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)
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Heart, Lung, and Blood Initial Review Group (HLBP)
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Georgia Regents University
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Osmond, David A; Zhang, Shali; Pollock, Jennifer S et al. (2014) Clopidogrel preserves whole kidney autoregulatory behavior in ANG II-induced hypertension. Am J Physiol Renal Physiol 306:F619-28
Pollock, David M (2014) 2013 Dahl Lecture: American Heart Association council for high blood pressure research clarifying the physiology of endothelin. Hypertension 63:e110-7
Fellner, Robert C; Cook, Anthony K; O'Connor, Paul M et al. (2014) High-salt diet blunts renal autoregulation by a reactive oxygen species-dependent mechanism. Am J Physiol Renal Physiol 307:F33-40
Kohan, Donald E; Barton, Matthias (2014) Endothelin and endothelin antagonists in chronic kidney disease. Kidney Int 86:896-904
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Donato, Anthony J; Lesniewski, Lisa A; Stuart, Deborah et al. (2014) Smooth muscle specific disruption of the endothelin-A receptor in mice reduces arterial pressure, and vascular reactivity and affects vascular development. Life Sci 118:238-43
Jin, Chunhua; Jeon, Yejoo; Kleven, Daniel T et al. (2014) Combined endothelin a blockade and chlorthalidone treatment in a rat model of metabolic syndrome. J Pharmacol Exp Ther 351:467-73
Kittikulsuth, W; Sullivan, J C; Pollock, D M (2013) ET-1 actions in the kidney: evidence for sex differences. Br J Pharmacol 168:318-26
Hyndman, Kelly A; Xue, Jing; MacDonell, Alexander et al. (2013) Distinct regulation of inner medullary collecting duct nitric oxide production from mice and rats. Clin Exp Pharmacol Physiol 40:233-9

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