The long-term goal of this Program Project Grant (PPG) is to generate new information about how fluid- electrolyte balance is regulated and thus contributes to blood pressure control. Our studies largely focus on mechanisms related to endothelin-1 (ET-1) and its associated receptors, ETA and ETB. Previous studies from investigators on the project team revealed a significant role for this system in controlling renal handling of salt and water balance, control of renal hemodynamics, and blood pressure regulation. Investigators have demonstrated that defects in this system results in hypertension that is highly sensitive to dietary salt intake. This is a complicated yet powerful system that balances the vasodilatory and pro-natriuretic actions of the ETB receptor with the vasoconstrictor pro-inflammatory effects of ETA receptor activation. Exploring both renal tubular actions, primarily in the collecting duct, along with hemodynamic effects represents a diverse approach that is unique to this PPG. Our proposed program has several major themes that seek to elucidate novel mechanisms of renal control of sodium handling. In Project 1, we have evidence that ET-1 contributes to circadian regulation of blood pressure, and so we will explore how ET-1 impacts sodium excretion at different times of day. Project 2 will closely examine how alterations in renal tubular fluid flow that are associated with varying body fluid volume status modulate production of ET-1 within the collecting duct system and how it is regulated by the primary cilia, polycystins and other mediators. Recent findings from Project 3 have demonstrated a unique regulatory system involving acetylation and deacetylation of NOS1 in the collecting duct that impacts sodium handling and salt-dependent changes in blood pressure. Furthermore, both NOS1 and NOS3 are expressed in principal cells of the collecting duct, and so we have proposed a novel hypothesis whereby these two enzymes are regulating different aspects of cellular function. In addition, Projects 2 and 3 investigate how NOS1 and NOS3 in the collecting duct modulate both ET-1 production and actions. Finally, two cores support this PPG: the administrative core and the animal and analytical core. The administrative core manages and coordinates overall PPG activities, provides financial accounting and budgetary support, schedules and arranges meetings of PPG investigators, and manages statistical analysis and data management activities. Core B, the animal and analytical core, is responsible for managing breeding and genotyping for rodents in all three projects. In conclusion, these studies are expected to uncover important regulatory pathways that will aid our understanding of fluid-electrolyte and blood pressure control in health and in disease.

Public Health Relevance

This PPG focuses on elucidating mechanisms by which the kidney controls sodium excretion, and therefore, has direct relevance to the serious health problem of salt-dependent hypertension and kidney disease. The three main projects each utilize relevant animal models and sophisticated in vitro techniques to uncover the pathways that lead to salt-dependent high blood pressure as well as uncovering ways to combat significant side effects of the relevant class of drugs known as endothelin receptor antagonists. We expect these studies will be important in guiding future clinical and therapeutic practices for a broad range of cardiovascular and related diseases.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Program Projects (P01)
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Heart, Lung, and Blood Initial Review Group (HLBP)
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Varagic, Jasmina
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University of Alabama Birmingham
Internal Medicine/Medicine
Schools of Medicine
United States
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Gao, Yang; Stuart, Deborah; Takahishi, Takamune et al. (2018) Nephron-Specific Disruption of Nitric Oxide Synthase 3 Causes Hypertension and Impaired Salt Excretion. J Am Heart Assoc 7:
De Miguel, Carmen; Sedaka, Randee; Kasztan, Malgorzata et al. (2018) Tauroursodeoxycholic acid (TUDCA) abolishes chronic high salt-induced renal injury and inflammation. Acta Physiol (Oxf) :e13227
Johnston, Jermaine G; Pollock, David M (2018) Circadian regulation of renal function. Free Radic Biol Med 119:93-107
Ramkumar, N; Stuart, D; Abraham, N et al. (2018) Nephron prorenin receptor deficiency alters renal medullary endothelin-1 and endothelin receptor expression. Physiol Res 67:S127-S136