Salt-sensitivity or salt-dependent elevations in blood pressure are evident in a majority of the human population. Renal defects in the control of sodium excretion are known to be major contributors to the development of salt-dependent hypertension. Work conducted by each of the Project Leaders over the past 10 years has provided important Information about the powerful role of the renal endothelin (ET- 1) system in the control of sodium excretion, renal hemodynamics, and blood pressure indicating that the endothelin system rivals the renin-angiotensin system in physiological significance. This includes important evidence that a high salt diet, even without hypertension, has a significant influence on renal hemodynamic function. Our studies have led us to hypothesize that the ETB receptor functions as a counter-balance to the powerful vasoconstrictor and pro-hypertensive actions of the ETA receptor. However, there is simply not enough information available about the specific conditions that determine the activity of these receptor systems. The current proposal builds on studies demonstrating that the ETA receptor plays a role in promoting hypertension and associated end-organ damage while a lack of ETB receptor function results in increased sensitivity to salt-induced hypertension. Therefore, the goal of the current Program Project is to determine the physiological actions of ET-1 using an array of experimental approaches ranging from the gene level to whole animal models to comprehensively explore the pathways regulating ET-1 activity in the kidney. The current Program is made of four Projects. Each project explores a unique aspect of the endothelin system in terms of both hemodynamics and tubular function and will elucidate the receptor subtype specific actions on inflammation, oxidative stress, renal hemodynamics and tubular function;a particular emphasis is on factors that influence the control of sodium excretion and blood pressure. These studies are expected to provide important new insight into a major system that regulates renal sodium excretion. In particular, this Program will investigate a full range of mechanisms that control ET-1 release and receptor specific actions in order to provide clinically relevant information.

Public Health Relevance

The Program Project 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. This Program will investigate a new pathway, the endothelin system, which plays a major role in the control of renal function and blood pressure. These studies also could contribute to novel therapeutic approaches given the current use and development of endothelin antagonists in humans.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
7P01HL095499-05
Application #
8661220
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Program Officer
Maric-Bilkan, Christine
Project Start
2010-08-06
Project End
2015-04-30
Budget Start
2014-08-05
Budget End
2015-04-30
Support Year
5
Fiscal Year
2014
Total Cost
$2,198,973
Indirect Cost
$494,605
Name
University of Alabama Birmingham
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
063690705
City
Birmingham
State
AL
Country
United States
Zip Code
35294
De Miguel, Carmen; Speed, Joshua S; Kasztan, Malgorzata et al. (2016) Endothelin-1 and the kidney: new perspectives and recent findings. Curr Opin Nephrol Hypertens 25:35-41
Pandit, Meghana M; Gao, Yang; van Hoek, Alfred et al. (2016) Osmolar regulation of endothelin-1 production by the inner medullary collecting duct. Life Sci 159:135-9
Heimlich, J Brett; Speed, Joshua S; O'Connor, Paul M et al. (2016) Endothelin-1 contributes to the progression of renal injury in sickle cell disease via reactive oxygen species. Br J Pharmacol 173:386-95
Davenport, Anthony P; Hyndman, Kelly A; Dhaun, Neeraj et al. (2016) Endothelin. Pharmacol Rev 68:357-418
Gohar, Eman Y; Giachini, Fernanda R; Pollock, David M et al. (2016) Role of the endothelin system in sexual dimorphism in cardiovascular and renal diseases. Life Sci 159:20-9
Guan, Zhengrong; Singletary, Sean T; Cha, Haword et al. (2016) Pentosan polysulfate preserves renal microvascular P2X1 receptor reactivity and autoregulatory behavior in DOCA-salt hypertensive rats. Am J Physiol Renal Physiol 310:F456-65
Hyndman, Kelly A; Arguello, Alexandra M; Morsing, Sofia K H et al. (2016) Dynamin-2 is a novel NOS1β interacting protein and negative regulator in the collecting duct. Am J Physiol Regul Integr Comp Physiol 310:R570-7
Heimlich, J B; Speed, J S; Bloom, C J et al. (2015) ET-1 increases reactive oxygen species following hypoxia and high-salt diet in the mouse glomerulus. Acta Physiol (Oxf) 213:722-30
Guan, Zhengrong; VanBeusecum, Justin P; Inscho, Edward W (2015) Endothelin and the renal microcirculation. Semin Nephrol 35:145-55
Kohan, Donald E (2015) Introduction: basic biology of the renal endothelin system. Semin Nephrol 35:121-4

Showing the most recent 10 out of 54 publications