Abstract 021: Nephron Specific Deletion of the Prorenin Receptor Modulates Blood Pressure and Urinary Na+ Excretion

Hypertension ◽  
2015 ◽  
Vol 66 (suppl_1) ◽  
Author(s):  
Nirupama Ramkumar ◽  
Deborah Stuart ◽  
Elena V Mironova ◽  
Vladislav Bugay ◽  
Mykola Mamenko ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Structural Defects ◽  
Ang Ii ◽  
Open Probability ◽  
Protein Levels ◽  
Prorenin Receptor ◽  
Collecting Ducts ◽  
Dependent Pathway ◽  
Early Lethality ◽  
Specific Deletion

The nephron prorenin receptor (PRR) may modulate blood pressure (BP) and Na+ balance. Since previous models of PRR knockout (KO) mice had early lethality and/or structural defects, we developed an inducible nephron-wide PRR KO using the Pax8/LC1 transgenes. Disruption of nephron PRR at 1 month of age caused no renal histological abnormalities. On a normal Na+ diet, wild-type (WT) and PRR KO mice had similar BP and Na+ excretion. However, PRR KO mice had elevated PRC (KO- 377 ± 77 vs WT- 127 ± 19 ng Ang-I/ml/hr) and a 50% decrease in renal ENaC-α protein. Protein levels of NHE3, NKCC2, NCC and ENaC-β/γ were similar between the two groups. Treatment with mouse prorenin (10 nM for 30 min) increased ENaC channel number by 2-fold, but not open probability, in isolated split-open cortical collecting ducts (CCD) from WT mice; this was prevented by Akt inhibition (A6730) but unaffected by blockade of AT-1 (losartan), ERK1/2 (U0126) or p38 MAPK (SB203580). Addition of prorenin (10 nM) did not change isolated CCD [Ca2+]i as assessed by Fura-2 loading (10 min exposure with readings every 3 sec). On a low Na+ diet, PRR KO mice had increased Na+ excretion (Day 2: KO - 66 ± 11 vs WT- 42 ± 6 μmol/day; Day 6: KO - 39 ± 4 vs ET- 23 ± 4 μmol/day) however, no differences in BP were observed. PRC was elevated in PRR KO mice on a low Na+ diet (KO- 384 ± 40 vs WT-174 ± 12 ng/ Ang-I/ml/hr). PRR KO mice had an attenuated hypertensive response to Angiotensin-II (Ang-II) infusion at 600 ng/Kg/min for 2 weeks (MAP: KO - 117 ± 4 vs WT - 133 ± 4 mm Hg over the course of Ang-II infusion). Urinary Na+ excretion was elevated in Ang-II treated PRR KO mice as compared to WT mice (KO-344 ± 14 vs WT-268 ±30 μmol/day). Taken together, these data indicate that nephron PRR, likely via direct prorenin/renin stimulation of an Akt-dependent pathway, stimulates CCD ENaC activity. Absence of nephron PRR promotes Na+ wasting and reduces the hypertensive response to Ang-II.

scholarly journals Renal tubular epithelial cell prorenin receptor regulates blood pressure and sodium transport

2016 ◽  
Vol 311 (1) ◽  
pp. F186-F194 ◽  
Author(s):  
Nirupama Ramkumar ◽  
Deborah Stuart ◽  
Elena Mironova ◽  
Vladislav Bugay ◽  
Shuping Wang ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Plasma Renin ◽  
Tubular Epithelial Cell ◽  
Ang Ii ◽  
Developmental Abnormalities ◽  
Signaling Mechanisms ◽  
Prorenin Receptor ◽  
Collecting Ducts ◽  
Renal Tubular

The physiological significance of the renal tubular prorenin receptor (PRR) has been difficult to elucidate due to developmental abnormalities associated with global or renal-specific PRR knockout (KO). We recently developed an inducible renal tubule-wide PRR KO using the Pax8/LC1 transgenes and demonstrated that disruption of renal tubular PRR at 1 mo of age caused no renal histological abnormalities. Here, we examined the role of renal tubular PRR in blood pressure (BP) regulation and Na+ excretion and investigated the signaling mechanisms by which PRR regulates Na+ balance. No detectable differences in BP were observed between control and PRR KO mice fed normal- or low-Na+ diets. However, compared with controls, PRR KO mice had elevated plasma renin concentration and lower cumulative Na+ balance with normal- and low-Na+ intake. PRR KO mice had an attenuated hypertensive response and reduced Na+ retention following angiotensin II (ANG II) infusion. Furthermore, PRR KO mice had significantly lower epithelial Na+ channel (ENaC-α) expression. Treatment with mouse prorenin increased, while PRR antagonism decreased, ENaC activity in isolated split-open collecting ducts (CD). The prorenin effect was prevented by protein kinase A and Akt inhibition, but unaffected by blockade of AT1, ERK1/2, or p38 MAPK pathways. Taken together, these data indicate that renal tubular PRR, likely via direct prorenin/renin stimulation of PKA/Akt-dependent pathways, stimulates CD ENaC activity. Absence of renal tubular PRR promotes Na+ wasting and reduces the hypertensive response to ANG II.

scholarly journals Collecting duct prorenin receptor knockout reduces renal function, increases sodium excretion, and mitigates renal responses in ANG II-induced hypertensive mice

2017 ◽  
Vol 313 (6) ◽  
pp. F1243-F1253 ◽  
Author(s):  
Minolfa C. Prieto ◽  
Virginia Reverte ◽  
Mykola Mamenko ◽  
Marta Kuczeriszka ◽  
Luciana C. Veiras ◽  
...  
Keyword(s):  
Renal Function ◽  
Collecting Duct ◽  
Ang Ii ◽  
Open Probability ◽  
Sodium Transporters ◽  
Prorenin Receptor ◽  
Active Channels ◽  
The Impact ◽  
Renal Responses ◽  
Stimulation Of

Augmented intratubular angiotensin (ANG) II is a key determinant of enhanced distal Na+ reabsorption via activation of epithelial Na+ channels (ENaC) and other transporters, which leads to the development of high blood pressure (BP). In ANG II-induced hypertension, there is increased expression of the prorenin receptor (PRR) in the collecting duct (CD), which has been implicated in the stimulation of the sodium transporters and resultant hypertension. The impact of PRR deletion along the nephron on BP regulation and Na+ handling remains controversial. In the present study, we investigate the role of PRR in the regulation of renal function and BP by using a mouse model with specific deletion of PRR in the CD (CDPRR-KO). At basal conditions, CDPRR-KO mice had decreased renal function and lower systolic BP associated with higher fractional Na+ excretion and lower ANG II levels in urine. After 14 days of ANG II infusion (400 ng·kg−1·min−1), the increases in systolic BP and diastolic BP were mitigated in CDPRR-KO mice. CDPRR-KO mice had lower abundance of cleaved αENaC and γENaC, as well as lower ANG II and renin content in urine compared with wild-type mice. In isolated CD from CDPRR-KO mice, patch-clamp studies demonstrated that ANG II-dependent stimulation of ENaC activity was reduced because of fewer active channels and lower open probability. These data indicate that CD PRR contributes to renal function and BP responses during chronic ANG II infusion by enhancing renin activity, increasing ANG II, and activating ENaC in the distal nephron segments.

Abstract 214: (pro) Renin Receptor Stimulates the Expression of Fibrotic Genes in Mouse Collecting Ducts Cells via Wnt/β-catenin Signaling, Independently of Angiotensin II

Hypertension ◽  
2012 ◽  
Vol 60 (suppl_1) ◽  
Author(s):  
Catherina A Cuevas ◽  
Alexis A Gonzalez ◽  
Nivaldo C Inestrosa ◽  
Carlos P Vio ◽  
Minolfa C Prieto
Keyword(s):  
Angiotensin Ii ◽  
Wnt Signaling ◽  
Cyclin D1 ◽  
Target Genes ◽  
Collecting Duct ◽  
Fold Change ◽  
Collagen I ◽  
Ang Ii ◽  
Protein Levels ◽  
Prorenin Receptor

The prorenin receptor (PRR) is upregulated in the kidney by high angiotensin II (Ang II) states such as those that occur with AngII-dependent hypertension and low salt diet. The PRR is an accessory protein of the vacuolar H-ATPase, which facilitates Wnt/β-catenin signaling. The Wnt/β-catenin pathway is involved in fibrosis processes. In the present study, we aimed to determine whether the stimulation of PRR in mouse collecting duct M-1 cells induces fibrotic genes independently of Ang II, and if this effect is mediated by activation of Wnt/β-catenin. Both Ang II (10 -7 M) and human recombinant prorenin (hRPr; 2,5 x 10 -8 M) treatments (8 and 16 hours) increased mRNA and protein levels of fibronectin and collagen I (1.5±0.08 and 1.5 ± 0.1 fold change, respectibely; p<0.05); however, the effects of hRPr were elicited earlier. Likewise, Ang II and hRPr stimulated the Wnt target genes, cyclin D1 and c-myc (cyclin D1: 2±0.2 for both; c-myc: 1.4 ± 0.03 and 1.2± 0.002 fold change for Ang II and hRPr, respectively; p<0.001). Ang II type 1 receptor (AT1R) blockade with candesartan (10 -7 M) completely prevented the Ang II-dependent stimulation but not the effects of hRPr on Wnt signaling genes. Upregulation of fibronectin and collagen I genes by Ang II or hRP at 16 h was prevented by Wnt signaling inhibition with Pyrvinium Pamoate (10 -7 M). The data indicate that in M-1 cells, activation of AT1R and PRR stimulate the synthesis of fibrotic genes via Wnt signaling by independent mechanisms.

Abstract P041: Proximal Tubule-specific Deletion Of Angiotensin Ii Type 1a Receptors In The Kidney Lowers Basal Blood Pressure And Attenuates Angiotensin Ii-induced Hypertension By Increasing Glomerular Filtration And The Pressure-natriuresis Response

Hypertension ◽  
2020 ◽  
Vol 76 (Suppl_1) ◽  
Author(s):  
Xiao C Li ◽  
Ana P Leite ◽  
Liang Zhang ◽  
Jia L Zhuo
Keyword(s):  
Blood Pressure ◽  
Angiotensin Ii ◽  
Proximal Tubule ◽  
Pressor Response ◽  
Control Group ◽  
Ang Ii ◽  
Induced Hypertension ◽  
Basal Blood Pressure ◽  
Pressure Natriuresis ◽  
Specific Deletion

The present study tested the hypothesis that intratubular angiotensin II (Ang II) and AT 1a receptors in the proximal tubules of the kidney plays an important role in basal blood pressure control and in the development of Ang II-induced hypertension. Mutant mice with proximal tubule-specific deletion of AT 1a receptors in the kidney, PT- Agtr1a -/- , were generated to test the hypothesis. Eight groups (n=7-12 per group) of adult male wild-type (WT) and PT- Agtr1a -/- mice were infused with or without Ang II for 2 weeks (1.5 mg/kg, i.p.). Basal systolic, diastolic, and mean arterial pressures were ~13 ± 3 mmHg lower in PT- Agtr1a -/- than WT mice ( P <0.01). Basal glomerular filtration rate (GFR), as measured using transdermal FITC-sinistrin, was significantly higher in PT- Agtr1a -/- mice (WT: 160.4 ± 7.0 μl/min vs. PT- Agtr1a -/- : 186.0 ± 6.0 μl/min, P <0.05). Basal 24 h urinary Na + excretion (U Na V) was significantly higher in PT- Agtr1a -/- than WT mice ( P <0.01). In response to Ang II infusion, both WT and PT- Agtr1a -/- mice developed hypertension, and the magnitude of the pressor response to Ang II was similar in WT (Δ43 ± 3 mmHg, P <0.01) and PT- Agtr1a -/- mice (Δ39 ± 5 mmHg, P <0.01). However, the absolute blood pressure level was still 16 ± 3 mmHg lower in PT- Agtr1a -/- mice ( P <0.01). Ang II significantly decreased GFR to 132.2 ± 7.0 μl/min in WT mice ( P <0.01), and to 129.4 ± 18.6 μl/min in PT- Agtr1a -/- mice ( P <0.01), respectively. In WT mice, U Na V increased from 139.3 ± 22.3 μmol/24 h in the control group to 196.4 ± 29.6 μmol/24 h in the Ang II-infused group ( P <0.01). In PT- Agtr1a -/- mice, U Na V increased from 172.0 ± 10.2 μmol/24 h in the control group to 264.7 ± 35.4 μmol/24 h in the Ang II-infused group ( P <0.01). The pressor response to Ang II was attenuated, while the natriuretic response was augmented by losartan in WT and PT- Agtr1a -/- mice ( P <0.01). Finally, proximal tubule-specific deletion of AT 1a receptors significantly augmented the pressure-natriuresis response and natriuretic responses to acute saline infusion ( P <0.01) or a 2% high salt diet ( P <0.01). We concluded that deletion of AT 1a receptors selectively in the proximal tubules lowers basal blood pressure and attenuates Ang II-induced hypertension by increasing GFR and promoting the natriuretic response in PT- Agtr1a -/- mice.

scholarly journals VSMC-Specific Deletion of FAM3A Attenuated Ang II-Promoted Hypertension and Cardiovascular Hypertrophy

2020 ◽  
Vol 126 (12) ◽  
pp. 1746-1759 ◽  
Author(s):  
Rui Xiang ◽  
Ji Chen ◽  
Shuangyue Li ◽  
Han Yan ◽  
Yuhong Meng ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Cardiovascular Diseases ◽  
Internal Mammary Artery ◽  
Ang Ii ◽  
Hypertensive Patients ◽  
Spontaneously Hypertensive ◽  
Internal Mammary ◽  
Atp Signaling ◽  
Regulation Of Blood Pressure ◽  
Specific Deletion

Rationale: Dysregulated purinergic signaling transduction plays important roles in the pathogenesis of cardiovascular diseases. However, the role and mechanism of vascular smooth muscle cell (VSMC)-released ATP in the regulation of blood pressure, and the pathogenesis of hypertension remain unknown. FAM3A (family with sequence similarity 3 member A) is a new mitochondrial protein that enhances ATP production and release. High expression of FAM3A in VSMC suggests it may play a role in regulating vascular constriction and blood pressure. Objective: To determine the role and mechanism of FAM3A-ATP signaling pathway in VSMCs in the regulation of blood pressure and the pathogenesis of hypertension. Methods and Results: In the media layer of hypertensive rat and mouse arteries, and the internal mammary artery of hypertensive patients, FAM3A expression was increased. VSMC-specific deletion of FAM3A reduced vessel contractility and blood pressure levels in mice. Moreover, deletion of FAM3A in VSMC attenuated Ang II (angiotensin II)-induced vascular constriction and remodeling, hypertension, and cardiac hypertrophy in mice. In cultured VSMCs, Ang II activated HSF1 (heat shock factor 1) to stimulate FAM3A expression, activating ATP-P2 receptor pathway to promote the change of VSMCs from contractile phenotype to proliferative phenotype. In the VSMC layer of spontaneously hypertensive rat arteries, Ang II-induced hypertensive mouse arteries and the internal mammary artery of hypertensive patients, HSF1 expression was increased. Treatment with HSF1 inhibitor reduced artery contractility and ameliorated hypertension of spontaneously hypertensive rats. Conclusions: FAM3A is an important regulator of vascular constriction and blood pressure. Overactivation of HSF1-FAM3A-ATP signaling cascade in VSMCs plays important roles in Ang II-induced hypertension and cardiovascular diseases. Inhibitors of HSF1 could be potentially used to treat hypertension.

scholarly journals Enhancement of renin and prorenin receptor in collecting duct of Cyp1a1-Ren2 rats may contribute to development and progression of malignant hypertension

2011 ◽  
Vol 300 (2) ◽  
pp. F581-F588 ◽  
Author(s):  
Minolfa C. Prieto ◽  
Dustyn E. Williams ◽  
Liu Liu ◽  
Kimberly L. Kavanagh ◽  
John J. Mullins ◽  
...  
Keyword(s):  
Gene Expression ◽  
Collecting Duct ◽  
Normal Diet ◽  
Malignant Hypertension ◽  
Soluble Form ◽  
Transgenic Rat ◽  
Ang Ii ◽  
Transgenic Rats ◽  
Protein Levels ◽  
Prorenin Receptor

To determine whether in the transgenic rat model [TGR(Cyp1a1Ren2)] with inducible ANG II-dependent malignant hypertension changes in the activation of intrarenal renin-angiotensin system may contribute to the pathogenesis of hypertension, we examined the gene expression of angiotensinogen (AGT) in renal cortical tissues and renin and prorenin receptor [(P)RR] in the collecting duct (CD) of the kidneys from Cyp1a1Ren2 rats ( n = 6) fed a normal diet containing 0.3% indole-3-carbinol (I3C) for 10 days and noninduced rats maintained on a normal diet (0.6% NaCl diet; n = 6). Rats induced with I3C developed malignant hypertension and exhibited alterations in the expression of renin and (P)RR expressed by the CD cells. In the renal medullary tissues of the Cyp1a1Ren2 transgenic rats with malignant hypertension, renin protein levels in CD cells were associated with maintained renin content and lack of suppression of the endogenous Ren1c gene expression. Furthermore, these tissues exhibited increased levels of (P)RR transcript, as well as of the protein levels of the soluble form of this receptor, the s(P)RR. Intriguingly, although previous findings demonstrated that urinary AGT excretion is augmented in Cyp1a1Ren2 transgenic rats with malignant hypertension, in the present study we did not find changes in the gene expression of AGT in renal cortical tissues of these rats. The data suggest that upregulation of renin and the s(P)RR in the CD, especially in the renal medullary tissues of Cyp1a1Ren2 transgenic rats with malignant hypertension, along with the previously demonstrated increased availability of AGT in the urine of these rats, may constitute a leading mechanism to explain elevated formation of kidney ANG II levels in this model of ANG II-dependent hypertension.

Abstract 014: Collecting Duct Specific Deletion of the (Pro)renin Receptor Modulates ENaC Expression

Hypertension ◽  
2016 ◽  
Vol 68 (suppl_1) ◽  
Author(s):  
Nirupama Ramkumar ◽  
Deborah Stuart ◽  
Kai Song ◽  
Nikita Abraham ◽  
Shuping Wang ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Collecting Duct ◽  
Plasma Renin ◽  
Cre Recombinase ◽  
Protein Isoforms ◽  
Ang Ii ◽  
Renal Tubular ◽  
Renal Expression ◽  
Specific Deletion

The renal tubular (pro)renin receptor (PRR) has been shown to modulate water balance, blood pressure and Na + homeostasis. We recently reported that inducible nephron wide deletion of the PRR results in Na + wasting, reduced epithelial Na + channel (ENaC) expression in the kidney and attenuated hypertensive response to angiotensin-II (Ang-II) infusion. In this study, we examined the effects of PRR deletion in collecting duct (CD) specific mouse models targeting either the principal cells (PC) or intercalated cells (IC). PC-specific PRR knockout (KO) mice were obtained by crossing floxed PRR mice with mice harboring AQP-2 Cre recombinase. Compared to floxed mice, PC specific KO PRR mice had no differences in PRR immunostaining but had 50% reduction in PRR mRNA in micro-dissected cortical CDs. No differences in blood pressure were observed between the two groups at baseline or following Ang-II infusion at 600 ng/kg/min. Similarly, plasma renin concentration and renal expression of ENaC protein isoforms were comparable between the two groups. To achieve IC-specific PRR deletion, floxed PRR mice were bred with mice expressing B-1 Cre recombinase. Compared to floxed controls, IC-specific PRR KO mice were smaller (KO body weight: 5.9 ± 1.3 g vs controls: 11.1± 1.2 g) and did not survive beyond 30 days after birth. IC-specific PRR KO mice also demonstrated marked reduction in renal medullary PRR immunostaining along with decreased renal expression of ENaC-α protein (50% reduction compared to controls), similar to the findings in nephron wide deletion of PRR. Taken together, these findings suggest that IC specific deletion of PRR but not PC-specific deletion modulates renal ENaC expression. Further studies evaluating ENaC activity in isolated cortical CDs from PC and IC specific PRR KO mice will help delineate the functional role of CD PRR in Na + homeostasis.

scholarly journals Collecting duct principal, but not intercalated, cell prorenin receptor regulates renal sodium and water excretion

2018 ◽  
Vol 315 (3) ◽  
pp. F607-F617 ◽  
Author(s):  
Nirupama Ramkumar ◽  
Deborah Stuart ◽  
Elena Mironova ◽  
Nikita Abraham ◽  
Yang Gao ◽  
...  
Keyword(s):  
Water Transport ◽  
Collecting Duct ◽  
Urine Volume ◽  
Urine Osmolality ◽  
Open Probability ◽  
Water Excretion ◽  
Intercalated Cell ◽  
Water Handling ◽  
Prorenin Receptor ◽  
Collecting Ducts

The collecting duct is the predominant nephron site of prorenin and prorenin receptor (PRR) expression. We previously demonstrated that the collecting duct PRR regulates epithelial Na+ channel (ENaC) activity and water transport; however, which cell type is involved remains unclear. Herein, we examined the effects of principal cell (PC) or intercalated cell (IC) PRR deletion on renal Na+ and water handling. PC or IC PRR knockout (KO) mice were obtained by crossing floxed PRR mice with mice harboring Cre recombinase under the control of the AQP2 or B1 subunit of the H+ ATPase promoters, respectively. PC KO mice had reduced renal medullary ENaC-α abundance and increased urinary Na+ losses on a low-Na+ diet compared with controls. Conversely, IC KO mice had no apparent differences in Na+ balance or ENaC abundance compared with controls. Acute treatment with prorenin increased ENaC channel number and open probability in acutely isolated cortical collecting ducts from control and IC PRR KO, but not PC PRR KO, mice. Furthermore, compared with controls, PC KO, but not IC KO mice, had increased urine volume, reduced urine osmolality, and reduced abundance of renal medullary AQP2. Taken together, these findings indicate that PC, but not IC, PRR modulates ENaC activity, urinary Na+ excretion, and water transport.

scholarly journals Losartan prevents the elevation of blood pressure in adipose-PRR deficient female mice while elevated circulating sPRR activates the renin-angiotensin system

2019 ◽  
Vol 316 (3) ◽  
pp. H506-H515 ◽  
Author(s):  
Eva Gatineau ◽  
Dianne M. Cohn ◽  
Marko Poglitsch ◽  
Analia S. Loria ◽  
Ming Gong ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Systolic Blood Pressure ◽  
Renin Angiotensin System ◽  
Soluble Form ◽  
Ang Ii ◽  
High Fat ◽  
Angiotensin System ◽  
Renin Angiotensin ◽  
Female Mice ◽  
Prorenin Receptor

Deletion of the prorenin receptor (PRR) in adipose tissue elevates systolic blood pressure (SBP) and the circulating soluble form of PRR (sPRR) in male mice fed a high-fat (HF) diet. However, sex differences in the contribution of adipose-PRR and sPRR to the regulation of the renin-angiotensin system (RAS) in key organs for blood pressure control are undefined. Therefore, we assessed blood pressure and the systemic and intrarenal RAS status in adipose-PRR knockout (KO) female mice. Blockade of RAS with losartan blunted SBP elevation in HF diet-fed adipose-PRR KO mice. ANG II levels were significantly increased in the renal cortex of HF diet-fed adipose-PRR KO female mice, but not systemically. HF diet-fed adipose-PRR KO mice exhibited higher vasopressin levels, water retention, and lower urine output than wild-type (WT) mice. The results also showed that deletion of adipose-PRR increased circulating sPRR and total hepatic sPRR contents, suggesting the liver as a major source of elevated plasma sPRR in adipose-PRR KO mice. To mimic the elevation of circulating sPRR and define the direct contribution of systemic sPRR to the regulation of the RAS and vasopressin, C57BL/6 female mice fed a standard diet were infused with recombinant sPRR. sPRR infusion increased plasma renin levels, renal and hepatic angiotensinogen expression, and vasopressin. Together, these results demonstrate that the deletion of adipose-PRR induced an elevation of SBP likely mediated by an intrarenal ANG II-dependent mechanism and that sPRR participates in RAS regulation and body fluid homeostasis via its capacity to activate the RAS and increase vasopressin levels. NEW & NOTEWORTHY The elevation of systolic blood pressure appears to be primarily mediated by cortical ANG II in high-fat diet-fed adipose-prorenin receptor knockout female mice. In addition, our data support a role for soluble prorenin receptor in renin-angiotensin system activation and vasopressin regulation.

Upregulation of p67phoxand gp91phoxin aortas from angiotensin II-infused mice

2000 ◽  
Vol 279 (5) ◽  
pp. H2234-H2240 ◽  
Author(s):  
M. Eugenia Cifuentes ◽  
Federico E. Rey ◽  
Oscar A. Carretero ◽  
Patrick J. Pagano
Keyword(s):  
Blood Pressure ◽  
Angiotensin Ii ◽  
Protein Level ◽  
Primary Source ◽  
Ang Ii ◽  
Simultaneous Treatment ◽  
Protein Levels ◽  
Enhanced Chemiluminescence ◽  
Vascular Regulation ◽  
Primary Location

Although NAD(P)H oxidase-derived superoxide (O2−) is increased during the development of angiotensin II (ANG II)-dependent hypertension, vascular regulation at the protein level has not been reported. We have shown that four major components of NAD(P)H oxidase are located primarily in the vascular adventitia as a primary source of vascular O2−. Here we compare vascular levels of O2−and NAD(P)H oxidase in normotensive and ANG II-infused hypertensive mice and show that, after 7 days of ANG II infusion (750 μg · kg−1· day−1ip) in C57B1/6 mice, systolic blood pressure was increased compared with that after sham infusion, concomitant with increased O2−in the thoracic aorta as measured using lucigenin (25 μM)-enhanced chemiluminescence. Both p67phoxand gp91phoxwere detectable by Western blotting in aortic homogenates, and we observed increased protein levels of NAD(P)H oxidase subunits. These ANG II-induced increases were normalized by simultaneous treatment with the AT1receptor antagonist losartan. Moreover, the primary location of these subunits was the adventitia as detected immunohistochemically. Our results suggest that ANG II-induced increases in O2−are due to increased adventitial NAD(P)H oxidase activity, brought about by the heightened expression and interaction of its components.

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