Recent studies indicate that the peptide hormone relaxin has multiple beneficial actions in the cardio-renal system under pathological conditions due to its vasodilatory, anti-fibrotic, and angiogenic properties. Therefore, relaxin holds great promise as a novel therapeutic intervention for patients with kidney disease. The tremendous therapeutic potential of relaxin in hypertension induced chronic kidney disease can only be determined by first carefully investigating the actions of this peptide in experimental models of disease. This proposal will determine the molecular mechanisms of the renoprotective actions of relaxin during hypertension by testing the hypothesis that relaxin stimulates the endothelin B receptor - nitric oxide pathway to lower blood pressure and prevent progression of renal injury in hypertensive rats. Proposed studies will also investigate the potential for relaxin gene therapy in the treatment of hypertension and chronic kidney disease. This novel proposal will investigate these specific aims: (1) to test the hypothesis that relaxin increases NO bioavailability during hypertension via increased NOS activity and reduced oxidative stress, (2) to determine if the renoprotective effects of relaxin are mediated by activation of endothelin type B (ETB) receptors, and (3) to determine if kidney specific upregulation of relaxin is antihypertensive and can prevent end organ damage. The candidate will use the work described in this proposal as the basis of an independent line of research into the role of relaxin in the prevention of chronic kidney disease, and a comprehensive training program has been designed to move the applicant to a career as an independent investigator. Dr. Chris Baylis, an exceptional renal physiologist and mentor, will serve as the candidate's mentor. Her expertise and the superb environment of the University of Florida, rich in clinical and basic sciences, will offer the candidate the best opportunity for achieving her goal of becoming an independent investigator in the field of renal physiology. PUBLIC HEALTH RELEVANCE: High blood pressure and kidney disease are major health problems throughout the world, and the incidence and costs of these diseases are growing rapidly; therefore, new therapies that provide better efficacy with minimal adverse effects are urgently required. This proposal seeks to improve the current understanding of the molecular mechanisms involved in the renoprotective actions of relaxin in order to provide a rational approach for developing better therapeutic strategies for hypertension and kidney disease. PUBLIC HEALTH RELEVANCE: This application investigates the molecular mechanisms of the renoprotective actions of relaxin during hypertension and determines if kidney-specific overexpression of relaxin is prevents end organ damage during hypertension. We propose that relaxin activates the endothelin B receptor - nitric oxide pathway in rats to prevent renal injury during experimental hypertension. This proposal and career development plan will enable the applicant to become an independent renal physiologist and establish a successful research program.