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.

Angiotensin receptor subtypes in thin and muscular juxtamedullary efferent arterioles of rat kidney

2003 ◽  
Vol 285 (3) ◽  
pp. F507-F514 ◽  
Author(s):  
Claudia M. B. Helou ◽  
Martine Imbert-Teboul ◽  
Alain Doucet ◽  
Rabary Rajerison ◽  
Catherine Chollet ◽  
...  
Keyword(s):  
Rat Kidney ◽  
Angiotensin Receptors ◽  
Receptor Subtypes ◽  
Ang Ii ◽  
Rt Pcr ◽  
Signaling Mechanism ◽  
Peritubular Capillaries ◽  
Intracellular Ca ◽  
Afferent Arterioles ◽  
Receptor Mrnas

ANG II controls the vascular tone of pre- and postglomerular arterioles, and thereby glomerular filtration, through binding to either AT1A, AT1B, or AT2 receptors. AT1 receptors, which are coupled to intracellular Ca2+ signaling, have vasoconstricting effects, whereas AT2 receptors, whose signaling mechanism is unknown, induce vasodilatation. The angiotensin receptors have been characterized in afferent arterioles, which express the three types of receptors, but not in efferent arterioles. Two subpopulations of juxtamedullary efferent arterioles, muscular ones which terminate as vasa rectae and thin ones which terminate as peritubular capillaries, have been described. They display functional heterogeneity with regard to the ANG II response. To evaluate whether these differences are associated with differential expression of ANG II receptors, we examined the expression pattern of AT1A, AT1B, and AT2 receptor mRNAs by RT-PCR in these arterioles and studied the effect of valsartan, a specific AT1-receptor antagonist. Results indicate that muscular arterioles express AT1A, AT1B, and AT2 receptors, whereas thin arterioles only express the AT1A and AT2 types, and at a much lower level. Valsartan fully inhibited ANG II-induced increases in intracellular Ca2+ in both arteriolar types, but with different kinetics. In muscular arterioles, inhibition was monoexponential, whereas it displayed a marked positive cooperativity in thin arterioles. Finally, the apparent affinity for valsartan was higher in muscular than in thin arterioles. In conclusion, this study further documents the differences between muscular and thin efferent arterioles with regard to ANG II signalization in the rat kidney.

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.

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.

Properties of AT1a and AT1b angiotensin receptors expressed in adrenocortical Y-1 cells

1996 ◽  
Vol 270 (5) ◽  
pp. E831-E839 ◽  
Author(s):  
Y. Tian ◽  
A. J. Baukal ◽  
K. Sandberg ◽  
K. E. Bernstein ◽  
T. Balla ◽  
...  
Keyword(s):  
Inhibitory Concentration ◽  
Adrenal Tumor ◽  
Inositol Phosphates ◽  
Angiotensin Receptors ◽  
Receptor Subtypes ◽  
Ang Ii ◽  
Transfected Cells ◽  
Receptor Cdna ◽  
Peptide Antagonist ◽  
Native Ligand

Adrenocortical Y-1 cells were stably transfected with the AT1a and AT1b subtypes of the rat angiotensin (ANG)IIAT1 receptor cDNA to study the pharmacological and functional properties of the two receptors. Selected clones of transfected cells expressing the AT1a or AT1b receptor subtypes bound the native ligand ANG II and the peptide antagonist [Sar1,Ile8]ANG II with similar affinities, but they differed in their relative affinities for the nonpeptide antagonist losartan (half-maximal inhibitory concentration 9.7 and 4.7 nM), ANG III (126 and 33 nM), and the peptide antagonist [Sar1,Gly8]ANG II (6.2 and 1.2 nM). Photoaffinity labeling of the expressed receptors revealed a single component of 65 kDa for both receptor subtypes, suggesting that both receptors were glycosylated in a similar manner. The sensitivity of 125I-ANG II binding to AT1a and AT1b receptors to guanine nucleotides was unaffected by pertussis toxin treatment. ANG II stimulated the formation of inositol phosphates and increased the level of cytoplasmic Ca2+ in both At1a- and AT1b-transfected Y-1 cells. However, ANG II had little effect on forskolin-induced adenosine 3',5'-cyclic monophosphate accumulation, causing only minor inhibition in AT1a-transfected cells and slight enhancement in AT1b-transfected cells. These data indicate that AT1a and AT1b receptors show small but significant differences in their binding pharmacology and, upon activation, are coupled through Gq/G11 to the phosphoinositide-Ca2+ signaling pathway. However, neither AT1a nor AT1b receptors exhibit coupling to Gi and inhibition of adenylate cyclase when expressed in murine adrenal tumor cells.

Beta-adrenoceptor-mediated release of angiotensin II from mesenteric arteries

1986 ◽  
Vol 250 (1) ◽  
pp. H144-H148 ◽  
Author(s):  
M. Nakamaru ◽  
E. K. Jackson ◽  
T. Inagami
Keyword(s):  
Renin Angiotensin System ◽  
Ringer Solution ◽  
Mesenteric Arteries ◽  
Angiotensin Receptors ◽  
Ang Ii ◽  
Angiotensin System ◽  
Renin Angiotensin ◽  
Beta Adrenoceptor ◽  
Essential Components

Essential components of the renin-angiotensin system such as renin enzymes, angiotensinogen, converting enzyme, and angiotensin receptors have been found in vascular tissues. Locally generated angiotensin (ANG) II may regulate vascular tone by contracting vascular smooth muscle or potentiating sympathetic activity. Recently it was suggested that beta-adrenoceptor-induced enhancement of noradrenergic neurotransmission is mediated by the vascular renin-angiotensin system. The present study was designated to obtain direct evidence for the release of ANG II from the vasculature by beta-adrenoceptor activation. Isolated rat mesenteric arteries were perfused in vitro with Krebs-Ringer solution, and released ANG II was concentrated in a Sep-Pak C-18 cartridge connected to the perfusion system. High-pressure liquid chromatography combined with radioimmunoassay clearly demonstrated the presence of ANG I, II, and a small amount of ANG III in the perfusate. Isoproterenol (10(-9) - 10(-6) M) induced the enhancement of pressor responses to nerve stimulation. This effect was markedly suppressed by propranolol (5 X 10(-7) M), captopril (2 X 10(-6) M), or [Sar1-Ile8]ANG II (10(-6) M). Isoproterenol (10(-9) - 10(-6) M) caused increase in the release of ANG II from mesenteric arteries. The increase in ANG II release during isoproterenol (10(-6) M) infusion was blocked by propranolol (10(-6) M). Captopril (2 X 10(-6) M) also inhibited the increase in ANG II induced by isoproterenol. These results indicate that locally generated ANG II is released from isolated perfused rat mesenteric arteries and its release is mediated by beta-adrenoceptors.

scholarly journals Luminal ANG II is internalized as a complex with AT1R/AT2R heterodimers to target endoplasmic reticulum in LLC-PK1 cells

2017 ◽  
Vol 313 (2) ◽  
pp. F440-F449 ◽  
Author(s):  
Fernanda M. Ferrão ◽  
Luiza H. D. Cardoso ◽  
Heather A. Drummond ◽  
Xiao C. Li ◽  
Jia L. Zhuo ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Biological Effects ◽  
Intracellular Localization ◽  
Renin Angiotensin System ◽  
Renal Physiology ◽  
Ang Ii ◽  
Independent Manner ◽  
Plasmic Reticulum ◽  
Intracellular Ca ◽  
Living Cell Imaging

ANG II has many biological effects in renal physiology, particularly in Ca2+ handling in the regulation of fluid and solute reabsorption. It involves the systemic endocrine renin-angiotensin system (RAS), but tissue and intracrine ANG II are also known. We have shown that ANG II induces heterodimerization of its AT1 and AT2 receptors (AT1R and AT2R) to stimulate sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA) activity. Thus, we investigated whether ANG II-AT1R/AT2R complex is formed and internalized, and also examined the intracellular localization of this complex to determine how its effect might be exerted on renal intracrine RAS. Living cell imaging of LLC-PK1 cells, quantification of extracellular ANG II, and use of the receptor antagonists, losartan and PD123319, showed that ANG II is internalized with AT1R/AT2R heterodimers as a complex in a microtubule-dependent and clathrin-independent manner, since colchicine—but not Pitstop2—blocked this process. This result was confirmed by an increase of β-arrestin phosphorylation after ANG II treatment, clathrin-mediated endocytosis being dependent on dephosphorylation of β-arrestin. Internalized ANG II colocalized with an endoplasmic reticulum (ER) marker and increased levels of AT1R, AT2R, and PKCα in ER-enriched membrane fractions. This novel evidence suggests the internalization of an ANG II-AT1/AT2 complex to target ER, where it might trigger intracellular Ca2+ responses.

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.

Renal nerve stimulation leads to the activation of the Na+/H+ exchanger isoform 3 via angiotensin II type I receptor

2015 ◽  
Vol 308 (8) ◽  
pp. F848-F856 ◽  
Author(s):  
Roberto B. Pontes ◽  
Renato O. Crajoinas ◽  
Erika E. Nishi ◽  
Elizabeth B. Oliveira-Sales ◽  
Adriana C. Girardi ◽  
...  
Keyword(s):  
Nerve Stimulation ◽  
Low Frequency ◽  
Renin Angiotensin System ◽  
Receptor Activation ◽  
Sodium Reabsorption ◽  
Urinary Flow ◽  
Type I ◽  
Ang Ii ◽  
Renal Nerve ◽  
Renal Nerve Stimulation

Renal nerve stimulation at a low frequency (below 2 Hz) causes water and sodium reabsorption via α1-adrenoreceptor tubular activation, a process independent of changes in systemic blood pressure, renal blood flow, or glomerular filtration rate. However, the underlying mechanism of the reabsorption of sodium is not fully understood. Since the sympathetic nervous system and intrarenal ANG II appear to act synergistically to mediate the process of sodium reabsorption, we hypothesized that low-frequency acute electrical stimulation of the renal nerve (ESRN) activates NHE3-mediated sodium reabsorption via ANG II AT1 receptor activation in Wistar rats. We found that ESRN significantly increased urinary angiotensinogen excretion and renal cortical ANG II content, but not the circulating angiotensinogen levels, and also decreased urinary flow and pH and sodium excretion via mechanisms independent of alterations in creatinine clearance. Urinary cAMP excretion was reduced, as was renal cortical PKA activity. ESRN significantly increased NHE3 activity and abundance in the apical microvillar domain of the proximal tubule, decreased the ratio of phosphorylated NHE3 at serine 552/total NHE3, but did not alter total cortical NHE3 abundance. All responses mediated by ESRN were completely abolished by a losartan-mediated AT1 receptor blockade. Taken together, our results demonstrate that higher NHE3-mediated proximal tubular sodium reabsorption induced by ESRN occurs via intrarenal renin angiotensin system activation and triggering of the AT1 receptor/inhibitory G-protein signaling pathway, which leads to inhibition of cAMP formation and reduction of PKA activity.

Induction of NMDA and GABAA Receptor-Mediated Ca2+ Oscillations With KCC2 mRNA Downregulation in Injured Facial Motoneurons

2003 ◽  
Vol 89 (3) ◽  
pp. 1353-1362 ◽  
Author(s):  
Hiroki Toyoda ◽  
Koji Ohno ◽  
Junko Yamada ◽  
Masahiko Ikeda ◽  
Akihito Okabe ◽  
...  
Keyword(s):  
Nmda Receptor ◽  
Receptor Activation ◽  
Nerve Transection ◽  
Mediated Effects ◽  
Endogenous Gaba ◽  
Acid Type ◽  
Intracellular Ca ◽  
Facial Motoneurons ◽  
Neural Survival ◽  
Nmda Receptor Activation

To clarify the changes that occur in γ-aminobutyric acid type A (GABAA) receptor-mediated effects and contribute to alterations in the network activities after neuronal injury, we studied intracellular Ca2+ concentration ([Ca2+]i) dynamics in a rat facial-nerve-transection model. In facial motoneurons, an elevation of the resting [Ca2+]i, GABA-mediated [Ca2+]itransients, enhancement of the glutamate-evoked [Ca2+]i increases, and spontaneous [Ca2+]ioscillations were induced by axotomy. All these axotomy-induced modifications were abolished by the GABAA-receptor antagonist bicuculline and N-methyl-d-aspartate (NMDA)-receptor antagonistd(−)-2-amino-5-phosphonopentanoic acid. A downregulation of K+-Cl− cotransporter (KCC2) mRNA, an increase in intracellular Cl−concentration ([Cl−]i), and transformation of GABAergic hyperpolarization to depolarization were also induced by axotomy. We suggest that in axotomized neurons KCC2 downregulation impairs Cl− homeostasis and makes GABA act depolarizing, resulting in endogenous GABA inducing [Ca2+]i oscillations via facilitation of NMDA-receptor activation. Such GABAA-receptor-mediated [Ca2+]i oscillations may play a role in neural survival and regeneration.

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