Roxadustat (FG-4592) prevents Ang II hypertension by targeting angiotensin receptors and eNOS

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)

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Abstract P646: Vascular AT1 Angiotensin Receptors Regulate Sodium Transporter Abundance in Kidney Epithelium

Hypertension ◽

10.1161/hyp.66.suppl_1.p646 ◽

2015 ◽

Vol 66 (suppl_1) ◽

Author(s):

Matthew A Sparks ◽

Donna L Ralph ◽

Daian Chen ◽

Hooman A Azad ◽

Susan B Gurley ◽

...

Keyword(s):

Angiotensin Receptors ◽

Loop Of Henle ◽

Ang Ii ◽

At1 Receptors ◽

Renal Vasoconstriction ◽

Lower Baseline ◽

Induced Hypertension ◽

Sodium Transporter ◽

Pressure Natriuresis ◽

Specific Deletion

Vasoconstriction is a signature physiological action of angiotensin II (AngII) acting via AT1 receptors (AT1R). In order to define the contribution of AT1R in vascular smooth muscle cells (VSMCs) to BP control, we generated mice with cell-specific deletion of AT1AR from VSMCs (SMKOs) using Cre-loxp technology. Baseline BP was reduced by ~7 mmHg and responses to AngII-induced hypertension were significantly blunted by in SMKO mice compared to controls (16 vs. 30 mm Hg change in BP from baseline after 4 wks AngII, P<0.02). Baseline renal blood flow (RBF) was higher, and renal vasoconstriction after Ang II was impaired in SMKOs. Moreover, SMKO mice displayed Na+ sensitivity and exaggerated natriuresis during chronic AngII infusion. To investigate the mechanism of the lower baseline BP and the enhanced natriuresis during AngII infusion (1000ng/kg/min for 5 days), we measured a panel of key Na+ transporters in the kidney by immunoblot. Baseline measurements in SMKO vs. controls detected reductions in NKCC2 in both cortex (0.8±0.03 vs. 1±0.03; P=0.0002) and medulla (0.6±0.02 vs. 1±0.05; P<0.0001); medullary NHE3 was similarly reduced (0.6±0.07 vs. 1±0.07; P=0.002). In controls, AngII infusion was associated with reduced levels of cortical and medullary NHE3 and medullary NKCC, consistent with the pressure-natriuresis response, whereas cortical NKCC, NCC and ENaC were all significantly activated. By contrast, in SMKOs, there was no AngII infusion dependent depression in cortical or medullary NHE3, nor medullary NKCC. However, the extent of increase in activated (cleaved) αENaC was significantly less than controls (cortex: 1.46±0.16 vs. 2.58±0.17, P=0.002; medulla: 1.49±0.09 vs. 2.22±0.31, P=0.01). Yet, 24 hr urinary aldosterone excretion was not different between the groups (18.6±2.7 vs. 15.8±4.5 ng/24hrs). Our studies indicate that the lower baseline BP in SMKO mice is associated with reduced Na+ transporter abundance along the loop of Henle, and that attenuated hypertension and improved natriuresis during AngII infusion are associated with diminished ENaC activation. In conclusion, we suggest that vascular-epithelial cross-talk modulates renal Na+ handling and thereby contributes to control of BP at baseline and during hypertension.

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Vasodepressor action of angiotensin in conscious chickens

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.1982.243.3.h456 ◽

1982 ◽

Vol 243 (3) ◽

pp. H456-H462 ◽

Cited By ~ 6

Author(s):

Y. Nakamura ◽

H. Nishimura ◽

M. C. Khosla

Keyword(s):

Blood Pressure ◽

Pressor Response ◽

Direct Action ◽

Angiotensin Receptors ◽

Ang Ii ◽

Prostaglandin Synthetase ◽

Vasopressin Antagonist ◽

Native Chicken ◽

Blood Pressure Responses ◽

Depressor Action

In chronically cannulated conscious chickens, Gallus gallus, native chicken angiotensin II ([Asp1,Val5]ANG II) caused biphasic blood pressure responses, a depressor followed by a pressor response. The pressor response appears to be mediated primarily by catecholamines. The depressor responses increased with increasing doses and were accompanied by tachycardia. The onset of the depressor action of [Asp1,Val5]ANG II (2.49 +/- 0.22 s) was nearly as quick as that of acetylcholine or histamine. Replacement of aspartic acid in position 1 with sarcosine or asparagine reduced both depressor and pressor potencies, whereas there was no difference either in depressor or pressor potencies between [Asp1,Val5] and [Asp1,Ile5]ANG II. The depressor response to [Asp1,Val5]ANG II was not inhibited by atropine, a vasopressin antagonist, prostaglandin synthetase inhibitors, methysergide, or propranolol but was blocked markedly by [Sar1, Ile8]ANG II and partially by [Sar1,Thr8]ANG II. The results suggest that the vasodepressor action of ANG II is mediated by angiotensin receptors and may possibly be a direct action on the vascular smooth muscle.

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

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.1996.270.5.e831 ◽

1996 ◽

Vol 270 (5) ◽

pp. E831-E839 ◽

Cited By ~ 10

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.

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

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.1986.250.1.h144 ◽

1986 ◽

Vol 250 (1) ◽

pp. H144-H148 ◽

Cited By ~ 7

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.

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Angiotensin receptors alter myocardial infarction-induced remodeling of the guinea pig cardiac plexus

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00004.2015 ◽

2015 ◽

Vol 309 (2) ◽

pp. R179-R188 ◽

Cited By ~ 8

Author(s):

Jean C. Hardwick ◽

Shannon E. Ryan ◽

Emily N. Powers ◽

E. Marie Southerland ◽

Jeffrey L. Ardell

Keyword(s):

Myocardial Infarction ◽

Guinea Pig ◽

Neuronal Excitability ◽

Synaptic Function ◽

Receptor Expression ◽

Angiotensin Receptors ◽

Ang Ii ◽

Muscarinic Agonists ◽

Neuronal Remodeling ◽

Drug Treatments

Neurohumoral remodeling is fundamental to the evolution of heart disease. This study examined the effects of chronic treatment with an ACE inhibitor (captopril, 3 mg·kg−1·day−1), AT1 receptor antagonist (losartan, 3 mg·kg−1·day−1), or AT2 receptor agonist (CGP42112A, 0.14 mg·kg−1·day−1) on remodeling of the guinea pig intrinsic cardiac plexus following chronic myocardial infarction (MI). MI was surgically induced and animals recovered for 6 or 7 wk, with or without drug treatment. Intracellular voltage recordings from whole mounts of the cardiac plexus were used to monitor changes in neuronal responses to norepinephrine (NE), muscarinic agonists (bethanechol), or ANG II. MI produced an increase in neuronal excitability with NE and a loss of sensitivity to ANG II. MI animals treated with captopril exhibited increased neuronal excitability with NE application, while MI animals treated with CGP42112A did not. Losartan treatment of MI animals did not alter excitability with NE compared with untreated MIs, but these animals did show an enhanced synaptic efficacy. This effect on synaptic function was likely due to presynaptic AT1 receptors, since ANG II was able to reduce output to nerve fiber stimulation in control animals, and this effect was prevented by inclusion of losartan in the bath solution. Analysis of AT receptor expression by Western blot showed a decrease in both AT1 and AT2 receptors with MI that was reversed by all three drug treatments. These data indicate that neuronal remodeling of the guinea pig cardiac plexus following MI is mediated, in part, by activation of both AT1 and AT2 receptors.

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Corticosteroids decrease glomerular angiotensin receptors

AJP Renal Physiology ◽

10.1152/ajprenal.1987.252.3.f453 ◽

1987 ◽

Vol 252 (3) ◽

pp. F453-F457 ◽

Cited By ~ 3

Author(s):

J. G. Douglas

Keyword(s):

Mineralocorticoid Receptor ◽

Mesangial Cells ◽

Angiotensin Receptors ◽

Electrolyte Balance ◽

Ang Ii ◽

Glomerular Mesangial Cells ◽

Receptor Density ◽

Receptor Modulation ◽

Glomerular Hemodynamics

Angiotensin II (ANG II) receptors of glomerular mesangial cells are regulated in vivo by changes in Na balance, effects that are presumed to be secondary to changes in circulating ANG II. However, since changes in ANG II were accompanied by parallel changes in plasma aldosterone in all models tested, it is possible that aldosterone may have also participated in the modulation of glomerular ANG II receptors. To test this hypothesis, short-term aldosterone infusions within the physiological range were employed to favor actions that would be mediated through a high-affinity mineralocorticoid receptor. The glucocorticoid, dexamethasone, was also tested to determine the mineralocorticoid specificity of the response. Two infusion rates were associated with a decrease in glomerular ANG II receptor density of 33 and 45%, respectively. There were no changes in the affinity of ANG II in either tissue or in adrenal receptor density. Serum potassium and urinary Na/K ratio were lower in the aldosterone group. Spironolactone abolished the effect of aldosterone consistent with an action mediated through a specific mineralocorticoid receptor. Dexamethasone administration produced similar downregulation of glomerular ANG II receptor and was unaccompanied by a change in electrolyte balance or blood volume. These studies support the hypothesis that corticosteroids modulate glomerular ANG II receptors and validate the complexity of glomerular receptor modulation. The downregulation observed would be expected to diminish the ability of ANG II to influence glomerular hemodynamics in models such as mineralocorticoid and glucocorticoid-induced hypertension.

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Involvement of AT2 receptors at NRVL in tonic baroreflex suppression by endogenous angiotensins

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.1997.272.5.h2204 ◽

1997 ◽

Vol 272 (5) ◽

pp. H2204-H2210 ◽

Cited By ~ 5

Author(s):

K. S. Lin ◽

J. Y. Chan ◽

S. H. Chan

Keyword(s):

Suppressive Effect ◽

Angiotensin Receptors ◽

Ang Ii ◽

Sprague Dawley ◽

Inhibitory Modulation ◽

Sprague Dawley Rats ◽

Peptide Antagonist ◽

Endogenous Activity ◽

At2 Receptors

We evaluated the role of endogenous angiotensin II and III (ANG II and ANG III) at the rostral nucleus reticularis ventrolateralis (NRVL) in the modulation of baroreceptor reflex (BRR) response and the subtype of angiotensin receptors involved in this process. Adult male Sprague-Dawley rats anesthetized and maintained with pentobarbital sodium were used. Exogenous application of ANG II or ANG III (10, 20, or 40 pmol) by bilateral microinjection into the NRVL significantly suppressed the BRR response to transient hypertension induced by phenylephrine (5 micrograms/kg i.v.). The suppressive effect of ANG II (20 pmol) was reversed by an equimolar dose (1.6 nmol) of its peptide antagonist, [Sar1, Ile8]ANG II, and the nonpeptide antagonists for AT1 and AT2 receptors, losartan and PD-123319, respectively. On the other hand, the inhibitory action of ANG III (20 pmol) was blunted by its peptide antagonist. [Ile7]ANG III or PD-123319, but not by losartan. Blocking the endogenous activity of the angiotensins by microinjection into the bilateral NRVL of [Sar1, Ile8]ANG II, [Ile7]ANG III, or PD-123319 elicited an appreciable enhancement of the BRR response, whereas losartan produced minimal effect. These results suggest that, under physiological conditions, both endogenous ANG II and ANG III may exert a tonic inhibitory modulation on the BRR response by acting selectively on the AT2 receptors at the NRVL.

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Angiotensin receptors: distribution, signalling and function

Clinical Science ◽

10.1042/cs1000481 ◽

2001 ◽

Vol 100 (5) ◽

pp. 481-492 ◽

Cited By ~ 91

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.

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

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.2001.281.6.h2337 ◽

2001 ◽

Vol 281 (6) ◽

pp. H2337-H2365 ◽

Cited By ~ 160

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.

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