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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Scientist Development Award - Research & Training (K01)
Project #
5K01DK095018-02
Application #
8487401
Study Section
Diabetes, Endocrinology and Metabolic Diseases B Subcommittee (DDK)
Program Officer
Rankin, Tracy L
Project Start
2012-07-01
Project End
2017-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
2
Fiscal Year
2013
Total Cost
$126,832
Indirect Cost
$9,395
Name
University of Mississippi Medical Center
Department
Pharmacology
Type
Schools of Medicine
DUNS #
928824473
City
Jackson
State
MS
Country
United States
Zip Code
39216
Gillis, Ellen E; Mooney, Jennifer N; Garrett, Michael R et al. (2016) Sildenafil Treatment Ameliorates the Maternal Syndrome of Preeclampsia and Rescues Fetal Growth in the Dahl Salt-Sensitive Rat. Hypertension 67:647-53
Sasser, Jennifer M; Murphy, Sydney R; Granger, Joey P (2015) Emerging drugs for preeclampsia--the endothelium as a target. Expert Opin Emerg Drugs 20:527-30
Sasser, Jennifer M; Brinson, Krystal N; Tipton, Ashlee J et al. (2015) Blood pressure, sex, and female sex hormones influence renal inner medullary nitric oxide synthase activity and expression in spontaneously hypertensive rats. J Am Heart Assoc 4:
Gillis, Ellen E; Williams, Jan M; Garrett, Michael R et al. (2015) The Dahl salt-sensitive rat is a spontaneous model of superimposed preeclampsia. Am J Physiol Regul Integr Comp Physiol 309:R62-70
Sasser, Jennifer M (2014) New targets for renal interstitial fibrosis: relaxin family peptide receptor 1-angiotensin type 2 receptor heterodimers. Kidney Int 86:9-10
Sasser, Jennifer M; Cunningham Jr, Mark W; Baylis, Chris (2014) Serelaxin reduces oxidative stress and asymmetric dimethylarginine in angiotensin II-induced hypertension. Am J Physiol Renal Physiol 307:F1355-62
Sasser, Jennifer M (2013) The emerging role of relaxin as a novel therapeutic pathway in the treatment of chronic kidney disease. Am J Physiol Regul Integr Comp Physiol 305:R559-65