Glial-specific ablation of angiotensinogen lowers arterial pressure in renin and angiotensinogen transgenic mice

Sherrod, Mikhiela; Davis, Deborah R.; Zhou, Xizhou; Cassell, Martin D.

doi:10.1152/ajpregu.00435.2005

Cited by 29 publications

(25 citation statements)

References 49 publications

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“…Both methods show that AGT is widely expressed in astrocytes (32,131), and in those cells, was localized in the nucleus (122). Genetic deletion of glial-specific AGT lowers arterial pressure in double transgenic mice expressing both human renin and human AGT (121), and antisense inhibition of glial AGT in rats results is altered baroreflex regulation and increased exercise tolerance (43,119). AGT is also expressed in neurons, specifically within nuclei of the brain important for cardiovascular (CV) regulation, such as the SFO, RVLM, PB, and PVN (58,136,150).…”

Section: Localization Of Ras Components Required For Ang II Productionmentioning

confidence: 99%

Mechanisms of brain renin angiotensin system-induced drinking and blood pressure: importance of the subfornical organ

Coble¹,

Grobe

Johnson³

et al. 2015

American Journal of Physiology-Regulatory, Integrative and Comp

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Coble JP, Grobe JL, Johnson AK, Sigmund CD. Mechanisms of brain renin angiotensin system-induced drinking and blood pressure: importance of the subfornical organ. Am J Physiol Regul Integr Comp Physiol 308: R238 -R249, 2015. First published December 17, 2014 doi:10.1152/ajpregu.00486.2014.-It is critical for cells to maintain a homeostatic balance of water and electrolytes because disturbances can disrupt cellular function, which can lead to profound effects on the physiology of an organism. Dehydration can be classified as either intra-or extracellular, and different mechanisms have developed to restore homeostasis in response to each. Whereas the renin-angiotensin system (RAS) is important for restoring homeostasis after dehydration, the pathways mediating the responses to intra-and extracellular dehydration may differ. Thirst responses mediated through the angiotensin type 1 receptor (AT 1R) and angiotensin type 2 receptors (AT 2R) respond to extracellular dehydration and intracellular dehydration, respectively. Intracellular signaling factors, such as protein kinase C (PKC), reactive oxygen species (ROS), and the mitogen-activated protein (MAP) kinase pathway, mediate the effects of central angiotensin II (ANG II). Experimental evidence also demonstrates the importance of the subfornical organ (SFO) in mediating some of the fluid intake effects of central ANG II. The purpose of this review is to highlight the importance of the SFO in mediating fluid intake responses to dehydration and ANG II.angiotensin; blood pressure; barin; fluid; renin FLUID BALANCE is crucial for the homeostasis and survival of organisms because they have to properly maintain fluid and electrolyte concentrations for the normal function of all cells. Fluid balance can go awry in pathological states such as in chronic kidney disease and diabetes. Among its many roles in maintaining homeostasis, the renin-angiotensin system (RAS) is an important regulator of fluid balance. The RAS achieves this through the actions of its main effector peptide, angiotensin II (ANG II) through the ANG II type 1 (AT 1 R) and type 2 (AT 2 R) receptors. Activation of AT 1 R by blood-borne ANG II in target tissues causes increases in sodium and water retention, arginine vasopressin (AVP), and aldosterone release, vasoconstriction, increased sympathetic nervous system activity, and increased fluid intake. ANG II is produced by the consecutive enzymatic action of renin on its substrate angiotensinogen (AGT) and by angiotensin-converting enzyme (ACE) on its substrate angiotensin I (ANG I). The renin-AGT cleavage step is generally the rate-limiting step in the production of ANG II, and this is certainly true in the brain where the amount of renin is limiting. The RAS exists in two forms: a circulatory form where ANG II acts as an endocrine factor, and a tissue-specific form, where local production of ANG II acts in an autocrine or paracrine manner to induce AT 1 R signaling on ANG II producing or nearby cells (75). Intracrine, or intracellular forms of the RAS, hav...

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Section: Localization Of Ras Components Required For Ang II Productionmentioning

confidence: 99%

Mechanisms of brain renin angiotensin system-induced drinking and blood pressure: importance of the subfornical organ

Coble¹,

Grobe

Johnson³

et al. 2015

American Journal of Physiology-Regulatory, Integrative and Comp

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“…24,25 We showed that both glial and neuronal overexpression of renin and AGT leads to a modest elevation of blood pressure, and a glial-specific knockout of AGT in a model of systemic AGT overexpression with hypertension normalizes blood pressure. 26,27 Ang II has been postulated to act as a neurotransmitter and has been detected in nuclei, as well as in axonal projections between nuclei controlling cardiovascular function 28 (reviewed in Reference 29). One implication of the colocalization of renin, AGT, and Ang II is the potential for intracellular synthesis of Ang II.…”

Section: The Agt Gene and Proteinmentioning

confidence: 99%

Genetic Basis of Hypertension

2006

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H ypertension is a common and complex human disease that causes significant morbidity and mortality worldwide. Unfortunately, despite recent advances in understanding and treating hypertension, its prevalence continues to rise. Across the globe, Ϸ26% of the adult population experiences hypertension, and Kearney et al 1 estimate that this could rise to Ϸ29% by the year 2025. According to the American Heart Association, one third of the United States adult population is hypertensive, and one third of these remain undiagnosed. Hypertension is the most common risk factor for stroke and myocardial infarction and predisposes affected individuals to heart failure, ventricular arrhythmias, renal failure, blindness, and other serious medical problems, resulting in Ϸ22 000 deaths each year in the United States.Essential hypertension accounts for Ϸ90% of hypertensive cases and is the 13th leading cause of death in the United States. Factors that may predispose a person to essential hypertension include weight, age, sex, ethnicity, physical activity, diet, cigarette smoke, stress, hormones, other medical conditions (eg, diabetes), and, of course, genetics. Indeed, studies of ambulatory blood pressure measurements in twins suggest that essential hypertension has a strong genetic component. 2 However, the fact that patients often differentially respond to diverse classes of antihypertensive medications indicates that the etiology of hypertension likely varies considerably among patients, especially when large populations are considered. 3 Consequently, researchers must attempt to tease out what must be a dynamic interplay among heterogeneous genetic backgrounds, diverse environmental factors, and differential etiologies in the pathogenesis of this disorder, all of which make attempts to understand the genetic basis of hypertension a challenge.In this review, we will revisit the evidence supporting or refuting an association of the angiotensinogen (AGT) gene with hypertension. We will begin by describing the basics of the AGT gene and protein, followed by some of the known physiological roles of the classical and tissue renin-angiotensin system (RAS) in blood pressure regulation. A rationale for the implication of AGT in essential hypertension will be subsequently presented, emphasizing the role of linkage analyses and association studies. Particular attention will be given to the role of AGT gene polymorphisms in the etiology of essential hypertension. The reader is forewarned, however, that interpretation of the hypertension genetics literature is complicated, because it is replete with apparently conflicting results obtained largely from association studies using the case-control design. Whereas some of the disagreement among reports must arise from the factors discussed above (ie, genetic, etiologic, and environmental heterogeneity), a substantial proportion may be because of poorly defined inclusion criteria or inadequate appreciation of the importance of statistical power and replication. A critical review of the topic s...

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“…However, RAS derived from glia seems to have a pivotal role in cardiovascular control by the central nervous system (Morimoto et al 2002;McKinley et al 2003;Sherrod et al 2005). Moreover, the differential modulation of baroreflex by neuron-and glia-derived Angiotensin II has been recently demonstrated.…”

Section: Introductionmentioning

confidence: 99%

Differential Regulation of the Renin-Angiotensin System by Nicotine in WKY and SHR Glia

2008

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Given that (1) the renin-angiotensin system (RAS) is compartmentalized within the central nervous system in neurons and glia (2) the major source of brain angiotensinogen is the glial cells, (3) the importance of RAS in the central control of blood pressure, and (4) nicotine increases the probability of development of hypertension associated to genetic predisposition; the objective of the present study was to evaluate the effects of nicotine on the RAS in cultured glial cells from the brainstem and hypothalamus of Wistar Kyoto (WKY) and spontaneously hypertensive (SHR) rats. Ligand binding, real-time PCR and western blotting assays were used to compare the expression of angiotensinogen, angiotensin converting enzyme, angiotensin converting enzyme 2 and angiotensin II type1 receptors. We demonstrate, for the first time, that there are significant differences in the basal levels of RAS components between WKY and SHR rats in glia from 1-day-old rats. We also observed that nicotine is able to modulate the renin-angiotensin system in glial cells from the brainstem and hypothalamus and that the SHR responses were more pronounced than WKY ones. The present data suggest that nicotine effects on the RAS might collaborate to the development of neurogenic hypertension in SHR through modulation of glial cells.

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Glial-specific ablation of angiotensinogen lowers arterial pressure in renin and angiotensinogen transgenic mice

Cited by 29 publications

References 49 publications

Mechanisms of brain renin angiotensin system-induced drinking and blood pressure: importance of the subfornical organ

Mechanisms of brain renin angiotensin system-induced drinking and blood pressure: importance of the subfornical organ

Genetic Basis of Hypertension

Differential Regulation of the Renin-Angiotensin System by Nicotine in WKY and SHR Glia

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