Renal microvascular function is an essential element in the control of glomerular capillary pressure, glomerular filtration rate (GFR) and sodium excretion. Salt-sensitive hypertensive patients exhibit a blunted pressure-natriuretic response, and susceptibility to hypertensive renal injury, possibly arising from impaired hemodynamic control. Our laboratory has an established interest in the mechanisms involved in controlling renal blood flow and GFR. Project 2 will examine a novel hypothesis that chronic elevation of dietary salt modifies the renal microvascular response to endothelin-1 (ET-1) to facilitate salt excretion through receptorspecific pathways. Recent studies establish that ETA receptors contribute to salt-sensitive hypertension, whereas ETB receptors stimulate endothelium-dependent vasorelaxation and inhibit sodium reabsorption. However, ETB receptor physiology is complex as they can produce opposing vasoconstriction and vasodilation within the pre-glomerular circulation. We have shown that afferent arterioles of rats fed a high salt diet exhibit a marked rightward shift in ET-1-mediated vasoconstriction and attenuated autoregulatory reactivity (preliminary data), which may involve ETB receptors. These novel observations suggest that the salt-induced enhancement of ETB receptor expression reduces autoregulatory sensitivity to facilitate ETB receptor mediated excretion of salt. While this may have a positive effect in the short-term, reduced autoregulatory efficiency does leave the kidney vulnerable to other hemodynamic insults, like hypertension, that may hasten the progression to renal injury. Therefore, it is important to establish the role of ETB receptors in the afferent arteriolar response to high salt. The central hypothesis for Project 2 is that a high salt diet enhances ETB receptor-specific pathways to promote afferent arteriolar dilation, blunt autoregulatory efficiency and facilitate sodium excretion. We propose to address this central hypothesis by investigating three specific aims.
Aim 1 will test the hypotheses that a high salt diet enhances afferent arteriolar ETBdependent vasorelaxation resulting in increased GFR and that this effect is prevented by ETB receptor deficiency.
Aim 2 will test the hypothesis that a high salt diet blunts autoregulatory efficiency through mechanisms linked to ETB receptor activation.
Aim 3 will test the hypothesis that a high salt diet changes ETB receptor activity to blunt autoregulatory efficiency by reducing afferent arteriolar reactivity to P2 or PI receptor activation via ATP or adenosine, respectively. These studies will provide unique insights into how the kidney responds to salt to facilitate NaCI excretion.

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. The Administrative Core plays an important role in coordinating these activities, which is particularly important in the current program due to the integration of basic and clinical science

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Program Projects (P01)
Project #
Application #
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Georgia Regents University
United States
Zip Code
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