Guanylyl cyclase/natriuretic peptide receptor-A gene disruption causes increased adrenal angiotensin II and aldosterone levels

2007 ◽  
Vol 293 (1) ◽  
pp. F121-F127 ◽  
Author(s):  
Di Zhao ◽  
Elangovan Vellaichamy ◽  
Naveen K. Somanna ◽  
Kailash N. Pandey
Keyword(s):  
Dependent Manner ◽  
Natriuretic Peptide Receptor ◽  
Ang Ii ◽  
High Salt Diet ◽  
Salt Diet ◽  
Peptide Receptor ◽  
Arterial Blood ◽  
Low Salt ◽  
Natriuretic Peptide Receptor A ◽  
Dose Dependent

Disruption of the guanylyl cyclase-A/natriuretic peptide receptor-A (GC-A/NPRA) gene leads to elevated arterial blood pressure and congestive heart failure in mice lacking NPRA. This study was aimed at determining whether Npr1 (coding for GC-A/NPRA) gene copy number affects adrenal ANG II and aldosterone (Aldo) levels in a gene-dose-dependent manner in Npr1 gene-targeted mice. Adrenal ANG II and Aldo levels increased in 1-copy mice compared with 2-copy mice, but decreased in 3-copy and 4-copy mice. In contrast, renal ANG II levels decreased in 1-copy (25%), 3-copy (38%), and 4-copy (39%) mice compared with 2-copy mice. The low-salt diet stimulated adrenal ANG II and Aldo levels in 1-copy (20 and 2,441%), 2-copy (15 and 2,339%), 3-copy (20 and 424%), and 4-copy (31 and 486%) mice, respectively. The high-salt diet suppressed adrenal ANG II and Aldo levels in 1-copy (46 and 29%) and 2-copy (38 and 17%) mice. On the other hand, the low-salt diet stimulated renal ANG II levels in 1-copy (45%), 2-copy (45%), 3-copy (59%), and 4-copy (48%) mice. However, the high-salt diet suppressed renal ANG II levels in 1-copy (28%) and 2-copy (27%) mice. In conclusion, NPRA signaling antagonizes adrenal ANG II and Aldo levels in a gene-dose dependent manner. Increased adrenal ANG II and Aldo levels may play an important role in elevated arterial blood pressure and progressive hypertension, leading to renal and vascular injury in Npr1 gene-disrupted mice.

Genetic disruption of atrial natriuretic peptide receptor-A alters renin and angiotensin II levels

2001 ◽  
Vol 281 (4) ◽  
pp. F665-F673 ◽  
Author(s):  
Shang-Jin Shi ◽  
Huong T. Nguyen ◽  
Guru Dutt Sharma ◽  
L. Gabriel Navar ◽  
Kailash N. Pandey
Keyword(s):  
Natriuretic Peptide ◽  
Systolic Arterial Pressure ◽  
Inhibitory Response ◽  
Mutant Mice ◽  
Natriuretic Peptide Receptor ◽  
Ang Ii ◽  
Wild Type ◽  
Compensatory Response ◽  
Peptide Receptor ◽  
Natriuretic Peptide Receptor A

We have studied cardiovascular and renal phenotypes in Npr1 (genetic determinant of natriuretic peptide receptor-A; NPRA) gene-disrupted mutant mouse model. The baseline systolic arterial pressure (SAP) in 0-copy mutant (−/−) mice (143 ± 2 mmHg) was significantly higher than in 2-copy wild-type (+/+) animals (104 ± 2 mmHg); however, the SAP in 1-copy heterozygotes (+/−) was at an intermediate value (120 ± 4 mmHg). To determine whether Npr1 gene function affects the renin-angiotensin-aldosterone system (RAAS), we measured the components of RAAS in plasma, kidney, and adrenal gland of 0-copy, 1-copy, and 2-copy male mice. Newborn (2 days after the birth) 0-copy pups showed 2.5-fold higher intrarenal renin contents compared with 2-copy wild-type counterparts (0-copy 72 ± 12 vs. 2-copy 30 ± 7 μg ANG I · mg protein−1 · h−1, respectively). The intrarenal ANG II level in 0-copy pups was also higher than in 2-copy controls (0-copy 33 ± 5 vs. 2-copy 20 ± 2 pg/mg protein, respectively). However, both young (3 wk) and adult (16 wk) 0-copy mutant mice showed a dramatic 50–80% reduction in plasma renin concentrations (PRCs) and in expression of renal renin message compared with 2-copy control animals. In contrast, the adrenal renin content and mRNA expression levels were 1.5- to 2-fold higher in 0-copy adult mice than in 2-copy animals. The results suggest that inhibition of renal and systemic RAAS is a compensatory response that prevents greater increases in elevated arterial pressures in adult NPRA null mutant mice. However, the greater renin and ANG II levels seen in 0-copy newborn pups provide evidence that the direct effect of NPRA activation on renin is an inhibitory response.

Renal endosomes contain angiotensin peptides, converting enzyme, and AT1A receptors

1999 ◽  
Vol 277 (2) ◽  
pp. F303-F311 ◽  
Author(s):  
John D. Imig ◽  
Gabriel L. Navar ◽  
Li-Xian Zou ◽  
Katie C. O’Reilly ◽  
Patricia L. Allen ◽  
...  
Keyword(s):  
High Salt ◽  
Dietary Sodium ◽  
Kidney Cortex ◽  
Ang Ii ◽  
Converting Enzyme ◽  
High Salt Diet ◽  
Salt Diet ◽  
Angiotensin Peptides ◽  
Low Salt ◽  
Ace Activity

Kidney cortex and proximal tubular angiotensin II (ANG II) levels are greater than can be explained on the basis of circulating ANG II, suggesting intrarenal compartmentalization of these peptides. One possible site of intracellular accumulation is the endosomes. In the present study, we tested for endosomal ANG I, ANG II, angiotensin type 1A receptor (AT1A), and angiotensin converting enzyme (ACE) activity and determined whether these levels are regulated by salt intake. Male Sprague-Dawley rats were fed chow containing either high or low dietary sodium for 10–14 days. Blood and kidneys were harvested and processed for measurement of plasma, kidney, and renal intermicrovillar cleft and endosomal angiotensin levels. Kidney ANG I averaged 179 ± 20 fmol/g and ANG II averaged 258 ± 36 fmol/g in rats fed a high-sodium diet and were significantly higher, averaging 347 ± 58 fmol/g and 386 ± 55 fmol/g, respectively, in rats fed a low-salt diet. Renal intermicrovillar clefts and endosomes contained ANG I and ANG II. Intermicrovillar cleft ANG I and ANG II levels averaged 8.4 ± 2.6 and 74 ± 26 fmol/mg, respectively, in rats fed a high-salt diet and 7.6 ± 1.7 and 70 ± 25 fmol/mg in rats fed a low-salt diet. Endosomal ANG I and ANG II levels averaged 12.3 ± 4.4 and 43 ± 19 fmol/mg, respectively, in rats fed a high-salt diet, and these levels were similar to those observed in rats fed a low-salt diet. Renal endosomes from rats fed a low-salt diet demonstrated significantly more AT1A receptor binding compared with rats fed a high-salt diet. ACE activity was detectable in renal intermicrovillar clefts and was 2.5-fold higher than the levels observed in renal endosomes. Acute enalaprilat treatment decreased ACE activity in renal intermicrovillar clefts by 90% and in renal endosomes by 84%. Likewise, intermicrovillar cleft and endosomal ANG II levels decreased by 61% and 52%, respectively, in enalaprilat-treated animals. These data demonstrate the presence of intact angiotensin peptides and ACE activity in renal intermicrovillar clefts and endosomes, indicating that intact angiotensin peptides are formed and/or trafficked through intracellular endosomal compartments and are dependent on ACE activity.

Abstract P331: Renal Medullary Infusion of BAF312, a Sphingosine-1-phosphate Receptor-1 Agonist, Attenuates Angiotensin II-induced Hypertension

Hypertension ◽  
2016 ◽  
Vol 68 (suppl_1) ◽  
Author(s):  
Qing Zhu ◽  
Junping Hu ◽  
Pin-Lan Li ◽  
Ningjun Li
Keyword(s):  
Collecting Duct ◽  
Renal Medulla ◽  
Ang Ii ◽  
High Salt Diet ◽  
Salt Diet ◽  
Low Salt ◽  
Induced Hypertension ◽  
Sphingosine 1 Phosphate ◽  
S1p Receptor ◽  
Cardiovascular Functions

Sphingosine-1-phosphate (S1P) is a bioactive sphingolipid metabolite formed by phosphorylation of sphingosine and participates in the regulation of cardiovascular functions. We have recently shown that S1P increases sodium excretion in the renal medulla possibly through inhibiting epithelial sodium channel via the S1P receptor 1 (S1P1), which is mainly localized in collecting ducts with a higher expression level in the renal medulla than the cortex. The present study tested the hypothesis that infusion of an agonist to activate S1P1 in the renal medulla attenuates angiotensin (ANG) II-induced hypertension. Treatment of the mice with a high salt diet (HS, 4% NaCl) for 2 week significantly increased the levels of S1P1 in the renal medulla compared with that in low salt (LS) control by Western blot analysis, whereas this HS-induced increase in S1P1 level was blocked in mice treated with ANG II (600ng/kg/min, sc) (relative S1P1 levels: 1.0±0.19, 1.9±0.14 and 0.9 ±0.18 in LS, HS and HS+ANG II-treated mice, respectively). Infusion of a subpressor dose of ANG II (300ng/kg/min, sc) increased the mean arterial pressure (MAP) in mice with collecting duct-specific knockout of S1P1, but not in S1P1 floxed control mice (MAP: 132±4.7 vs. 96±1.1 mmHg). In contrast, infusion of BAF312, a selective agonist of S1P1, into the renal medulla attenuated the hypertension induced by a pressor dose of ANG II (600 ng/kg/min, sc) in uninephrectomized mice (MAP: 102±1.8, 161 ±7.1 and 133±3.9 in vehicle, ANG II and ANG II+BAF312-treated mice, respectively). These data suggest that inhibition of S1P1 level in the renal medulla may contribute to the pathogenesis of ANG II-induced hypertension and that stimulating the S1P1 pathway may be used as a therapeutic strategy for the treatment of hypertension.

Regulation ofP-450 4A activity in the glomerulus of the rat

1999 ◽  
Vol 276 (6) ◽  
pp. R1749-R1757 ◽  
Author(s):  
Osamu Ito ◽  
Richard J. Roman
Keyword(s):  
Arachidonic Acid ◽  
Salt Intake ◽  
High Salt ◽  
Dependent Manner ◽  
Hydroxyeicosatetraenoic Acid ◽  
Dietary Salt ◽  
High Salt Diet ◽  
Salt Diet ◽  
Dietary Salt Intake ◽  
Low Salt

We recently reported that an enzyme of the cytochrome P-450 4A family is expressed in the glomerulus, but there is no evidence that 20-hydroxyeicosatetraenoic acid (20-HETE) can be produced by this tissue. The purpose of present study was to determine whether glomeruli isolated from the kidney of rats can produce 20-HETE and whether the production of this metabolite is regulated by nitric oxide (NO) and dietary salt intake. Isolated glomeruli produced 20-HETE, dihydroxyeicosatrienoic acids, and 12-hydroxyeicosatetraenoic acid (4.13 ± 0.38, 4.20 ± 0.38, and 2.10 ± 0.20 pmol ⋅ min−1⋅ mg protein−1, respectively) when incubated with arachidonic acid (10 μM). The formation of 20-HETE was dependent on the availability of NADPH and the[Formula: see text] of the incubation medium. The formation of 20-HETE was inhibited by NO donors in a concentration-dependent manner. The production of 20-HETE was greater in glomeruli isolated from the kidneys of rats fed a low-salt diet than in kidneys of rats fed a high-salt diet (5.67 ± 0.32 vs. 2.83 ± 0.32 pmol ⋅ min−1⋅ mg protein−1). Immunoblot experiments indicated that the expression of P-450 4A protein in glomeruli from the kidneys of rats fed a low-salt diet was sixfold higher than in kidneys of rats fed a high-salt diet. These results indicate that arachidonic acid is primarily metabolized to 20-HETE and dihydroxyeicosatrienoic acids in glomeruli and that glomerular P-450 activity is modulated by NO and dietary salt intake.

scholarly journals LOCALIZATION OF ANGIOTENSIN II RESPONSES IN THE TROUT CARDIOVASCULAR SYSTEM

1994 ◽  
Vol 194 (1) ◽  
pp. 117-138 ◽  
Author(s):  
K Olson ◽  
A Chavez ◽  
D Conklin ◽  
K Cousins ◽  
A Farrell ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Angiotensin Ii ◽  
Gill Arch ◽  
Cell Swelling ◽  
Dependent Manner ◽  
Ang Ii ◽  
Bladder Smooth Muscle ◽  
Perfused Heart ◽  
Arterial Blood ◽  
Dose Dependent

The renin/angiotensin system (RAS) is a tonic anti-drop regulator of arterial blood pressure in many teleosts. In trout, angiotensin II (ANG II) has no direct constrictor effect on large arteries or veins and the identity of specific cardiovascular pressor effectors is unknown. Potential targets of angiotensin activation were examined in the present experiments using perfused organs and isolated tissues from the rainbow trout Oncorhynchus mykiss. Perfused gill (arches 2 and 3), perfused skeletal muscle-kidney (via the dorsal aorta; PDA) and perfused splanchnic (via the celiacomesenteric; PCM) circulations vasoconstrict in response to salmonid ANG II in a dose-dependent manner. ANG II was significantly (P¾0.05) more potent in the PCM than in the PDA, and both preparations were more responsive than the gills: pD2=8.0±0.20 (10) for PCM; pD2=7.5±0.07 (13) for PDA; pD2=6.9 ±0.21 (8) for gill arch 3; pD2=6.7±0.23 (8) for gill arch 2; mean ± s.e.m. (N), respectively. Salmonid angiotensin I (ANG I) also produced a dose-dependent constriction of the PDA and PCM. Angiotensin converting enzyme (ACE) activated nearly 100 % of ANG I to ANG II in a single pass through the PDA, whereas PCM conversion was estimated to be less than 10 %. Inhibitors of adrenergic constriction partially prevented ANG II responses in the PDA but did not affect PCM responses. ANG II did not affect paced rings of ventricular muscle in the presence of high or low [Ca2+] or epinephrine concentrations, nor did it have any inotropic or chronotropic effects in the in situ perfused heart. Red blood cell swelling was unaffected by ANG II. Similarly, the effects of ANG II on gut, urinary bladder and gall bladder smooth muscle were negligible or non-existent; thus, an increase in splanchnic resistance due to extravascular compression can be discounted. These results indicate that, in trout, the systemic microcirculation is the major cardiovascular effector of angiotensin-mediated pressor responses. In addition, the RAS has little direct effect on non-vascular smooth muscle or the heart. From an evolutionary perspective, the initial site of direct systemic RAS action appears to be the vascular microcirculation.

Contribution of cytochrome P-450 ω-hydroxylase to altered arteriolar reactivity with high-salt diet and hypertension

2000 ◽  
Vol 278 (5) ◽  
pp. H1517-H1526 ◽  
Author(s):  
Jefferson C. Frisbee ◽  
John R. Falck ◽  
Julian H. Lombard
Keyword(s):  
Renal Mass ◽  
High Salt ◽  
Ang Ii ◽  
Cremaster Muscle ◽  
High Salt Diet ◽  
Salt Diet ◽  
Low Salt ◽  
Resting Tone ◽  
Cytochrome P 450 ◽  
Arteriolar Diameter

The present study evaluated the contribution of cytochrome P-450 ω-hydroxylase in modulating the reactivity of cremaster muscle arterioles in normotensive rats on high-salt (HS) and low-salt (LS) diet and in rats with reduced renal mass hypertension (RRM-HT). Changes in arteriolar diameter in response to ACh, sodium nitroprusside (SNP), ANG II, and elevated O2 were measured via television microscopy under control conditions and following cytochrome P-450 ω-hydroxylase inhibition with 17-octadecynoic acid (17-ODYA) or N-methylsulfonyl-12,12-dibromododec-11-enamide (DDMS). In normotensive rats on either LS or HS diet, resting tone was unaffected and arteriolar reactivity to ACh or SNP was minimally affected by cytochrome P-450 ω-hydroxylase inhibition. In RRM-HT rats, cytochrome P-450 ω-hydroxylase inhibition reduced resting tone and significantly enhanced arteriolar dilation to ACh and SNP. Treatment with 17-ODYA or DDMS inhibited arteriolar constriction to ANG II and O2 in all the groups, although the degree of inhibition was greater in RRM-HT than in normotensive animals. These results suggest that metabolites of cytochrome P-450 ω-hydroxylase contribute to the altered reactivity of skeletal muscle arterioles to vasoconstrictor and vasodilator stimuli in RRM-HT.

scholarly journals Natriuretic peptide receptor 1 expression influences blood pressures of mice in a dose-dependent manner

1998 ◽  
Vol 95 (5) ◽  
pp. 2547-2551 ◽  
Author(s):  
P. M. Oliver ◽  
S. W. M. John ◽  
K. E. Purdy ◽  
R. Kim ◽  
N. Maeda ◽  
...  
Keyword(s):  
Natriuretic Peptide ◽  
Dependent Manner ◽  
Natriuretic Peptide Receptor ◽  
Peptide Receptor ◽  
Blood Pressures ◽  
Dose Dependent

Sympathetic control of BP and BP variability in borderline hypertensive rats on high- vs. low-salt diet

1999 ◽  
Vol 277 (3) ◽  
pp. R650-R657 ◽  
Author(s):  
David R. Brown ◽  
Sheng-Gang Li ◽  
James E. Lawler ◽  
David C. Randall
Keyword(s):  
Early Stage ◽  
High Salt ◽  
Group Differences ◽  
Hypertensive Rats ◽  
High Salt Diet ◽  
Salt Diet ◽  
Percent Change ◽  
Arterial Blood ◽  
Low Salt ◽  
Change In Mean

This experiment tested the effect of a high-salt diet on the interaction between arterial blood pressure (BP) and sympathetic nerve activity (SNA) at rest and during a controlled behavioral stress at an early stage in the development of hypertension in borderline hypertensive rats (BHR). Ten rats were maintained on a high-salt diet (8% NaCl) while 14 were fed a low-salt diet (0.8% NaCl) for 8 wk. They were trained in a Pavlovian paradigm by following a conditional stimulus tone (CS+) with a 0.5-s shock. SNA and BP were measured by implanted electrodes around the left renal nerve and a catheter in the femoral artery, respectively. There were no detectable between-group differences in BP or in BP variability in the resting animal at the end of the 8-wk dietary treatment. Moreover, there were no significant between-group differences in the changes in SNA evoked by the CS+ tone. Conversely, the amplitude of the initial conditional increase in BP was significantly ( P< 0.05) larger in the high-salt (6 ± 0.6 mmHg; mean ± SEM) compared with the low-salt (4 ± 0.4 mmHg) group. In addition, the BP excursion (peak/trough) during CS+ was larger in the high (18.2 ± 6.1 mmHg)- vs. low-salt (5.8 ± 0.4 mmHg) diet-fed subjects. The ratio of the average percent change in mean BP to the average percent change in SNA at the beginning of CS+ was 0.029 ± 0.004 for the low-salt group and 0.041 ± 0.006 for the high-salt group. We find that, before the development of overt hypertension, the enhanced conditional BP response in the high-salt BHR appears to reside at the interface between changes in SNA and the effector response and not within the central nervous system. These observations help explain the increasing BP variability typically observed with the development of hypertension in humans.

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