Insulin treatment enhances AT1 receptor function in OK cells

2005 ◽  
Vol 288 (6) ◽  
pp. F1213-F1219 ◽  
Author(s):  
Anees Ahmad Banday ◽  
Athar H. Siddiqui ◽  
Michelle M. Menezes ◽  
Tahir Hussain
Keyword(s):  
Insulin Treatment ◽  
Receptor Expression ◽  
Receptor Protein ◽  
Protein Synthesis Inhibitor ◽  
Proximal Tubule Cell ◽  
Mrna Levels ◽  
Ang Ii ◽  
Receptor Function ◽  
Ok Cells ◽  
Stimulation Of

Increased renal sodium retention is considered a major risk factor contributing to hypertension associated with chronic hyperinsulinemia and obesity. However, the molecular mechanism involved is not understood. The present study investigates the effect of insulin treatment on AT1 receptor expression and ANG II-induced stimulation of Na/H exchanger (NHE) and Na-K-ATPase (NKA) in opossum kidney (OK) cells, a proximal tubule cell line. The presence of the AT1 receptors in OK cells was confirmed by the specific binding of 125I-sar-ANG II and by detecting ∼43-kDa protein on Western blot analysis with AT1 receptor antibody and blocking peptide as well as by expression of AT1 receptor mRNA as determined by RT-PCR. Insulin treatment (100 nM for 24 h) caused an increase in 125I-sar-ANG II binding, AT1 receptor protein content, and mRNA levels. The whole cell lysate and membrane showed similar insulin-induced increase in the AT1 receptor protein expression, which was blocked by genistein (100 nM), a tyrosine kinase inhibitor, and cycloheximide (1.5 μg/ml), a protein synthesis inhibitor. Determination of ethyl isopropyl amiloride-sensitive 22Na+ uptake, a measure of the NHE activity, revealed that ANG II (1–100 pM)-induced stimulation of NHE in insulin-treated cells was significantly greater than in the control cells. Similarly, ANG II (1–100 pM)-induced stimulation of ouabain-sensitive 86Rb+ uptake, a measure of NKA activity in insulin-treated cells, was significantly greater than in the control cells. ANG II stimulation of both the transporters was blocked by AT1 receptor antagonist losartan, suggesting the involvement of AT1 receptors. Thus chronic insulin treatment causes upregulation of AT1 receptors, which evoked ANG II-induced stimulation of NHE and NKA. We propose that insulin-induced increase in the renal AT1 receptor function serves as a mechanism responsible for the increased renal sodium reabsorption and thus may contribute to development of hypertension in conditions associated with hyperinsulinemia.

Kidney angiotensin and angiotensin receptor expression in prenatally programmed hypertension

2004 ◽  
Vol 287 (2) ◽  
pp. F262-F267 ◽  
Author(s):  
V. Matti Vehaskari ◽  
Tyrus Stewart ◽  
Derek Lafont ◽  
Christopher Soyez ◽  
Dale Seth ◽  
...  
Keyword(s):  
Mrna Level ◽  
Renin Angiotensin System ◽  
Receptor Expression ◽  
Receptor Protein ◽  
Mrna Levels ◽  
Ang Ii ◽  
Angiotensin Receptor ◽  
Subtype B ◽  
Abnormal Pattern ◽  
Intrarenal Ras

Adult hypertension may be programmed by the prenatal environment in humans and in experimental animals. The potential role of the intrarenal renin-angiotensin system (RAS) in prenatally programmed hypertension was investigated. Hypertension in rat offspring was induced by maternal protein restriction during pregnancy. The offspring were studied on day 1 of life and immediately preceding the development of hypertension on day 28. ANG I and II contents were determined by radioimmunoassy. Angiotensin receptor protein and mRNA levels were quantified by immunoblotting and real-time RT-PCR, respectively. Plasma and kidney ANG I and II were unchanged in the offspring from low-protein pregnancies (LP). ANG II type 1 receptor (AT1R) protein abundance was low in the newborn LP kidney ( P < 0.05) but rose above control values by 28 days of age ( P < 0.05); the rise was associated with an increase in AT1R subtype A ( P < 0.01), but not subtype B, mRNA level. ANG II type 2 receptor protein expression was decreased on day 1 ( P < 0.05) and increased on day 28 ( P < 0.05) in LP kidneys. The results show that prenatal programming of hypertension is associated with an abnormal pattern of intrarenal RAS ontogeny that may play a pathogenetic role, for instance, by constitutively altering renal hemodynamics or Na reabsorption.

scholarly journals Regulation of interleukin 6 receptor expression in human monocytes and monocyte-derived macrophages. Comparison with the expression in human hepatocytes.

1989 ◽  
Vol 170 (5) ◽  
pp. 1537-1549 ◽  
Author(s):  
J Bauer ◽  
T M Bauer ◽  
T Kalb ◽  
T Taga ◽  
G Lengyel ◽  
...  
Keyword(s):  
Plasma Cells ◽  
Human Peripheral Blood ◽  
Receptor Expression ◽  
Mrna Levels ◽  
Blood Monocytes ◽  
Inflammatory Conditions ◽  
High Concentrations ◽  
Human Primary Hepatocytes ◽  
Stimulation Of

IL-6 is a cytokine with pleiotropic biological functions, including induction of the hepatic acute phase response and differentiation of activated B cells into Ig-secreting plasma cells. We found that human peripheral blood monocytes express the IL-6-R, which is undetectable on the large majority of lymphocytes of healthy individuals. Stimulation of monocytes by endotoxin or IL-1 causes a rapid downregulation of IL-6-R mRNA levels and a concomitant enhancement of IL-6 mRNA expression. IL-6 itself was found to suppress the IL-6-R at high concentrations. A gradual decrease of IL-6-R mRNA levels was observed along in vitro maturation of monocytes into macrophages. We show that downregulation of IL-6-R mRNA levels by IL-1 and IL-6 is monocyte specific, since IL-6-R expression is stimulated by both IL-1 and IL-6 in cultured human primary hepatocytes. Our data indicate that under noninflammatory conditions, monocytes may play a role in binding of trace amounts of circulating IL-6. Repression of monocytic IL-6-R and stimulation of hepatocytic IL-6-R synthesis may represent a shift of the IL-6 tissue targets under inflammatory conditions.

Abstract 309: Sp-3 But not the NF-kB Transcription Factor Causes the Up-regulation of Angiotensin Type 1 Receptor Expression and Contributes to Hypertension in Aging FBN rats.

Hypertension ◽  
2014 ◽  
Vol 64 (suppl_1) ◽  
Author(s):  
Mohammad Saleem ◽  
Mohammad Asghar
Keyword(s):  
Blood Pressure ◽  
Transcription Factors ◽  
At1 Receptor ◽  
Receptor Expression ◽  
Receptor Protein ◽  
Receptor Function ◽  
Receptor Mrna ◽  
Hk2 Cells ◽  
Angiotensin Type

We recently reported that age-associated oxidative stress is causal to higher renal angiotensin Type 1 (AT1) receptor function and hypertension in aged Fisher 344 X Brown Norway (FBN) rats. We became interested in examining the mechanism of higher AT1 receptor function in the aging kidneys. Adult (3-month) and aging (21 month) FBN rats were subjected to conscious blood pressure measurement by telemetry approach. The levels of AT1 receptor mRNA in the kidney cortex was measured by qRT-PCR while nuclear Sp-3 and NF-kB-p65 redox-sensitive transcription factors were determined by western blotting. We found that blood pressure was higher in aged than in adult rats (adult vs. old: 110±1 vs. 130±1 mmHg) which was associated with higher AT1 receptor mRNA levels (adult vs. old: 1.51±0.72 vs. 7.86±1.03 DU), and nuclear levels of both Sp-3 (adult vs. old: 0.56±.01 vs. 1.54±.02 DU) and NF-kB-p65 (adult vs. old: 0.9±.01 vs. 1.5±0.01 DU). To further delineate whether sp-3 or NF-kB-p65 or both transcription factors are responsible for the up-regulation of AT1 receptor, human kidney (HK2) cells were transfected with Sp-3 and NF-kB-p65 plasmids. We found that Sp-3 plasmid but not NF-κB-p65 plasmid transfection caused an increase in the levels of AT1 receptor protein in HK2 cells (control vs. transfected: 135±22 vs. 235±10 DU). Furthermore, Sp-3 siRNA treatment resulted in the reduction of Sp-3 (control vs. transfected: 136±10 vs. 93±21 DU) and AT1 receptor protein levels (control vs. transfected: 270±38 vs. 172±201 DU) in HK2 cells. Our results suggest that sp-3 but not the NF-κB-p65 is involved in the up-regulation of renal AT1 receptor that may be contributing to hypertension in aging FBN rats.

Water deprivation upregulates ANG II AT1 binding and mRNA in rat subfornical organ and anterior pituitary

1997 ◽  
Vol 273 (1) ◽  
pp. E156-E163 ◽  
Author(s):  
G. L. Sanvitto ◽  
O. Johren ◽  
W. Hauser ◽  
J. M. Saavedra
Keyword(s):  
Paraventricular Nucleus ◽  
Median Eminence ◽  
Anterior Pituitary ◽  
Water Deprivation ◽  
Subfornical Organ ◽  
Receptor Expression ◽  
Mrna Levels ◽  
Ang Ii ◽  
At1 Receptors ◽  
Receptor Mrna

We studied angiotensin II (ANG II) receptor subtype expression in selected brain nuclei and pituitary gland after water deprivation by in vitro receptor autoradiography using 125I-labeled [Sar1]ANG II and by in situ hybridization using 35S-labeled AT1A, AT1B, and AT2 receptor-specific riboprobes. In control rats we found binding to AT1 receptors in the subfornical organ, paraventricular nucleus, median eminence, and anterior pituitary; AT1A mRNA expression in the subfornical organ and paraventricular nucleus; and AT1B mRNA expression in the anterior pituitary. No receptor mRNA was found in the median eminence. AT1 receptors and AT1A receptor mRNA levels were increased in the subfornical organ, and, in the anterior pituitary, AT1 receptors and AT1B receptor mRNA were increased, only after 5 days of water deprivation. No significant changes occurred after 1 or 3 days of water deprivation, and no regulation of ANG II receptor expression was detected in other brain areas. Our results show that prolonged water deprivation selectively regulates AT1 receptor expression and AT1A and AT1B receptor mRNA levels in the subfornical organ and anterior pituitary, respectively, supporting a role for these receptors during sustained dehydration.

scholarly journals Comparative expression analysis of the renin–angiotensin system components between white and brown perivascular adipose tissue

2008 ◽  
Vol 197 (1) ◽  
pp. 55-64 ◽  
Author(s):  
B Gálvez-Prieto ◽  
J Bolbrinker ◽  
P Stucchi ◽  
A I de las Heras ◽  
B Merino ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Renin Angiotensin System ◽  
Receptor Expression ◽  
Mrna Levels ◽  
Ang Ii ◽  
Perivascular Adipose Tissue ◽  
Angiotensin System ◽  
Renin Angiotensin ◽  
Vascular Bed ◽  
Brown Adipose

Recent studies have demonstrated that the rat adipose tissue expresses some of the components necessary for the production of angiotensin II (Ang II) and the receptors mediating its actions. The aim of this work is to characterize the expression of the renin–angiotensin system (RAS) components in perivascular adipose tissue and to assess differences in the expression pattern depending on the vascular bed and type of adipose tissue. We analyzed Ang I and Ang II levels as well as mRNA levels of RAS components by a quantitative RT-PCR method in periaortic (PAT) and mesenteric adipose tissue (MAT) of 3-month-old male Wistar–Kyoto rats. PAT was identified as brown adipose tissue expressing uncoupling protein-1 (UCP-1). It had smaller adipocytes than those from MAT, which was identified as white adipose tissue. All RAS components, except renin, were detected in both PAT and MAT. Levels of expression of angiotensinogen, Ang-converting enzyme (ACE), and ACE2 were similar between PAT and MAT. Renin receptor expression was five times higher, whereas expression of chymase, AT1a, and AT2 receptors were significantly lower in PAT compared with MAT respectively. In addition, three isoforms of the AT1a receptor were found in perivascular adipose tissue. The AT1b receptor was found at very a low expression level. Ang II levels were higher in MAT with no differences between tissues in Ang I. The results show that the RAS is differentially expressed in white and brown perivascular adipose tissues implicating a different role for the system depending on the vascular bed and the type of adipose tissue.

Abstract 246: Interleukin-1 Potentiates Renal Sodium Retention in Angiotensin Ii-dependent Hypertension by Preventing No-mediated Inhibition of the Na+-k+-2cl- Cotransporter

Hypertension ◽  
2013 ◽  
Vol 62 (suppl_1) ◽  
Author(s):  
Jiandong Zhang ◽  
Mehul B Patel ◽  
Robert Griffiths ◽  
Matthew Sparks ◽  
Steven D Crowley
Keyword(s):  
Interleukin 1 ◽  
Mrna Levels ◽  
Sodium Retention ◽  
Ang Ii ◽  
Immune Mediated ◽  
Lower Blood ◽  
Blood Pressures ◽  
No Bioavailability ◽  
Macrophage Cytokine ◽  
Stimulation Of

The current studies define the mechanism through which interleukin-1 receptor (IL-1R) activation exacerbates angiotensin (Ang) II-induced hypertension. We previously reported that IL-1R-deficient (KO) mice had attenuated elevations in blood pressure (BP) vs. wild-types (WT) in our hypertension model of uni-nephrectomy followed by 4 wks of Ang II infusion. As the IL-1 receptor modulates macrophage function, we blindly counted F4/80+ macrophages in KO and WT kidneys after 4 wks of Ang II. Compared to WTs, the KO kidneys contained more macrophages (13.6±1.7 vs. 17.9±0.8 per HPF; p=0.03) and had higher mRNA levels of the macrophage cytokine iNOS (1.0±0.2 vs. 1.7±0.3 au; p<0.05) that drives nitric oxide (NO) generation. As NO regulates renal sodium (Na) handling, we conducted Na balance studies during Ang II infusion. Over days 10-15 of Ang II during which WT and KO BPs separated, the KOs entered negative Na balance while that of the WTs remained positive (-16.8±16.8 vs. 34.8±7.5 μmol/day, p=0.01). Thus, the KOs were protected from Ang II-induced Na retention. To confirm that preserved NO bioavailability in the Ang II-infused KOs led to their lower blood pressures vs. WTs, we blocked NO generation in the groups with L-NAME starting on day 7 of Ang II when the WT and KO BPs were 179±3 vs. 165±6 mm Hg (p<0.01), and by day 14, the BPs had converged (186±5 vs. 185±8; p=NS). Thus, NO depletion abrogated the BP difference between groups. As NO is known to regulate activity of the Na-K-2Cl (NKCC2) cotransporter, we measured NKCC2 activity at day 10 of Ang II by quantitating urine (U) Na/Cr 3 hours after an IP injection of 0.5ml saline with or without furosemide (20mg/kg). Following saline injection alone, the KOs had a higher UNa/Cr than the WTs (237±38 vs. 120±14 mmol/mmol; p=0.01) whereas the UNa/Cr’s converged in response to furosemide (481±103 vs. 453±60; p=NS). By contrast, the UNa/Cr’s did not converge following an IP HCTZ challenge to block NCC channels (not shown). Thus, lower levels of NKCC2 activity in the IL-1R KOs protect them from Ang II-induced sodium retention. In sum, our studies define a novel immune-mediated mechanism of hypertension in which Ang II-induced stimulation of IL-1 signaling promotes renal sodium retention by limiting NO-mediated inhibition of NKCC2 activity.

scholarly journals Loss of renal medullary endothelin B receptor function during salt deprivation is regulated by angiotensin II

2012 ◽  
Vol 303 (5) ◽  
pp. F659-F666 ◽  
Author(s):  
Wararat Kittikulsuth ◽  
Jennifer S. Pollock ◽  
David M. Pollock
Keyword(s):  
Receptor Binding ◽  
Sodium Excretion ◽  
Receptor Expression ◽  
Ang Ii ◽  
Receptor Function ◽  
Blood Pressure Elevation ◽  
Salt Diet ◽  
Low Salt ◽  
Renal Inner Medulla ◽  
Endothelin B

We have recently demonstrated that chronic infusion of exogenous ANG II, which induces blood pressure elevation, attenuates renal medullary endothelin B (ETB) receptor function in rats. Moreover, this was associated with a reduction of ETB receptor expression in the renal inner medulla. The aim of this present work was to investigate the effect of a physiological increase in endogenous ANG II (low-salt diet) on the renal ET system, including ETB receptor function. We hypothesized that endogenous ANG II reduces renal medullary ETB receptor function during low-salt intake. Rats were placed on a low-salt diet (0.01–0.02% NaCl) for 2 wk to allow an increase in endogenous ANG II. In rats on normal-salt chow, the stimulation of renal medullary ETB receptor by ETB receptor agonist sarafotoxin 6c (S6c) causes an increase in water (3.6 ± 0.4 from baseline vs. 10.5 ± 1.3 μl/min following S6c infusion; P < 0.05) and sodium excretion (0.38 ± 0.06 vs. 1.23 ± 0.17 μmol/min; P < 0.05). The low-salt diet reduced the ETB-dependent diuresis (4.5 ± 0.5 vs. 6.1 ± 0.9 μl/min) and natriuresis (0.40 ± 0.11 vs. 0.46 ± 0.12 μmol/min) in response to acute intramedullary infusion of S6c. Chronic treatment with candesartan restored renal medullary ETB receptor function; urine flow was 7.1 ± 0.9 vs. 15.9 ± 1.7 μl/min ( P < 0.05), and sodium excretion was 0.4 ± 0.1 vs. 1.1 ± 0.1 μmol/min ( P < 0.05) before and after intramedullary S6c infusion, respectively. Receptor binding assays determined that the sodium-depleted diet resulted in a similar level of ETB receptor binding in renal inner medulla compared with rats on a normal-salt diet. Candesartan reduced renal inner medullary ETB receptor binding (1,414 ± 95 vs. 862 ± 50 fmol/mg; P < 0.05). We conclude that endogenous ANG II attenuates renal medullary ETB receptor function to conserve sodium during salt deprivation independently of receptor expression.

scholarly journals Regulation of angiotensin II type 2 receptor gene expression in the adrenal medulla by acute and repeated immobilization stress

2012 ◽  
Vol 215 (2) ◽  
pp. 291-301 ◽  
Author(s):  
Regina Nostramo ◽  
Andrej Tillinger ◽  
Juan M Saavedra ◽  
Ashok Kumar ◽  
Varunkumar Pandey ◽  
...  
Keyword(s):  
Gene Expression ◽  
Angiotensin Ii ◽  
Receptor Gene ◽  
Receptor Expression ◽  
Mrna Levels ◽  
Ang Ii ◽  
Catecholamine Biosynthesis ◽  
Receptor Mrna ◽  
Receptor Gene Expression

While the renin–angiotensin system is important for adrenomedullary responses to stress, the involvement of specific angiotensin II (Ang II) receptor subtypes is unclear. We examined gene expression changes of angiotensin II type 1A (AT1A) and type 2 (AT2) receptors in rat adrenal medulla in response to immobilization stress (IMO). AT2 receptor mRNA levels decreased immediately after a single 2-h IMO. Repeated IMO also decreased AT2 receptor mRNA levels, but the decline was more transient. AT1A receptor mRNA levels were unaltered with either single or repeated IMO, although binding was increased following repeated IMO. These effects of stress on Ang II receptor expression may alter catecholamine biosynthesis, as tyrosine hydroxylase and dopamine β-hydroxylase mRNA levels in PC12 cells are decreased with Ang II treatment in the presence of ZD7155 (AT1 receptor antagonist) or with CGP42112 (AT2 receptor agonist) treatment. Involvement of stress-triggered activation of the hypothalamic–pituitary–adrenocortical or sympathoadrenal axis in AT2 receptor downregulation was examined. Cultured cells treated with the synthetic glucocorticoid dexamethasone displayed a transcriptionally mediated decrease in AT2 receptor mRNA levels. However, glucocorticoids are not required for the immediate stress-triggered decrease in AT2 receptor gene expression, as demonstrated in corticotropin-releasing hormone knockout (Crh KO) mice and hypophysectomized rats, although they can regulate basal gene expression. cAMP and pituitary adenylate cyclase-activating polypeptide also reduced AT2 receptor gene expression and may mediate this response. Overall, the effects of stress on adrenomedullary AT1A and AT2 receptor expression may contribute to allostatic changes, such as regulation of catecholamine biosynthesis.

scholarly journals Selective knockdown of AT1 receptors by RNA interference inhibits Val5-ANG II endocytosis and NHE-3 expression in immortalized rabbit proximal tubule cells

2007 ◽  
Vol 293 (1) ◽  
pp. C367-C378 ◽  
Author(s):  
Xiao C. Li ◽  
Jia L. Zhuo
Keyword(s):  
Proximal Tubule ◽  
Physiological Effect ◽  
Mitogen Activated Protein Kinase ◽  
Receptor Protein ◽  
Proximal Tubule Cell ◽  
Ang Ii ◽  
Western Blots ◽  
Receptor Mediated Endocytosis ◽  
Mitogen Activated Protein

Receptor-mediated endocytosis of extracellular ANG II has been suggested to play an important role in the regulation of proximal tubule cell (PTC) function. Using immortalized rabbit PTCs as an in vitro cell culture model, we tested the hypothesis that extracellular ANG II is taken up by PTCs through angiotensin type 1 receptor (AT1; or AT1a) receptor-mediated endocytosis and that inhibition of ANG II endocytosis using a selective AT1 receptor small-interfering RNA (siRNA; AT1R siRNA) or endocytotic inhibitors exerts a physiological effect on total and apical sodium and hydrogen exchanger isoform 3 (NHE-3) protein abundance. Western blots and live cell imaging with FITC-labeled ANG II confirmed that transfection of PTCs with a human specific AT1R siRNA for 48 h selectively knocked down AT1 receptor protein by 76 ± 5% ( P < 0.01), whereas transfection with a scrambled siRNA had little effect. In nontransfected PTCs, exposure to extracellular ANG II (1 nM) for 60 min at 37°C increased intracellular ANG II accumulation by 67% (control: 566 ± 55 vs. ANG II: 943 ± 160 pg/mg protein, P < 0.05) and induced mitogen-activated protein kinase extracellular signal-regulated kinase (ERK) 1/2 phosphorylation (163 ± 15% of control, P < 0.01). AT1R siRNA reduced ANG II endocytosis to a level similar to losartan, which blocks cell surface AT1 receptors (557 ± 37 pg/mg protein, P < 0.05 vs. ANG II), or to colchicine, which disrupts cytoskeleton microtubules (613 ± 12 pg/mg protein, P < 0.05 vs. ANG II). AT1R siRNA, losartan, and colchicine all attenuated ANG II-induced ERK1/2 activation and total cell lysate and apical membrane NHE-3 abundance. The scrambled siRNA had no effect on ANG II endocytosis, ERK1/2 activation, or NHE-3 expression. These results suggest that AT1 receptor-mediated endocytosis of extracellular ANG II may regulate proximal tubule sodium transport by increasing total and apical NHE-3 proteins.

Abstract 6: Angiotensin II via Its Type 1 Receptor Up-regulates (Pro)renin Receptor Expression in Doca-salt Hypertension

Hypertension ◽  
2013 ◽  
Vol 62 (suppl_1) ◽  
Author(s):  
Wencheng Li ◽  
Yumei Feng
Keyword(s):  
Binding Protein ◽  
Camp Response Element Binding ◽  
Fold Change ◽  
Receptor Expression ◽  
Mrna Levels ◽  
Activator Protein 1 ◽  
Ang Ii ◽  
Salt Treatment ◽  
Salt Hypertension

We previously reported that brain (pro)renin receptor (PRR) expression levels are elevated in deoxycorticosterone acetate (DOCA)-salt induced hypertension; however, the underlining mechanism remains unknown. To address whether angiotensin (Ang II) type 1 receptor (AT1R) signals are involved in the regulation of PRR expression in DOCA-salt hypertension, C57Bl/6J mice were implanted with telemetry transmitters. After two weeks recovery, mice were treated with DOCA (50mg) or SHAM pellet, and supplied with 0.9% saline as drinking solution; at the same time, mice were ICV infused with artificial CSF or AT1R blocker losartan (3mg/kg/day) for 3 weeks. The mean arterial BP was significantly higher in DOCA-salt (132.3±6.3mmHg) compared to SHAM (100.2±2.3mmHg) mice. ICV infusion of losartan prevented the increase in BP (107.4±2.7mmHg) following DOCA-salt treatment. The PRR mRNA levels (fold change) were significantly increased in the paraventricular nucleus (PVN) of DOCA-salt (2.9±0.3) compared with SHAM mice (1.0±0.1, P<0.05). Interestingly, ICV infusion of losartan significantly attenuated PRR mRNA levels in the PVN (1.3±0.1) following DOCA-salt treatment (P<0.05). These data suggest a role of Ang II/AT1R in regulating PRR expression during DOCA-salt hypertension. A transcription factor prediction search showed cAMP response element-binding protein (CREB), activator protein-1 binding protein (AP-1), and NF-kB binding sites on the PRR promoter region. To test whether these Ang II/AT1R downstream transcription factors are involved in PRR regulation, Neuro-2A cells were treated with Ang II (100nM, 2 h) with or without CREB (CBP-CREB interaction inhibitor, 10μM), AP-1 (SR-11302, 10μM), or NF-κB (parthenolide, 10μM) inhibitors. PRR mRNA levels (fold change) were slightly but significantly increased (1.3±0.1 vs. vehicle, P<0.05) following Ang II treatment. CREB (0.8±0.2) or AP-1 (0.7±0.1) inhibitor abolished the increase in PRR mRNA induced by Ang II (P<0.01). The NF-kB inhibitor had no effect on Ang II-induced PRR mRNA elevation. In conclusion, Ang II via AT1R up-regulates PRR mRNA expression in the PVN of DOCA-hypertensive mice possibly through activation of CREB and AP-1 signaling pathways.

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