High salt (HS) diet leads to endothelial dysfunction, impaired vascular relaxation and increased oxidant stress in blood vessels. Salt-induced angiotensin II (ANG II) suppression is a crucial factor contributing to this vascular dysfunction. Normal vascular function can be restored in HS-fed animals by chronic i.v. infusion of a subpressor dose of ANG II to prevent salt-induced ANG II suppression. This protective action of ANG II is mediated via transactivation of the EGF receptor and subsequent activation of the ERK 1/2 pathway. The goal of this project is to elucidate the mechanisms by which ANG II maintains normal vascular relaxation via this pathway, with special emphasis on the role of ANG II in maintaining antioxidant defense mechanisms. The fundamental hypothesis of this project is that physiological levels of ANG II in the plasma are required to maintain normal endothelial function and to preserve anti-oxidant defense mechanisms by tonic activation of the AT1 receptor, which transactivates the epidermal growth factor (EGF) receptor leading to activation of the ERK 1/2 pathway and ultimately, activation of the master antioxidant and cytoprotective transcription factor Nrf2 [also known as nuclear factor (erythroid derived 2)-like 2]. We further hypothesize that the severe endothelial dysfunction that exists with high salt diet results from chronic exposure to low levels of ANG II due to salt-induced suppression of plasma renin activity--the normal physiological response to elevated dietary salt intake. These low levels of ANG II, in turn, lead to down regulation of antioxidant genes in resistance arteries by suppressing the Nrf2 pathway. This project has three specific aims: 1): To directly evaluate the role of reduced plasma ANG II levels in contributing to vascular oxidant stress and endothelial dysfunction utilizing congenic knockout rats with and without a normally functioning renin allele;2) To evaluate the role of the Nrf2 pathway in mediating the protective effect of physiological ANG II levels to prevent vascular oxidant stress and endothelial dysfunction in cerebral arteries. 3) To evaluate the role of physiological ANG II levels and the Nrf2 pathway in maintaining normal blood flow regulation at the level of the whole vascular bed. These studies could open entirely new areas of investigation related to a previously unknown role of physiological levels of ANG II, namely the maintenance of antioxidant defense mechanisms and normal vascular relaxation in resistance arteries via the Nrf2 pathway.

Public Health Relevance

Excessive dietary salt intake is not only a known risk factor for hypertension, but also contributes to cardiovascular disease and increased mortality in humans independent of its effects on blood pressure. This project will utilize salt-insensitive Sprague-Dawley rats and a novel strain of gene knockout rats lacking a functional renin gene to identify the mechanisms by which salt-induced suppression of the hormone angiotensin II leads to impaired regulation of the circulation independent of an elevation in blood pressure. These studies should provide valuable knowledge concerning the mechanisms that underlie the development and maintenance of salt-induced vascular dysfunction in humans, whether or not they develop hypertension.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
High Priority, Short Term Project Award (R56)
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Hypertension and Microcirculation Study Section (HM)
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OH, Youngsuk
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Medical College of Wisconsin
Schools of Medicine
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Allen, Linda A; Schmidt, James R; Thompson, Christopher T et al. (2018) High salt diet impairs cerebral blood flow regulation via salt-induced angiotensin ii suppression. Microcirculation :e12518
Lukaszewicz, Kathleen M; Durand, Matthew J; Priestley, Jessica R C et al. (2017) Evaluation of Vascular Control Mechanisms Utilizing Video Microscopy of Isolated Resistance Arteries of Rats. J Vis Exp :
Lukaszewicz, Kathleen M; Paudyal, Mahesh P; Falck, John R et al. (2016) Role of vascular reactive oxygen species in regulating cytochrome P450-4A enzyme expression in Dahl salt-sensitive rats. Microcirculation 23:540-548
Priestley, Jessica R C; Kautenburg, Katie E; Casati, Marc C et al. (2016) The NRF2 knockout rat: a new animal model to study endothelial dysfunction, oxidant stress, and microvascular rarefaction. Am J Physiol Heart Circ Physiol 310:H478-87
Raffai, Gábor; Lombard, Julian H (2016) Angiotensin-(1-7) Selectively Induces Relaxation and Modulates Endothelium-Dependent Dilation in Mesenteric Arteries of Salt-Fed Rats. J Vasc Res 53:105-118
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Lukaszewicz, Kathleen M; Falck, John R; Manthati, Vijaya L et al. (2013) Introgression of Brown Norway CYP4A genes on to the Dahl salt-sensitive background restores vascular function in SS-5(BN) consomic rats. Clin Sci (Lond) 124:333-42
Pavlov, Tengis S; Levchenko, Vladislav; O'Connor, Paul M et al. (2013) Deficiency of renal cortical EGF increases ENaC activity and contributes to salt-sensitive hypertension. J Am Soc Nephrol 24:1053-62
Durand, Matthew J; Lombard, Julian H (2013) Low-dose angiotensin II infusion restores vascular function in cerebral arteries of high salt-fed rats by increasing copper/zinc superoxide dimutase expression. Am J Hypertens 26:739-47
Beyer, Andreas M; Raffai, Gabor; Weinberg, Brian et al. (2012) Dahl salt-sensitive rats are protected against vascular defects related to diet-induced obesity. Hypertension 60:404-10

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