medullary renal blood flows and GFR and 3. Proteinuria. A pilot study will be done to determine the optimum duration of ATL146e infusion. Novel technique of contrast enhanced ultrasound (CEU) as well clearance techniques will be used to monitor renal hemodynamic changes. CEU has been used extensively in the field of cardiology and recent studies have demonstrated applications for its use in nephrology as well. Tha candidate is currently conducting GCRC-sponsored study using CEU in monitoring changes in regional renal blood flow in healthy human subjects. This project combines the strengths of the University of Virginia as a leader in both the study of adenosine A2A receptor agonist and diabetes. Dr Mark Okusa, candidate's promary mentor, has 7 years of background in research on A2A agonist. Dr. Eugene Barrett, the co-mentor, is an internationally recognized name in the field of diabetes research and the Director of the NIH- sponsored GCRC at UVA. This K23 leverages the strength of the insitutional commitment toward deveveloping indendent careers in clinical investigation, the research environment in diabetic kidney disease and adenosine receptors, and the resources of the General Clinical Research Center at the Unvirsity of Virginia. Funding will permit the applicant to receive formal training and a masters degree in Health Evaluation Sciences, Clinical Investigation and Patient Orients Researcg track. Dr William Knaus, the director of the Department of Public Health Sciences at UVA, is an advisor to the candidate and has designed a specific plan for the candidate's training and will monitor his progress during the years of award support.