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.
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.
|Spradley, Frank T; Sasser, Jennifer M; Musall, Jacqueline B et al. (2016) Nitric oxide synthase-mediated blood pressure regulation in obese melanocortin-4 receptor-deficient pregnant rats. Am J Physiol Regul Integr Comp Physiol 311:R851-R857|
|West, Crystal A; Sasser, Jennifer M; Baylis, Chris (2016) The enigma of continual plasma volume expansion in pregnancy: critical role of the renin-angiotensin-aldosterone system. Am J Physiol Renal Physiol 311:F1125-F1134|
|Wang, Xuexiang; Johnson, Ashley C; Sasser, Jennifer M et al. (2016) Spontaneous one-kidney rats are more susceptible to develop hypertension by DOCA-NaCl and subsequent kidney injury compared with uninephrectomized rats. Am J Physiol Renal Physiol 310:F1054-64|
|Gillis, Ellen E; Sasser, Jennifer M; Sullivan, Jennifer C (2016) Endothelin, sex, and pregnancy: unique considerations for blood pressure control in females. Am J Physiol Regul Integr Comp Physiol 310:R691-6|
|Ryan, Michael J; Coleman, T Taylor; Sasser, Jennifer M et al. (2016) Vascular smooth muscle-specific deletion of the leptin receptor attenuates leptin-induced alterations in vascular relaxation. Am J Physiol Regul Integr Comp Physiol 310:R960-7|
|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; 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; 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 (2014) New targets for renal interstitial fibrosis: relaxin family peptide receptor 1-angiotensin type 2 receptor heterodimers. Kidney Int 86:9-10|
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