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.
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.
| Kang, Kyu-Tae; Sullivan, Jennifer C; Pollock, Jennifer S (2018) Superoxide Dismutase Activity in Small Mesenteric Arteries Is Downregulated by Angiotensin II but Not by Hypertension. Toxicol Res 34:363-370 |
| 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 |
| Guan, Z; Wang, F; Cui, X et al. (2018) Mechanisms of sphingosine-1-phosphate-mediated vasoconstriction of rat afferent arterioles. Acta Physiol (Oxf) 222: |
| De Miguel, Carmen; Hamrick, William C; Hobbs, Janet L et al. (2017) Endothelin receptor-specific control of endoplasmic reticulum stress and apoptosis in the kidney. Sci Rep 7:43152 |
| Gohar, Eman Y; Kasztan, Malgorzata; Pollock, David M (2017) Interplay between renal endothelin and purinergic signaling systems. Am J Physiol Renal Physiol 313:F666-F668 |
| Gohar, Eman Y; Speed, Joshua S; Kasztan, Malgorzata et al. (2016) Activation of purinergic receptors (P2) in the renal medulla promotes endothelin-dependent natriuresis in male rats. Am J Physiol Renal Physiol 311:F260-7 |
| 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 |
| Jin, Chunhua; Speed, Joshua S; Pollock, David M (2016) High salt intake increases endothelin B receptor function in the renal medulla of rats. Life Sci 159:144-147 |
| 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 159:20-29 |
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