Angiotensin II (ANG II) does not utilize the Janus Kinase 2/Signal Transducers of Activated Transcription (JAK/STAT) pathway in the molecular mechanism of blood pressure response to a low salt diet

Angiotensin II (ANG II) exerts its effects on vascular smooth muscle cells through G protein-coupled AT1 receptors. ANG II stimulation activates the Janus kinase/signal transducers and activators of transcription (JAK/STAT) pathway by inducing tyrosine phosphorylation, activation, and association of JAK2 with the receptor. Association appears to be required for JAK2 phosphorylation. In the present study, electroporation experiments with neutralizing anti-Src homology phosphatase-1 (SHP-1) and anti-SHP-2 antibodies and time course determinations of SHP-1 and SHP-2 activation and complexation with JAK2 suggest that the tyrosine phosphatases, SHP-1 and SHP-2, have opposite roles in ANG II-induced JAK2 phosphorylation. SHP-1 appears responsible for JAK2 dephosphorylation and termination of the ANG II-induced JAK/STAT cascade. SHP-2 appears to have an essential role in JAK2 phosphorylation and initiation of the ANG II-induced JAK/STAT cascade leading to cell proliferation. The motif in the AT1 receptor that is required for association with JAK2 is also required for association with SHP-2. Furthermore, SHP-2 is required for JAK2-receptor association. SHP-2 may thus play a role as an adaptor protein for JAK2 association with the receptor, thereby facilitating JAK2 phosphorylation and activation.

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Angiotensin II utilizes Janus kinase 2 in hypertension, but not in the physiological control of blood pressure, during low-salt intake

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00071.2011 ◽

2011 ◽

Vol 301 (4) ◽

pp. R1169-R1176 ◽

Cited By ~ 15

Author(s):

Amy K. L. Banes-Berceli ◽

Hind Al-Azawi ◽

Daniel Proctor ◽

Harvey Qu ◽

Dominic Femminineo ◽

...

Keyword(s):

Blood Pressure ◽

Mean Arterial Pressure ◽

Arterial Pressure ◽

Janus Kinase ◽

Ang Ii ◽

Physiological Control ◽

Sodium Diet ◽

Low Sodium Diet ◽

Low Sodium ◽

Low Salt

Janus kinase (JAK) 2 is activated by ANG II in vitro and in vivo, and chronic blockade of JAK2 by the JAK2 inhibitor AG-490 has been shown recently to attenuate ANG II hypertension in mice. In this study, AG-490 was infused intravenously in chronically instrumented rats to determine if the blunted hypertension was linked to attenuation of the renal actions of ANG II. In male Sprague-Dawley rats, after a control period, ANG II at 10 ng·kg−1·min−1 was infused intravenously with or without AG-490 at 10 ng·kg−1·min−1 iv for 11 days. ANG II infusion (18 h/day) increased mean arterial pressure from 91 ± 3 to 168 ± 7 mmHg by day 11. That response was attenuated significantly in the ANG II + AG-490 group, with mean arterial pressure increasing only from 92 ± 5 to 127 ± 3 mmHg. ANG II infusion markedly decreased urinary sodium excretion, caused a rapid and sustained decrease in glomerular filtration rate to ∼60% of control, and increased renal JAK2 phosphorylation; all these responses were blocked by AG-490. However, chronic AG-490 treatment had no effect on the ability of a separate group of normal rats to maintain normal blood pressure when they were switched rapidly to a low-sodium diet, whereas blood pressure fell dramatically in losartan-treated rats on a low-sodium diet. These data suggest that activation of the JAK/STAT pathway is critical for the development of ANG II-induced hypertension by mediating its effects on renal sodium excretory capability, but the physiological control of blood pressure by ANG II with a low-salt diet does not require JAK2 activation.

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Role of Prostacyclin in Blood Pressure Regulation and Aldosterone Production in Conscious Rabbits

Clinical Science ◽

10.1042/cs0660033 ◽

1984 ◽

Vol 66 (1) ◽

pp. 33-37 ◽

Cited By ~ 8

Author(s):

Isamu Miyamori ◽

Toshio Morise ◽

Masatoshi Ikeda ◽

Hideo Koshida ◽

Yoshiyu Takeda ◽

...

Keyword(s):

Blood Pressure ◽

Angiotensin Ii ◽

Blood Pressure Response ◽

Control Level ◽

Ang Ii ◽

Pressure Regulation ◽

Aldosterone Production ◽

Hormonal Action ◽

Conscious Rabbits

1. The effects of subdepressor infusion of prostacyclin (PGI2, 5.3 pmol min−1 kg−1) on arterial pressure and aldosterone production induced by angiotensin II (ANG II) were studied in conscious rabbits. 2. Indomethacin pretreatment caused an augmented blood pressure response after ANG II infusion, which returned to near control level after concomitant infusion of a subdepressor dose of PGI2. 3. Aldosterone production after ANG II was significantly attenuated after pretreatment with indomethacin. PGI2 infusion restored this reduced response to near control level. 4. These results may suggest that PGI2 in the circulation could also serve to modulate the pressor and hormonal action(s) of ANG II.

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Cyclooxygenase-1 inhibition attenuates angiotensin II-salt hypertension and neurogenic pressor activity in the rat

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00245.2013 ◽

2013 ◽

Vol 305 (10) ◽

pp. H1462-H1470 ◽

Cited By ~ 13

Author(s):

Ninitha Asirvatham-Jeyaraj ◽

Andrew J. King ◽

Carrie A. Northcott ◽

Shivanshu Madan ◽

Gregory D. Fink

Keyword(s):

Blood Pressure ◽

Angiotensin Ii ◽

Whole Body ◽

Plasma Norepinephrine ◽

Ang Ii ◽

Salt Diet ◽

Depressor Response ◽

Cox Inhibitor ◽

Pressor Activity ◽

Cox 1

Cyclooxygenase (COX)-derived prostanoids contribute to angiotensin II (ANG II) hypertension (HTN). However, the specific mechanisms by which prostanoids act are unclear. ANG II-induced HTN is caused partly by increased sympathetic nervous system activity, especially in a setting of high dietary salt intake. This study tested the hypothesis that COX-derived prostanoids cause ANG II-salt sympathoexcitation and HTN. Experiments were conducted in conscious rats. Infusion of ANG II (150 ng·kg−1·min−1 sc) caused a marked HTN in rats on 2% salt diet, but a much smaller increase in blood pressure in rats on 0.4% salt diet. The nonselective COX inhibitor ketoprofen (2 mg/kg sc) given throughout the ANG-II infusion period attenuated HTN development in rats on 2% NaCl diet, but not in rats on 0.4% NaCl diet. The acute depressor response to ganglion blockade was used to assess neurogenic pressor activity in rats on 2% NaCl diet. Ketoprofen-treated rats showed a smaller fall in arterial pressure in response to ganglion blockade during ANG-II infusion than did nontreated controls. In additional experiments, ketoprofen-treated rats exhibited smaller increases in plasma norepinephrine levels and whole body norepinephrine spillover than we previously reported in ANG II-salt HTN. Finally, the effects of the selective COX-1 inhibitor SC560 (10 mg·kg−1·day−1 ip) and the selective COX-2 inhibitor nimesulide (10 mg·kg−1·day−1 ip) were investigated. Treatment with SC560 but not nimesulide significantly reduced blood pressure and the depressor response to ganglion blockade in ANG II-salt HTN rats. The results suggest that COX-1 products are critical for sympathoexcitation and the full development of ANG II-salt HTN in rats.

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Salt sensitivity in hypertensive rats with angiotensin II administration

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.1990.259.5.r1012 ◽

1990 ◽

Vol 259 (5) ◽

pp. R1012-R1016 ◽

Cited By ~ 12

Author(s):

K. Ando ◽

Y. Sato ◽

T. Fujita

Keyword(s):

Blood Pressure ◽

Angiotensin Ii ◽

Salt Sensitivity ◽

Ang Ii ◽

Short Term ◽

Salt Loading ◽

Salt Diet ◽

Dose Dependent Fashion ◽

Dose Dependent

We examined the salt sensitivity of blood pressure in angiotensin II (ANG II)-induced hypertension. Wistar rats, salt loaded (0.66, 2, or 8% salt-containing diet) for 4 or 12 days, were infused intravenously with 15 or 60 ng/min of ANG II. Systolic blood pressure (SBP) was not increased by long-term (12 days) salt loading, and SBP was unchanged with ANG II and normal-salt (0.66%) diet. However, when combined with salt loading, ANG II produced hypertension in a dose-dependent fashion; compared with control (120 +/- 2 mmHg), SBP was increased with 15 ng/min of ANG II and 8% salt diet (145 +/- 5 mmHg, P less than 0.05) and with 60 ng/min of ANG II and either 2 or 8% salt diet (149 +/- 8 and 174 +/- 8 mmHg, P less than 0.05, respectively). Na space (exchangeable Na) was increased in a roughly similar pattern and correlated significantly (r = 0.531, P less than 0.05) with SBP. However, with 15 ng/min of ANG II, Na space was not different among rats on either level of salt loading, although the 8% salt diet elevated SBP. Data obtained with short-term (4 days) treatment indicate that an elevated Na space preceded development of hypertension. With 15 ng/min of ANG II and 8% salt diet for 4 days, Na space was markedly (P less than 0.05) increased, but SBP was unchanged.(ABSTRACT TRUNCATED AT 250 WORDS)

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Activation of the renin-angiotensin system by a low-salt diet does not augment intratubular angiotensinogen and angiotensin II in rats

AJP Renal Physiology ◽

10.1152/ajprenal.00587.2012 ◽

2013 ◽

Vol 304 (5) ◽

pp. F505-F514 ◽

Cited By ~ 32

Author(s):

Weijian Shao ◽

Dale M. Seth ◽

Minolfa C. Prieto ◽

Hiroyuki Kobori ◽

L. Gabriel Navar

Keyword(s):

Angiotensin Ii ◽

Renal Injury ◽

Renin Angiotensin System ◽

Ang Ii ◽

Angiotensin System ◽

Salt Diet ◽

Low Salt ◽

Renin Mrna ◽

Excretion Rates ◽

Stimulation Of

In angiotensin II (ANG II) infusion hypertension, there is an augmentation of intratubular angiotensinogen (AGT) and ANG II leading to increased urinary AGT and ANG II excretion rates associated with tissue injury. However, the changes in urinary AGT and ANG II excretion rates and markers of renal injury during physiologically induced stimulation of the renin-angiotensin system (RAS) by a low-salt diet remain unclear. Male Sprague-Dawley rats received a low-salt diet (0.03% NaCl; n = 6) and normal-salt diet (0.3% NaCl, n = 6) for 13 days. Low-salt diet rats had markedly higher plasma renin activity and plasma ANG II levels. Kidney cortex renin mRNA, kidney AGT mRNA, and AGT immunoreactivity were not different; however, medullary renin mRNA, kidney renin content, and kidney ANG II levels were significantly elevated by the low-salt diet. Kidney renin immunoreactivity was also markedly increased in juxtaglomerular apparati and in cortical and medullary collecting ducts. Urinary AGT excretion rates and urinary ANG II excretion rates were not augmented by the low-salt diet. The low-salt diet caused mild renal fibrosis in glomeruli and the tubulointerstitium, but no other signs of kidney injury were evident. These results indicate that, in contrast to the response in ANG II infusion hypertension, the elevated plasma and intrarenal ANG II levels caused by physiological stimulation of RAS are not reflected by increased urinary AGT or ANG II excretion rates or the development of renal injury.

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Salt intake and angiotensin II alter microvessel density in the cremaster muscle of normal rats

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.1992.263.3.h664 ◽

1992 ◽

Vol 263 (3) ◽

pp. H664-H667 ◽

Cited By ~ 19

Author(s):

I. Hernandez ◽

A. W. Cowley ◽

J. H. Lombard ◽

A. S. Greene

Keyword(s):

Blood Pressure ◽

Angiotensin Ii ◽

Microvessel Density ◽

Salt Intake ◽

Plasma Renin ◽

Ang Ii ◽

Cremaster Muscle ◽

Salt Diet ◽

Dose Dependent Increase ◽

Dose Dependent

This study investigated the effect of salt intake and angiotensin II (ANG II) levels on microvessel density (MVD). Rats with indwelling arterial and venous catheters were placed on either a high-salt (HS; 4%) or a low-salt diet (LS; 0.4%) for 2 or 4 wk, and blood pressure, heart rate, and plasma renin activity were measured. Plasma ANG II was fixed at normal levels in half of the rats on HS by continuous intravenous infusion of ANG II (5 ng.kg-1.min-1). Samples of cremaster muscle were examined histologically to determine MVD. No difference in MVD was observed between HS and LS groups after 2 wk. After 4 wk on HS, MVD was reduced (22.4%, P less than 0.05) compared with the LS group. In rats fed HS, ANG II infusion induced a significant dose-dependent increase in MVD from 85.11 +/- 3.34 to 98.94 +/- 4.62 (ANG II, 5 ng.kg-1.min-1) and to 107.60 +/- 7.00 (ANG II, 10 ng.kg-1.min-1) (P less than 0.05), with no change in blood pressure. Maintenance of ANG II levels for 4 wk blocked the rarefaction due to salt. These results suggest that the decrease in MVD due to salt could be the result of a dietary-induced fall in plasma ANG II levels.

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Contribution of angiotensin II internalization to intrarenal angiotensin II levels in rats

AJP Renal Physiology ◽

10.1152/ajprenal.00322.2001 ◽

2002 ◽

Vol 283 (5) ◽

pp. F1003-F1010 ◽

Cited By ~ 37

Author(s):

Catherine Ingert ◽

Michèle Grima ◽

Catherine Coquard ◽

Mariette Barthelmebs ◽

Jean-Louis Imbs

Keyword(s):

Blood Pressure ◽

Angiotensin Ii ◽

Renal Cortex ◽

Salt Intake ◽

Ang Ii ◽

Converting Enzyme ◽

Salt Restriction ◽

Arterial Blood ◽

Low Salt ◽

Wistar Kyoto

This study was designed to determine the involvement of AT1 receptors in the uptake of ANG II in the kidney of rats exposed to differing salt intake. Male Wistar-Kyoto rats were treated with a normal-salt (NS; 1% NaCl, n = 7) or a low-salt (LS; 0.025% NaCl, n = 7) diet combined with (LS+Los, n = 7; NS+Los, n = 7) or without losartan (30 mg · kg−1 · day−1), an AT1 receptor antagonist. Renin (RA) and angiotensin-converting enzyme (ACE) activities and angiotensinogen, ANG I, and ANG II levels were measured in plasma, renal cortex, and medulla. In LS rats, in both plasma and renal cortex, the increase in RA was associated with an increase in ANG I and ANG II levels compared with NS rats, but intrarenal ANG II levels increased more than ANG I levels. In NS+Los rats, the increase in RA in plasma was followed by a marked increase in plasma ANG I and ANG II levels compared with NS rats whereas in the kidney the increase of renal RA was followed by a decrease of the levels of these peptides. The same pattern was observed in LS+Los rats, but the decrease in renal ANG II levels was much more pronounced in LS+Los rats than in NS+Los rats. Our results suggest that the increase in renal ANG II levels after salt restriction results mainly from an uptake of ANG II, via AT1 receptors. Such elevated intrarenal ANG II levels could contribute to maintain sodium and fluid balance and arterial blood pressure during salt-deficiency states.

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Blood pressure response to chronic episodic hypoxia: the renin-angiotensin system

Journal of Applied Physiology ◽

10.1152/japplphysiol.00152.2001 ◽

2002 ◽

Vol 92 (2) ◽

pp. 627-633 ◽

Cited By ~ 91

Author(s):

Eugene C. Fletcher ◽

Natalia Orolinova ◽

Michael Bader

Keyword(s):

Blood Pressure ◽

Angiotensin Ii ◽

Renin Angiotensin System ◽

High Salt ◽

High Salt Diet ◽

Angiotensin System ◽

Salt Diet ◽

Renin Angiotensin ◽

Low Salt ◽

Episodic Hypoxia

By using an inspired oxygen fraction that produces oxyhemoglobin desaturation equivalent to that seen in human sleep apnea, we have demonstrated that 35 days of recurrent episodic hypoxia (every 30 s for 7 h/day) results in an 8–13 mmHg persistent increase in diurnal systemic mean arterial blood pressure (MAP) in rats. Blockade of angiotensin II receptors (AT1a) eliminates this response. Separate groups of male Sprague-Dawley rats were fed high-salt (8%), ad libitum-salt, or low-salt (0.1%) diets for 7 wk: 2 wk of wash-in for baseline blood pressure measurement and 5 wk of experimental conditions. Rats in each salt group were subjected to episodic hypoxia whereas controls remained unhandled under normoxic conditions. MAP remained at basal levels in all nonepisodic hypoxia controls as well as high-salt-diet episodic hypoxia-exposed rats. Ad lib and low-salt episodic hypoxia rats showed an increase in MAP from 106 and 104 mmHg at baseline to 112 and 113 mmHg, respectively ( P < 0.05). Whole kidney renin mRNA was suppressed in high-salt controls and episodic hypoxia rats, whereas kidney AT1a mRNA showed opposite changes. Suppression of the renin-angiotensin system with a high-salt diet blocks the increase in MAP in episodic hypoxia-challenged rats, in part by suppressing local tissue renin levels. Upregulation of the tissue angiotensin II system appears to be necessary for the chronic blood pressure changes that occur from episodic hypoxia.

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