Nuclear localization of angiotensinogen in astrocytes

Sherrod, Mikhiela; Liu, Xuebo; Zhang, Xiaoji; Sigmund, Curt D.

doi:10.1152/ajpregu.00594.2004

Cited by 61 publications

(57 citation statements)

References 47 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The multiple forms of hAGT centering on 55 kDa reflect multiple glycosylated forms of the protein (5, 38). We previously reported that HepG2 cells also express multiple forms of hAGT protein, which become reduced to a single immunoreactive product after N-glycosidase treatment (34). Next, we demonstrated that equivalent levels of hAGT protein were detected in plasma of RA and RAC mice, confirming that removal of hAGT from the brain did not affect the ability of the liver to produce and secrete hAGT (Fig.…”

Section: Resultssupporting

confidence: 74%

“…We previously reported astrocytic AGT mRNA in areas of the medulla, midbrain, hypothalamus, thalamus, and hippocampus (44). We also identified a human glioma cell line that expresses AGT endogenously (34). In contrast to glial AGT, neuronal expression of AGT is much more regionally restricted to the nucleus of the solitary tract (NTS), PVN, parabrachial nucleus, RVLM, mesencephalic trigeminal nucleus, and the subfornical organ (SFO) (14,44).…”

Section: Discussionmentioning

confidence: 99%

“…Photos were taken using a fluorescent microscope at ϫ20 magnification. We previously validated and documented the specificity of the hAGT antisera used herein using both preabsorption and nontransgenic mice (23)(24)(25)34). Sections lacking primary antisera were used a negative controls.…”

Section: Methodsmentioning

confidence: 99%

See 2 more Smart Citations

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

Sherrod¹,

Davis²,

Zhou³

et al. 2005

American Journal of Physiology-Regulatory, Integrative and Comp

Self Cite

View full text Add to dashboard Cite

-Angiotensinogen (AGT) is mainly expressed in glial cells in close proximity to renin-expressing neurons in the brain. We previously reported that glial-specific overexpression of ANG II results in mild hypertension. Here, we tested the hypothesis that glial-derived AGT plays an important role in blood pressure regulation in hypertensive mice carrying human renin (hREN) and human AGT transgenes under the control of their own endogenous promoters. To perform a glial-specific deletion of AGT, we used an AGT transgene containing loxP sites (hAGT flox ), so the gene can be permanently ablated in the presence of cre-recombinase expression, driven by the glial fibrillary acidic protein (GFAP) promoter. Triple transgenic mice (RAC) containing a: 1) systemically expressed hREN transgene, 2) systemically expressed hAGT flox transgene, and 3) GFAP-cre-recombinase were generated and compared with double transgenic mice (RA) lacking cre-recombinase. Liver and kidney hAGT mRNA levels were unaltered in RAC and RA mice, as was the level of hAGT in the systemic circulation, consistent with the absence of cre-recombinase expression in those tissues. Whereas hAGT mRNA was present in the brain of RA mice (lacking cre-recombinase), it was absent from the brain of RAC mice expressing crerecombinase, confirming brain-specific elimination of AGT. Immunohistochemistry revealed a loss of AGT immunostaining glial cells throughout the brain in RAC mice. Arterial pressure measured by radiotelemetry was significantly lower in RAC than RA mice and unchanged from nontransgenic control mice. These data suggest that there is a major contribution of glial-AGT to the hypertensive state in mice carrying systemically expressed hREN and hAGT genes and confirm the importance of a glial source of ANG II substrate in the brain.renin-angiotensin system; glia; brain; hypertension DIRECT INJECTION OF ANG II into the brain can cause a rise in systemic blood pressure because of its ability to increase sympathetic outflow and vasopressin release (43). Brain ANG II can also cause long-term increases in arterial pressure through its dipsogenic effects. The importance of the endogenous local production and action of ANG II is supported by experiments directly injecting inhibitors, antagonists, and antisense oligonucleotides directed against the renin-angiotensin system (RAS) into the brain (11,27). Moreover, increased activity of the brain RAS has been implicated as a mechanism causing and maintaining hypertension in both genetic and experimental models (11,13,28,32). Despite overwhelming evidence supporting a cardiovascular role for brain ANG II, the precise mechanisms for its local synthesis in the brain remain unclear. Uncertainties that need to be resolved include identifying the precise cellular and regional production of local ANG II and its relationship to ANG II receptor-containing cells in cardiovascular control regions and the relative importance of circulating and locally produced ANG II in circumventricular organs vs. that locally produced inside th...

show abstract

Section: Resultssupporting

confidence: 74%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

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

Sherrod¹,

Davis²,

Zhou³

et al. 2005

American Journal of Physiology-Regulatory, Integrative and Comp

Self Cite

View full text Add to dashboard Cite

show abstract

“…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).…”

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

Self Cite

View full text Add to dashboard Cite

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...

show abstract

“…Although the direct demonstration of ANG II or ANG-(1-7) within the nuclear compartment of the kidney awaits further studies, identification of a renal cell line that expresses these RAS components may facilitate the elucidation of the processing pathways that contribute to the intracellular/nuclear generation of angiotensins. In this regard, Sigmund and colleagues (89) reported the presence of angiotensinogen in the nuclear compartment of glial cells and identified a putative NLS for the protein; however, the extent of processing of the precursor in the glial nuclei is not known. Both immunoreactive ANG-(1-7) and ANG II were detected in the perinuclear region of rat mesangial cells, in addition to the presence of intracellular ACE and ACE2 (9).…”

Section: Intracellular Formationmentioning

confidence: 99%

Review:Novel roles of nuclear angiotensin receptors and signaling mechanisms

Gwathmey

Alzayadneh

Pendergrass

et al. 2012

American Journal of Physiology-Regulatory, Integrative and Comp

111

View full text Add to dashboard Cite

The renin-angiotensin system (RAS) constitutes an important hormonal system in the physiological regulation of blood pressure. The dysregulation of the RAS is considered a major influence in the development and progression of cardiovascular disease and other pathologies. Indeed, experimental and clinical evidence indicates that blockade of this system with angiotensin-converting enzyme (ACE) inhibitors or angiotensin type 1 receptor (AT 1R) antagonists is an effective therapy to attenuate hypertension and diabetic renal injury, and to improve heart failure. Originally defined as a circulating system, multiple tissues express a complete RAS, and compelling evidence now favors an intracellular system involved in cell signaling and function. Within the kidney, intracellular expression of the three predominant ANG receptor subtypes is evident in the nuclear compartment. The ANG type 1 receptor (AT 1R) is coupled to the generation of reactive oxygen species (ROS) through the activation of phosphoinositol-3 kinase (PI3K) and PKC. In contrast, both ANG type 2 (AT 2R) and ANG-(1-7) (AT 7R) receptors stimulate nitric oxide (NO) formation, which may involve nuclear endothelial NO synthase (eNOS). Moreover, blockade of either ACE2-the enzyme that converts ANG II to ANG-(1-7)-or the AT 7 receptor exacerbates the ANG II-ROS response on renal nuclei. Finally, in a model of fetal programmed hypertension, the nuclear ROS response to ANG II is enhanced, while both AT 2 and AT7 stimulation of NO is attenuated, suggesting that an imbalance in the intracellular RAS may contribute to the development of programming events. We conclude that a functional intracellular or nuclear RAS may have important implications in the therapeutic approaches to cardiovascular disease. renin-angiotensin system; angiotensin converting enzyme; ACE2; neprilysin; kidney; nuclei; AT 1 ; AT 2 ; AT 7 , FROM THE EARLY STUDIES OF Tigerstedt and Bergman (101) that described renin activity in the kidney to the characterization of a pressor substance subsequently identified as ANG II by the laboratories of Braun-Menendez (6) (hypertensin) and Page (angiotonin) 50 years later (8), the characterization of the renin-angiotensin system (RAS) within the kidney and other tissues continues unabated to broaden our understanding of the functional aspects of this important hormonal system in blood pressure regulation and cardiovascular pathologies. Coupled with the discoveries of ANG I-converting enzyme (ACE) as the primary enzyme that forms ANG II in the circulation and tissue and the molecular identification of the ANG II type 1 receptor (AT 1 ) that confers the predominant actions of ANG II, the "classical" RAS was regarded as a sequential endocrine system to form ANG II for the maintenance of blood pressure through renal, vascular, and central mechanisms. There is, however, overwhelming evidence for a "nonclassical" RAS that results in the formation of novel peptide products with functional properties distinct from that of the ANG II-AT 1 receptor pathway (5,12,14,67,8...

show abstract

Nuclear localization of angiotensinogen in astrocytes

Cited by 61 publications

References 47 publications

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

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

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

Review:Novel roles of nuclear angiotensin receptors and signaling mechanisms

Contact Info

Product

Resources

About