scholarly journals Review: Novel roles of nuclear angiotensin receptors and signaling mechanisms

2012 ◽  
Vol 302 (5) ◽  
pp. R518-R530 ◽  
Author(s):  
TanYa M. Gwathmey ◽  
Ebaa M. Alzayadneh ◽  
Karl D. Pendergrass ◽  
Mark C. Chappell
Keyword(s):  
Cardiovascular Disease ◽  
Renin Angiotensin System ◽  
Angiotensin Receptors ◽  
Major Influence ◽  
Receptor Subtypes ◽  
Ang Ii ◽  
Physiological Regulation ◽  
Intracellular Expression ◽  
And Function

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 (AT1R) 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 (AT1R) 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 (AT2R) and ANG-(1–7) (AT7R) 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 AT7 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 AT2 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.

Angiotensin receptors: distribution, signalling and function

2001 ◽  
Vol 100 (5) ◽  
pp. 481-492 ◽  
Author(s):  
Diem T. DINH ◽  
Albert G. FRAUMAN ◽  
Colin I. JOHNSTON ◽  
Maurice E. FABIANI
Keyword(s):  
Cellular Differentiation ◽  
Cellular Growth ◽  
Angiotensin Receptors ◽  
Receptor Subtypes ◽  
At2 Receptor ◽  
Ang Ii ◽  
Peptide Fragments ◽  
Sympathetic Transmission ◽  
Angiotensin Peptide ◽  
And Function

Angiotensin II (Ang II) is a multi-functional hormone that plays a major role in regulating blood pressure and cardiovascular homoeostasis. The actions of Ang II are mediated by at least two receptor subtypes, designated AT1 and AT2. In addition, other angiotensin receptors have been identified which may recognize other angiotensin peptide fragments; however, until now only the AT1 and AT2 receptor have been cloned in animals or humans. Most of the well-described actions of Ang II, such as vasoconstriction, facilitation of sympathetic transmission, stimulation of aldosterone release and promotion of cellular growth are all mediated by the AT1 receptor. Much less is known about the function of the AT2 receptor, but recent studies suggest that it may play a role in mediating anti-proliferation, cellular differentiation, apoptosis and vasodilatation. In this review, we discuss recent advances in our understanding of Ang II receptors, in particular, their distribution, signalling and function.

Angiotensin receptors: signaling, vascular pathophysiology, and interactions with ceramide

2001 ◽  
Vol 281 (6) ◽  
pp. H2337-H2365 ◽  
Author(s):  
C. Berry ◽  
R. Touyz ◽  
A. F. Dominiczak ◽  
R. C. Webb ◽  
D. G. Johns
Keyword(s):  
Renin Angiotensin System ◽  
Receptor Activation ◽  
Angiotensin Receptors ◽  
Receptor Subtypes ◽  
Ang Ii ◽  
Mediated Effects ◽  
Signaling Mechanisms ◽  
Intracellular Ca ◽  
Acid Metabolites ◽  
Reactive Oxidant

Angiotensin II (ANG II) is a pleiotropic vasoactive peptide that binds to two distinct receptors: the ANG II type 1 (AT1) and type 2 (AT2) receptors. Activation of the renin-angiotensin system (RAS) results in vascular hypertrophy, vasoconstriction, salt and water retention, and hypertension. These effects are mediated predominantly by AT1 receptors. Paradoxically, other ANG II-mediated effects, including cell death, vasodilation, and natriuresis, are mediated by AT2 receptor activation. Our understanding of ANG II signaling mechanisms remains incomplete. AT1receptor activation triggers a variety of intracellular systems, including tyrosine kinase-induced protein phosphorylation, production of arachidonic acid metabolites, alteration of reactive oxidant species activities, and fluxes in intracellular Ca2+concentrations. AT2 receptor activation leads to stimulation of bradykinin, nitric oxide production, and prostaglandin metabolism, which are, in large part, opposite to the effects of the AT1 receptor. The signaling pathways of ANG II receptor activation are a focus of intense investigative effort. We critically appraise the literature on the signaling mechanisms whereby AT1 and AT2 receptors elicit their respective actions. We also consider the recently reported interaction between ANG II and ceramide, a lipid second messenger that mediates cytokine receptor activation. Finally, we discuss the potential physiological cross talk that may be operative between the angiotensin receptor subtypes in relation to health and cardiovascular disease. This may be clinically relevant, inasmuch as inhibitors of the RAS are increasingly used in treatment of hypertension and coronary heart disease, where activation of the RAS is recognized.

scholarly journals Biochemical evaluation of the renin-angiotensin system: the good, bad, and absolute?

2016 ◽  
Vol 310 (2) ◽  
pp. H137-H152 ◽  
Author(s):  
Mark C. Chappell
Keyword(s):  
Renin Angiotensin System ◽  
Cellular Growth ◽  
Receptor Subtypes ◽  
Ang Ii ◽  
Angiotensin System ◽  
Physiological Regulation ◽  
Renin Angiotensin ◽  
Angiotensin Peptides ◽  
The Status ◽  
Biochemical Evaluation

The renin-angiotensin system (RAS) constitutes a key hormonal system in the physiological regulation of blood pressure through peripheral and central mechanisms. Indeed, dysregulation of the RAS is considered a major factor in the development of cardiovascular pathologies, and pharmacological blockade of this system by the inhibition of angiotensin-converting enzyme (ACE) or antagonism of the angiotensin type 1 receptor (AT1R) offers an effective therapeutic regimen. The RAS is now defined as a system composed of different angiotensin peptides with diverse biological actions mediated by distinct receptor subtypes. The classic RAS comprises the ACE-ANG II-AT1R axis that promotes vasoconstriction; water intake; sodium retention; and increased oxidative stress, fibrosis, cellular growth, and inflammation. In contrast, the nonclassical RAS composed primarily of the ANG II/ANG III-AT2R and the ACE2-ANG-(1–7)-AT7R pathways generally opposes the actions of a stimulated ANG II-AT1R axis. In lieu of the complex and multifunctional aspects of this system, as well as increased concerns on the reproducibility among laboratories, a critical assessment is provided on the current biochemical approaches to characterize and define the various components that ultimately reflect the status of the RAS.

scholarly journals Vascular type 1 angiotensin receptors control blood pressure by augmenting peripheral vascular resistance in female mice

2018 ◽  
Vol 315 (4) ◽  
pp. F997-F1005 ◽  
Author(s):  
Erin Wolf ◽  
Edward J. Diaz ◽  
Alison N. Hollis ◽  
Thien A. Hoang ◽  
Hooman A. Azad ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Critical Role ◽  
Renin Angiotensin System ◽  
Angiotensin Receptors ◽  
Ang Ii ◽  
Angiotensin System ◽  
Female Mice ◽  
Vascular Type ◽  
The Impact

Angiotensin II (ANG II) is a major mediator of hypertension pathogenesis. In addition, there are well-documented differences in expression of the renin-angiotensin system (RAS) components and ANG II responses between males and females, which may explain sex differences in blood pressure (BP) and hypertension epidemiology. We previously showed that type 1A angiotensin (AT1A) receptors in vascular smooth muscle cells (VSMCs) play a critical role in BP regulation and hypertension pathogenesis, but these studies were carried out in male mice. Therefore, the major goal of the current studies was to examine the impact of VSMC AT1A receptors on BP and hypertension pathogenesis in female mice. We found that elimination of VSMC AT1A receptors in female mice reduced (≈8 mmHg) baseline BP without altering sodium sensitivity. The severity of ANG II-induced hypertension was diminished (≈33% reduction in BP), particularly during the last 2 wk of chronic ANG II infusion, compared with controls, but natriuresis was not altered during the first 5 days of ANG II infusion. Urinary norepinephrine levels were enhanced in female SMKO compared with control mice. There was a virtually complete elimination of ANG II-induced kidney hemodynamic responses with attenuation of acute vasoconstrictor responses in the systemic vasculature. These findings demonstrate that direct vascular actions of AT1A receptors play a prominent role in BP control and hypertension pathogenesis in female mice.

scholarly journals Local Bone Marrow Renin-Angiotensin System and Atherosclerosis

2011 ◽  
Vol 2011 ◽  
pp. 1-10 ◽  
Author(s):  
Yavuz Beyazit ◽  
Tugrul Purnak ◽  
Gulay Sain Guven ◽  
Ibrahim C. Haznedaroglu
Keyword(s):  
Bone Marrow ◽  
Renin Angiotensin System ◽  
Cellular Growth ◽  
Ang Ii ◽  
Angiotensin System ◽  
Renin Angiotensin ◽  
Local Bone ◽  
Growth Production ◽  
And Function

Local hematopoietic bone marrow (BM) renin-angiotensin system (RAS) affects the growth, production, proliferation differentiation, and function of hematopoietic cells. Angiotensin II (Ang II), the dominant effector peptide of the RAS, regulates cellular growth in a wide variety of tissues in pathobiological states. RAS, especially Ang II and Ang II type 1 receptor (AT1R), has considerable proinflammatory and proatherogenic effects on the vessel wall, causing progression of atherosclerosis. Recent investigations, by analyzing several BM chimeric mice whose BM cells were positive or negative for AT1R, disclosed that AT1R in BM cells participates in the pathogenesis of atherosclerosis. Therefore, AT1R blocking not only in vascular cells but also in the BM could be an important therapeutic approach to prevent atherosclerosis. The aim of this paper is to review the function of local BM RAS in the pathogenesis of atherosclerosis.

Characterization of angiotensin receptors mediating prostaglandin synthesis in C6 glioma cells

1991 ◽  
Vol 260 (5) ◽  
pp. R1000-R1006 ◽  
Author(s):  
N. Jaiswal ◽  
D. I. Diz ◽  
E. A. Tallant ◽  
M. C. Khosla ◽  
C. M. Ferrario
Keyword(s):  
Glioma Cells ◽  
C6 Glioma ◽  
C6 Glioma Cells ◽  
Angiotensin Receptors ◽  
Receptor Subtype ◽  
Receptor Subtypes ◽  
Dependent Manner ◽  
Ang Ii ◽  
Selective Antagonist ◽  
Pge2 Release

The heptapeptide angiotensin (ANG)-(1-7) mimics some but not all the central actions of ANG II, suggesting that receptor subtypes may exist. The effects of ANG-(1-7), ANG II, and ANG I on prostaglandin (PG) E2 and prostacyclin (PGI2) synthesis were investigated in neurally derived rat C6 glioma cells. All three ANG peptides stimulated PG release in a dose-dependent manner with the order of potency ANG-(1-7) greater than ANG I greater than ANG II. PGE2 release induced by ANG-(1-7) (10(-7) M) was partially blocked by [Sar1,Ile8]ANG II (10(-6) M), [Sar1,Thr8]ANG II (10(-6) M), or the subtype 1 selective antagonist Du Pont 753 (10(-5) M) but not by the subtype 2 selective antagonist CGP 42112A (10(-7)-10(-5) M). PGI2 release was inhibited only by [Sar1,Thr8]ANG II. ANG II-induced PGE2 release was blocked by [Sar1,Thr8]ANG II (10(-6) M), [Sar1,Ile8]ANG II (10(-6) M), or Du Pont 753 (10(-7) M) but not by CGP 42112A (10(-7)-10(-5) M). In contrast, ANG II-induced PGI2 release was blocked by Du Pont 753 (10(-7) M) as well as [Sar1,Ile8]ANG II (10(-6) M) but not by [Sar1,Thr8]ANG II or CGP 42112A. Thus ANG II-stimulated PGE2 and PGI2 syntheses in C6 glioma cells are mediated via receptor subtype 1. ANG-(1-7)-induced PGE2 synthesis is also mediated via subtype 1 receptors; however, PGI2 release was blocked by [Sar1,Thr8]ANG II only.(ABSTRACT TRUNCATED AT 250 WORDS)

scholarly journals Functional expression of the renin-angiotensin system in human podocytes

2006 ◽  
Vol 290 (3) ◽  
pp. F710-F719 ◽  
Author(s):  
Max C. Liebau ◽  
D. Lang ◽  
J. Böhm ◽  
N. Endlich ◽  
Martin J. Bek ◽  
...  
Keyword(s):  
Renin Angiotensin System ◽  
Functional Expression ◽  
Kidney Cortex ◽  
Receptor Subtypes ◽  
Ang Ii ◽  
Angiotensin Receptor ◽  
Angiotensin System ◽  
Renin Angiotensin ◽  
Beneficial Effects ◽  
Glomerular Proteinuria

Experimental and clinical studies impressively demonstrate that angiotensin-converting enzyme inhibitors (ACEI) and angiotensin receptor blockers (ARB) significantly reduce proteinuria and retard progression of glomerular disease. The underlying intraglomerular mechanisms are not yet fully elucidated. As podocyte injury constitutes a critical step in the pathogenesis of glomerular proteinuria, beneficial effects of ACEI and ARB may partially result from interference with a local renin-angiotensin system (RAS) in podocytes. The knowledge of expression and function of a local RAS in podocytes is limited. In this study, we demonstrate functional expression of key components of the RAS in differentiated human podocytes: podocytes express mRNA for angiotensinogen, renin, ACE type 1, and the AT1 and AT2 angiotensin receptor subtypes. In Western blot experiments and immunostainings, expression of the AT1 and AT2 receptor was demonstrated both in differentiated human podocytes and in human kidney cortex. ANG II induced a concentration-dependent increase in cytosolic Ca2+ concentration via AT1 receptors in differentiated human podocytes, whereas it did not increase cAMP. Furthermore, ANG II secretion was detected, which was blocked by neither the ACEI captopril nor the renin inhibitor remikiren nor the chymase inhibitor chymostatin. ANG II secretion of podocytes was not increased by mechanical stress. Finally, ANG II was found to increase staurosporine-induced apoptosis in podocytes. We speculate that ACEI and ARB exert their beneficial effects, in part, by interfering with a local RAS in podocytes. Further experiments are required to identify the underlying molecular mechanism(s) of podocyte protection.

Abstract P611: Immortalization of Sheep Proximal Tubule Cells Retain the Ability to Internalize Angiotensinogen that Traffics to the Mitochondria and Nucleus

Hypertension ◽  
2016 ◽  
Vol 68 (suppl_1) ◽  
Author(s):  
Nildris Cruz-Diaz ◽  
Yixin Su ◽  
James C Rose ◽  
Bryan A Wilson ◽  
Mark C Chappell
Keyword(s):  
Cell Line ◽  
Time Course ◽  
Secretory Pathway ◽  
Protein A ◽  
Renin Angiotensin System ◽  
Subcellular Fractionation ◽  
Cell System ◽  
Ang Ii ◽  
Mitochondrial Fractions ◽  
Intracellular Expression

Although there is compelling evidence for an intracellular renin-angiotensin system (RAS) that includes localization of AT1, AT2 and AT7/Mas receptors (R) on the nucleus and mitochondria of various cell types, the mechanism for the intracellular expression of angiotensins remains equivocal as the precursor protein angiotensinogen (Aogen) enters the secretory pathway upon synthesis. Proximal tubules (PTs) of the kidney present a unique cell system since the PTs internalize Aogen and transgenic mice lacking either the PT protein transporter megalin or liver Aogen exhibit reduced renal content of both Aogen and Ang II. We reported that isolated sheep PTs readily internalize Aogen, and subcellular fractionation revealed that Aogen was evident in the nuclear and mitochondrial fractions. The present study sought to establish a permanent cell line derived from the sheep PT to facilitate the characterization of Aogen internalization and processing. Sheep PT cells were isolated by protease digestion and Percoll density gradient separation, maintained in culture to promote epithelial cell growth and immortalized by SV-40 transfection. A clone (SPT-1) was obtained that expressed the SGLT-2 protein, a selective PT marker. SPT-1 cells were incubated with recombinant 125 I-Aogen at 37°C in DMEM/F12 media. A time course [0.5 to 6 hrs] revealed linear uptake of Aogen [r = 0.995] that did not saturate by 6 hrs. Pre-treatment of the SPT-1 cells with renin/ACE/neprilysin/chymase inhibitors [INHIB] or AT1R/AT2R/AT7/MasR antagonists [ANTAG] failed to attenuate Aogen internalization [Control: 209 ± 22; INHIB: 200 ± 21; ANTAG: 217 ± 15 fmol/hr/mg, n=3] while Ang II or Ang-(1-7) [10 μM, each] also did not inhibit, but tended to increase Aogen uptake [238 ± 24 and 244 ± 15 fmol/hr/mg, respectively, n=3]. Subcellular fractionation studies revealed that 12.0 ± 0.2% [n=3] of the total internalized Aogen was localized to the mitochondrial fraction with a higher content in the nucleus following an 18 hr uptake. We conclude that the established SPT-1 cell line which retains the capacity to internalize Aogen and expresses a similar pattern of protein trafficking to isolated PTs, may constitute a relevant model to elucidate the pathway for intracellular expression of angiotensins.

Abstract 396: Inhibition of Prolyl Hydroxylase Domain-containing Protein Downregulates Vascular Angiotensin II Type 1 Receptor

Hypertension ◽  
2012 ◽  
Vol 60 (suppl_1) ◽  
Author(s):  
Toshihiro Ichiki
Keyword(s):  
Cellular Response ◽  
Target Genes ◽  
Interstitial Fibrosis ◽  
Critical Role ◽  
Hypoxia Inducible Factor ◽  
Renin Angiotensin System ◽  
Prolyl Hydroxylase ◽  
Ang Ii ◽  
Prolyl Hydroxylase Domain

Background: Prolyl hydroxylase domain-containing protein (PHD) mediates hydroxylation of hypoxia-inducible factor (HIF)-1α and thereby induces proteasomal degradation of HIF-1α. Inhibition of PHD by hypoxia or hypoxia mimetics such as cobalt chloride (CoCl2) stabilizes HIF-1 and increases the expression of target genes such as vascular endothelial growth factor (VEGF). Although hypoxia activates the systemic renin angiotensin system (RAS), the role of PHD in regulating RAS remains unknown. We examined the effect of PHD inhibition on the expression of angiotensin (Ang) II type 1 receptor (AT1R) and its signaling. Methods and Results: Hypoxia (1% O2), CoCl2 (100-300 μmol/L), and dimethyloxalylglycine (0.25-1.0 mmol/L), all known to inhibit PHD, reduced AT1R expression by 37.7±7.6, 39.6±8.4-69.7±9.9, and 13.4±6.1-25.2±7.0%, respectively (p<0.01) in cultured vascular smooth muscle cell. The same stimuli increased the expression of nuclear HIF-1α and VEGF (p<0.05), suggesting that PHD activity is inhibited. Knockdown of PHD2, a major isoform of PHDs, by RNA interference also reduced AT1R expression by 55.3±6.0% (p<0.01). CoCl2 decreased AT1R mRNA through transcriptional and posttranscriptional mechanisms (p<0.01 and <0.05, respectively). CoCl2 and PHD2 knockdown diminished Ang II-induced ERK phosphorylation (P<0.01). Over-expression of the constitutively active HIF-1α did not impact the AT1R gene promoter activity. Oral administration of CoCl2 (14 mg/kg/day) to C57BL/6J mice receiving Ang II infusion (490 ng/kg/min) for 4 weeks significantly reduced the expression of AT1R in the aorta by 60.9±11.3% (p<0.05) and attenuated coronary perivascular fibrosis by 85% (p<0.01) without affecting blood pressure. However, CoCl2 did not affect Ang II-induced renal interstitial fibrosis. Conclusion: PHD inhibition downregulates AT1R expression independently of HIF-1α, reduces the cellular response to Ang II, and attenuates profibrotic effect of Ang II on the coronary arteries. PHD inhibition may be beneficial for the treatment of cardiovascular diseases, in which activation of RAS plays a critical role.

Abstract 227: The Protective Effect of Kidney-Specific ACE Inhibition Against Chronic Angiotensin II Infusions is Associated with Blunted Intrarenal Renin-Angiotensin System Activation

Hypertension ◽  
2012 ◽  
Vol 60 (suppl_1) ◽  
Author(s):  
Jorge F Giani ◽  
Tea Djandjoulia ◽  
Nicholas Fetcher ◽  
Sebastien Fuchs ◽  
Dale M Seth ◽  
...  
Keyword(s):  
Renin Angiotensin System ◽  
Fold Increase ◽  
Ace Inhibition ◽  
Sham Operation ◽  
Ang Ii ◽  
Angiotensin System ◽  
Renin Angiotensin ◽  
Intrarenal Ras ◽  
Failed Induction

Introduction: The responses to chronic angiotensin (Ang) II infusions of gene-targeted mice lacking kidney angiotensin-converting enzyme (ACE), in terms of intrarenal Ang II accumulation, hypertension, sodium and water retention are all blunted or absent. The objective of this study was to determine if these reduced responses were associated with changes in the intrarenal renin-angiotensin system (RAS). METHODS: Mice lacking intrarenal ACE (ACE10/10) were generated by targeted homologous recombination placing the expression of ACE only in macrophages. As a result, these mice have normal circulating ACE levels, but no kidney ACE. Wild-type (WT) mice of the same background (C57Bl/J) served as controls. Mice were subjected to sham-operation or subcutaneous infusion of Ang II for two weeks (n=6-10, 400 ng/kg/min via osmotic minipump). Mean arterial pressure (MAP) was followed by telemetry. At the end of the experiment, the kidneys were collected for analysis. Ang II content was measured by RIA. Renal abundance of ACE, angiotensinogen (AGT) and Ang II receptor type 1 (AT1R) were determined by Western Blot in total kidney homogenates. Results: At baseline, the MAP of WT and ACE 10/10 mice was similar 110 ± 4 mmHg vs. 109 ± 3 mmHg respectively (p>0.05). However, when subjected to chronic Ang II infusions, the hypertensive response was blunted in ACE 10/10 mice (129 ± 6 mmHg) vs. WT (146 ± 5 mmHg; P<0.05). Also, intrarenal Ang II accumulation was lower in ACE10/10 mice (724 ± 81 fmol/g) vs. WT (1130 ± 105 fmol/g, p<0.05). In non-treated mice, intrarenal RAS components analysis revealed that the absence of ACE in ACE10/10 mice was accompanied by a significant reduction in AGT (0.41 ± 0.06) and increased AT1R expression (1.32 ± 0.05) when compared to WT (normalized to 1.00, p<0.05 in both instances). Importantly, after chronic Ang II infusions, AGT, ACE and AT1R expression increased in WT (1.36, 1.26 and 1.17 fold increase respectively compared to non-treated WT, p<0.05) but not in the ACE10/10 mice (1.19, 1.06, 0.89 fold increase respectively compared to non-treated ACE10/10, p>0.05). Conclusion: The blunted hypertension and Ang II accumulation of mice devoid of kidney ACE in response to Ang II infusions is associated with a failed induction of renal AGT and the AT1R.

Sign in / Sign up

Export Citation Format

Share Document