scholarly journals Blood pressure and renal blow flow responses in heme oxygenase-2 knockout mice

2009 ◽  
Vol 297 (6) ◽  
pp. R1822-R1828 ◽  
Author(s):  
David E. Stec ◽  
Trinity Vera ◽  
Megan V. Storm ◽  
Gerald R. McLemore ◽  
Michael J. Ryan
Keyword(s):  
Nitric Oxide ◽  
Blood Pressure ◽  
Heme Oxygenase ◽  
Acute Administration ◽  
Ang Ii ◽  
Wild Type ◽  
Renal Circulation ◽  
Kidney Weight ◽  
Blood Pressures ◽  
Regulation Of Blood Pressure

Heme oxygenase (HO) is the enzyme responsible for the breakdown of heme-generating carbon monoxide (CO) and biliverdin in this process. HO-2 is the constitutively expressed isoform in most tissues, such as the kidney and vasculature. CO generated by HO is believed to be an important vasodilator in the renal circulation along with another gas, nitric oxide (NO). To determine the importance of HO-2 in the regulation of blood pressure and renal blood flow (RBF), we treated HO-2 knockout (KO) mice chronically with either ANG II or NG-nitroarginine methyl ester (l-NAME). Basal blood pressures were not different between wild-type (WT), heterozygous (HET), or KO mice and averaged 113 ± 3 vs. 115 ± 2 vs. 116 ± 2 mmHg. Similar increases in blood pressure to chronic ANG II as well as l-NAME treatment were observed in all groups with blood pressures increasing an average of 30 mmHg in response to ANG II and 15 mmHg in response to l-NAME. Basal RBFs were not different between the groups averaging 6.0 ± 0.5 ( n = 6) vs. 4.8 ± 0.6 ( n = 10) vs. 5.8 ± 0.7 ( n = 6) ml·min−1·g−1 kidney weight in WT, HET, and KO mice. HO-2 KO and HET mice exhibited an attenuated decrease in RBF in response to acute administration of ANG II, while no differences were observed with l-NAME. Our data indicate that blood pressure and RBF responses to increased ANG II or inhibition of nitric oxide are not significantly enhanced in HO-2 KO mice.

scholarly journals Differential effects of Mas receptor deficiency on cardiac function and blood pressure in obese male and female mice

2017 ◽  
Vol 312 (3) ◽  
pp. H459-H468 ◽  
Author(s):  
Yu Wang ◽  
Robin Shoemaker ◽  
David Powell ◽  
Wen Su ◽  
Sean Thatcher ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Cardiac Function ◽  
Left Ventricular ◽  
Ang Ii ◽  
Wild Type ◽  
Male And Female ◽  
Reduced Ejection Fraction ◽  
Female Mice ◽  
Induced Hypertension ◽  
Blood Pressures

Angiotensin-(1–7) [ANG-(1–7)] acts at Mas receptors (MasR) to oppose effects of angiotensin II (ANG II). Previous studies demonstrated that protection of female mice from obesity-induced hypertension was associated with increased systemic ANG-(1–7), whereas male obese hypertensive mice exhibited increased systemic ANG II. We hypothesized that MasR deficiency ( MasR−/−) augments obesity-induced hypertension in males and abolishes protection of females. Male and female wild-type ( MasR+/+) and MasR−/− mice were fed a low-fat (LF) or high-fat (HF) diet for 16 wk. MasR deficiency had no effect on obesity. At baseline, male and female MasR−/− mice had reduced ejection fraction (EF) and fractional shortening than MasR+/+ mice. Male, but not female, HF-fed MasR+/+ mice had increased systolic and diastolic (DBP) blood pressures compared with LF-fed controls. In HF-fed females, MasR deficiency increased DBP compared with LF-fed controls. In contrast, male HF-fed MasR−/− mice had lower DBP than MasR+/+ mice. We quantified cardiac function after 1 mo of HF feeding in males of each genotype. HF-fed MasR−/− mice had higher left ventricular (LV) wall thickness than MasR+/+ mice. Moreover, MasR+/+, but not MasR−/−, mice displayed reductions in EF from HF feeding that were reversed by ANG-(1–7) infusion. LV fibrosis was reduced in HF-fed MasR+/+ but not MasR−/− ANG-(1–7)-infused mice. These results demonstrate that MasR deficiency promotes obesity-induced hypertension in females. In males, HF feeding reduced cardiac function, which was restored by ANG-(1–7) in MasR+/+ but not MasR−/− mice. MasR agonists may be effective therapies for obesity-associated cardiovascular conditions. NEW & NOTEWORTHY MasR deficiency abolishes protection of female mice from obesity-induced hypertension. Male MasR-deficient obese mice have reduced blood pressure and declines in cardiac function. ANG-(1–7) infusion restores obesity-induced cardiac dysfunction of wild-type, but not MasR-deficient, male mice. MasR agonists may be cardioprotective in obese males and females.

Role of NOX2 in the regulation of afferent arteriole responsiveness

2009 ◽  
Vol 296 (1) ◽  
pp. R72-R79 ◽  
Author(s):  
Mattias Carlström ◽  
En Yin Lai ◽  
Zufu Ma ◽  
Andreas Patzak ◽  
Russell D. Brown ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Blood Pressure ◽  
Renal Perfusion ◽  
Afferent Arteriole ◽  
Ang Ii ◽  
Wild Type ◽  
Simultaneous Application ◽  
Nitric Oxide Deficiency ◽  
Sensitizing Effect

NADPH oxidases (NOX) are the major source of reactive oxygen species (ROS) in the vasculature and contribute to the control of renal perfusion. The role of NOX2 in the regulation of blood pressure and afferent arteriole responsiveness was investigated in NOX2−/− and wild-type mice. Arteriole constrictions to ANG II (10−14–10−6 mol/l) were weaker in NOX2−/− compared with wild types. Nω-nitro-l-arginine methyl ester (l-NAME; 10−4 mol/l) treatment reduced basal diameters significantly more in NOX2−/− (−18%) than in wild types (−6%) and augmented ANG II responses. Adenosine (10−11–10−4 mol/l) constricted arterioles of wild types but not of NOX2−/−. However, simultaneous inhibition of adenosine type-2 receptors induced vasoconstriction, which was stronger in NOX2−/−. Adenosine (10−8 mol/l) enhanced the ANG II response in wild type, but not in NOX2−/−. This sensitizing effect by adenosine was abolished by apocynin. Chronic ANG II pretreatment (14 days) did not change the ANG II responses in NOX2−/−, but strengthened the response in wild types. ANG II pretreatment augmented the l-NAME response in NOX2−/− (−33%), but not in wild types. Simultaneous application of l-NAME and ANG II caused a stronger constriction in the NOX2−/− (−64%) than in wild types (−46%). Basal blood pressures were similar in both genotypes, however, chronic ANG II infusion elevated blood pressure to a greater extent in wild-type (15 ± 1%) than in NOX2−/− (8 ± 1%) mice. In conclusion, NOX2 plays an important role in the control of afferent arteriole tone and is involved in the contractile responses to ANG II and/or adenosine. NOX2 can be activated by elevated ANG II and may play an important role in ANG II-induced hypertension. NOX2-derived ROS scavenges nitric oxide, causing subsequent nitric oxide-deficiency.

scholarly journals Knockout of Na+-glucose cotransporter SGLT1 mitigates diabetes-induced upregulation of nitric oxide synthase NOS1 in the macula densa and glomerular hyperfiltration

2019 ◽  
Vol 317 (1) ◽  
pp. F207-F217 ◽  
Author(s):  
Panai Song ◽  
Winnie Huang ◽  
Akira Onishi ◽  
Rohit Patel ◽  
Young Chul Kim ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Blood Pressure ◽  
Gene Knockout ◽  
Macula Densa ◽  
Wild Type ◽  
Kidney Weight ◽  
Renin Mrna ◽  
Sglt2 Inhibition ◽  
Glomerular Size ◽  
Akita Mice

Na+-glucose cotransporter (SGLT)1 mediates glucose reabsorption in late proximal tubules. SGLT1 also mediates macula densa (MD) sensing of an increase in luminal glucose, which increases nitric oxide (NO) synthase 1 (MD-NOS1)-mediated NO formation and potentially glomerular filtratrion rate (GFR). Here, the contribution of SGLT1 was tested by gene knockout (−/−) in type 1 diabetic Akita mice. A low-glucose diet was used to prevent intestinal malabsorption in Sglt1−/− mice and minimize the contribution of intestinal SGLT1. Hyperglycemia was modestly reduced in Sglt1−/− versus littermate wild-type Akita mice (480 vs. 550 mg/dl), associated with reduced diabetes-induced increases in GFR, kidney weight, glomerular size, and albuminuria. Blunted hyperfiltration was confirmed in streptozotocin-induced diabetic Sglt1−/− mice, associated with similar hyperglycemia versus wild-type mice (350 vs. 385 mg/dl). Absence of SGLT1 attenuated upregulation of MD-NOS1 protein expression in diabetic Akita mice and in response to SGLT2 inhibition in nondiabetic mice. During SGLT2 inhibition in Akita mice, Sglt1−/− mice had likewise reduced blood glucose (200 vs. 300 mg/dl), associated with lesser MD-NOS1 expression, GFR, kidney weight, glomerular size, and albuminuria. Absence of Sglt1 in Akita mice increased systolic blood pressure, associated with suppressed renal renin mRNA expression. This may reflect fluid retention due to blunted hyperfiltration. SGLT2 inhibition prevented the blood pressure increase in Sglt1−/− Akita mice, possibly due to additive glucosuric/diuretic effects. The data indicate that SGLT1 contributes to diabetic hyperfiltration and limits diabetic hypertension. Potential mechanisms include its role in glucose-driven upregulation of MD-NOS1 expression. This pathway may increase GFR to maintain volume balance when enhanced MD glucose delivery indicates upstream saturation of SGLTs and thus hyperreabsorption.

Endothelial-derived nitric oxide and angiotensinogen: blood pressure and metabolism during mouse pregnancy

2001 ◽  
Vol 280 (1) ◽  
pp. R174-R182 ◽  
Author(s):  
Lukas A. Hefler ◽  
Clemens B. Tempfer ◽  
Rene M. Moreno ◽  
William E. O'Brien ◽  
Anthony R. Gregg
Keyword(s):  
Nitric Oxide ◽  
Blood Pressure ◽  
Urine Analysis ◽  
Renin Angiotensin System ◽  
Mutant Mice ◽  
Enos Gene ◽  
Metabolic Characteristics ◽  
Mutant Strains ◽  
Blood Pressures ◽  
Regulation Of Blood Pressure

The regulation of blood pressure during pregnancy involves several biological pathways. Candidate genes implicated in hypertensive diseases during pregnancy include those of the renin-angiotensin system and nitric oxide synthase (NOS). We evaluated blood pressure and metabolic characteristics during pregnancy in mutant mice. These included mice with a null mutation in the endothelial NOS (eNOS) gene ( Nos3−/− ), four copies of the angiotensinogen gene ( Agt2/2 ), and mutations in both genes [four copies of Agt and heterozygous deficient for eNOS (Agt2/2Nos3+/− ), four copies of Agt and homozygous deficient for eNOS ( Agt2/2Nos3−/− )]. Blood pressure measurements of nulliparous females from mutant strains were compared with two common laboratory strains C57Bl6/J and SV129 throughout their first pregnancy. Serum and urine analysis for the evaluation of renal and liver physiology were measured in the prepregnant state and during the third trimester of pregnancy. Throughout pregnancy blood pressures in all mutant strains were higher compared with controls. Agt2/2Nos3−/− showed the highest blood pressures and C57Bl6/J the lowest. Control mice, but not mutant mice, showed a second trimester decline in blood pressure. No immediate differences were noted regarding behavioral characteristics, renal or liver function parameters. Mice deficient for eNOS, mice with overexpression of Agt, and mice with mutations in both genes demonstrated higher blood pressure throughout pregnancy. There was no evidence of renal dysfunction, liver dysfunction, or hemolysis among any of the strains studied. We conclude that Nos3 and Agt are important genes in the regulation of blood pressure during pregnancy.

scholarly journals Interaction of Angiotensin II and Nitric Oxide in Isolated Perfused Afferent Arterioles of Mice

2001 ◽  
Vol 12 (6) ◽  
pp. 1122-1127
Author(s):  
ANDREAS PATZAK ◽  
RALF MROWKA ◽  
EBERHARD STORCH ◽  
BERTHOLD HOCHER ◽  
PONTUS B. PERSSON
Keyword(s):  
Nitric Oxide ◽  
Angiotensin Ii ◽  
Enos Gene ◽  
Acute Administration ◽  
Ang Ii ◽  
Wild Type ◽  
Afferent Arterioles ◽  
Dose Responses ◽  
Arteriolar Diameter

Abstract. The present study was performed to evaluate angiotensin II (Ang II)—nitric oxide (NO) interaction in afferent arterioles (Af) of wild-type mice and mice that are homozygous (-/-) for disruption of the endothelial NO synthase (eNOS) gene. Af were microperfused, and the dose responses were assessed for the NO precursor L-arginine (n= 4), NO inhibitor NG-nitro-L-arginine methyl ester (L-NAME,n= 5), L-NAME after pretreatment with L-arginine (n= 5), Ang II (n= 8), and Ang II after pretreatment with L-NAME (n= 7). Acute administration of L-arginine and L-NAME (both in doses from 10-6to 10-3mol/L) did not change arteriolar diameter. Moreover, pretreatment with L-arginine did not change the response to L-NAME. However, Ang II, applied in doses of 10-12, 10-10, 10-8, and 10-6mol/L, significantly reduced the lumen to 66.5 ± 7.0% and 62.2 ± 8.0% at 10-8and 10-6mol/L Ang II, respectively. The contraction was augmented after L-NAME pretreatment (19.5 ± 13.6% and 25.5 ± 10.2% at 10-8and 10-6mol/L Ang II, respectively). In eNOS (-/-) mice (n= 8), the response to Ang II also was enhanced (9.1 ± 6.0% and 11.2 ± 8.2% at 10-8and 10-6mol/L Ang II, respectively). Female mice did not differ from male mice in their reactivity to Ang II (n= 9) and Ang II + L-NAME pretreatment (n= 11). The study shows that (1) it is feasible to microperfuse mouse Af, (2) the basal production of endothelial NO is very low and not inducible by L-arginine in Af of mice, and (3) a counteracting effect of NO is initiated by Ang II. High Ang II sensitivity in eNOS (-/-) mice underscores the considerable role of endothelial-derived NO to balance Ang II vasoconstriction in Af.

Neuregulin-1 Compensates for Endothelial Nitric Oxide Synthase Deficiency

2021 ◽  
Author(s):  
Hadis Shakeri ◽  
Jente R.A. Boen ◽  
Sofie De Moudt ◽  
Jhana O. Hendrickx ◽  
Arthur J.A. Leloup ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Cardiac Fibrosis ◽  
Separate Experiment ◽  
No Production ◽  
Ang Ii ◽  
Wild Type ◽  
Paracrine Factor ◽  
Renal Hypertrophy ◽  
Neuregulin 1 ◽  
Endothelial Nitric Oxide

Endothelial cells (ECs) secrete different paracrine signals that modulate the function of adjacent cells; two examples of these paracrine signals are nitric oxide (NO) and neuregulin-1 (NRG1), a cardioprotective growth factor. Currently, it is undetermined whether one paracrine factor can compensate for the loss of another. Herein, we hypothesized that NRG1 can compensate for endothelial NO synthase (eNOS) deficiency. Methods. We characterized eNOS null and wild type (WT) mice by cardiac ultrasound and histology and we determined circulating NRG1 levels. In a separate experiment, 8 groups of mice were divided into 4 groups of eNOS null mice and wild type (WT) mice; half of the mice received angiotensin II (Ang II) to induce a more severe phenotype. Mice were randomized to daily injections with NRG1 or vehicle for 28 days. Results. eNOS deficiency increased NRG1 plasma levels, indicating that ECs increase their NRG1 expression when NO production is deleted. eNOS deficiency also increased blood pressure, lowered heart rate, induced cardiac fibrosis, and affected diastolic function. In eNOS null mice, Ang II administration increased cardiac fibrosis, but also induced cardiac hypertrophy and renal fibrosis. NRG1 administration prevented the cardiac and renal hypertrophy and fibrosis caused by Ang II infusion and eNOS deficiency. Moreover, Nrg1 expression in the myocardium is shown to be regulated by miR-134. Conclusion. This study indicates that administration of endothelium-derived NRG1 can compensate for eNOS deficiency in the heart and kidneys.

scholarly journals Nitric oxide synthase-mediated blood pressure regulation in obese melanocortin-4 receptor-deficient pregnant rats

2016 ◽  
Vol 311 (5) ◽  
pp. R851-R857 ◽  
Author(s):  
Frank T. Spradley ◽  
Jennifer M. Sasser ◽  
Jacqueline B. Musall ◽  
Jennifer C. Sullivan ◽  
Joey P. Granger
Keyword(s):  
Nitric Oxide ◽  
Blood Pressure ◽  
Mesenteric Arteries ◽  
Elevated Blood Pressure ◽  
Pressure Regulation ◽  
Elevated Blood ◽  
Pregnant Rats ◽  
Melanocortin 4 Receptor ◽  
Regulation Of Blood Pressure

Although obesity increases the risk for hypertension in pregnancy, the mechanisms responsible are unknown. Increased nitric oxide (NO) production results in vasodilation and reduced blood pressure during normal pregnancy in lean rats; however, the role of NO is less clear during obese pregnancies. We examined the impact of obesity on NO synthase (NOS)-mediated regulation of blood pressure during pregnancy by testing the hypothesis that NOS activity, expression, and regulation of vascular tone and blood pressure are reduced in obese pregnant rats. At gestational day 19, melanocortin-4 receptor (MC4R)-deficient obese rats (MC4R) had greater body weight and fat mass with elevated blood pressure and circulating sFlt-1 levels compared with MC4R pregnant rats. MC4R pregnant rats also had less circulating cGMP levels and reduced total NOS enzymatic activity and expression in mesenteric arteries. Despite decreased biochemical measures of NO/NOS in MC4R rats, NOS inhibition enhanced vasoconstriction only in mesenteric arteries from MC4R rats, suggesting greater NOS-mediated tone. To examine the role of NOS on blood pressure regulation in obese pregnant rats, MC4R and MC4R pregnant rats were administered the nonselective NOS inhibitor NG-nitro-l-arginine methyl ester (l-NAME, 100 mg/l) from gestational day 14 to 19 in drinking water. The degree by which l-NAME raised blood pressure was similar between obese and lean pregnant rats. Although MC4R obese pregnant rats had elevated blood pressure associated with reduced total NOS activity and expression, they had enhanced NOS-mediated attenuation of vasoconstriction, with no evidence of alterations in NOS-mediated regulation of blood pressure.

scholarly journals Proximal Tubule-Specific Deletion of Angiotensin II Type 1a Receptors in the Kidney Attenuates Circulating and Intratubular Angiotensin II–Induced Hypertension in PT- Agtr1a −/− Mice

Hypertension ◽  
2021 ◽  
Author(s):  
Xiao Chun Li ◽  
Ana Paula Oliveira Leite ◽  
Xiaowen Zheng ◽  
Chunling Zhao ◽  
Xu Chen ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Angiotensin Ii ◽  
Fusion Protein ◽  
Proximal Tubule ◽  
Proximal Tubules ◽  
Normal Blood ◽  
Ang Ii ◽  
Normal Blood Pressure ◽  
Wild Type ◽  
Induced Hypertension

The present study used a novel mouse model with proximal tubule-specific knockout of AT 1a receptors in the kidney, PT- Agtr1a −/− , to test the hypothesis that intratubular Ang II (angiotensin II) and AT 1a receptors in the proximal tubules are required for maintaining normal blood pressure and the development of Ang II–induced hypertension. Twenty-six groups (n=6–15 per group) of adult male wild-type, global Agtr1a −/− , and PT- Agtr1a −/− mice were infused with Ang II (1.5 mg/kg per day, IP), or overexpressed an intracellular Ang II fusion protein in the proximal tubules for 2 weeks. Basal telemetry blood pressure were ≈15±3 mm Hg lower in PT- Agtr1a −/− than wild-type mice and ≈13±3 mm Hg higher than Agtr1a −/− mice ( P <0.01). Basal glomerular filtration was ≈23.9% higher ( P <0.01), whereas fractional proximal tubule Na + reabsorption was lower in PT- Agtr1a −/− mice ( P <0.01). Deletion of AT 1a receptors in the proximal tubules augmented the pressure-natriuresis response ( P <0.01) and natriuretic responses to salt loading or Ang III infusion ( P <0.01). Ang II induced hypertension in wild-type, PT- Agtr1a −/− and PT- Nhe3 −/− mice, but the pressor response was ≈16±2 mm Hg lower in PT- Agtr1a −/− and PT- Nhe3 −/− mice ( P <0.01). Deletion of AT 1a receptors or NHE3 (Na + /H + exchanger 3) in the proximal tubules attenuated ≈50% of Ang II–induced hypertension in wild-type mice ( P <0.01), but blocked intracellular Ang II fusion protein-induced hypertension in PT- Agtr1a −/− mice ( P <0.01). Taken together, the results of the present study provide new insights into the critical role of intratubular Ang II/AT 1 (AT 1a )/NHE3 pathways in the proximal tubules in normal blood pressure control and the development of Ang II–induced hypertension.

scholarly journals Genetic deletion of AT1a receptors attenuates intracellular accumulation of ANG II in the kidney of AT1a receptor-deficient mice

2007 ◽  
Vol 293 (2) ◽  
pp. F586-F593 ◽  
Author(s):  
Xiao C. Li ◽  
L. Gabriel Navar ◽  
Yuan Shao ◽  
Jia L. Zhuo
Keyword(s):  
Blood Pressure ◽  
Sodium Excretion ◽  
Rat Kidney ◽  
Systolic Pressure ◽  
Weight Ratio ◽  
Urinary Sodium Excretion ◽  
Urinary Sodium ◽  
Ang Ii ◽  
Wild Type ◽  
Deficient Mice

We and others have previously shown that high levels of ANG II are accumulated in the rat kidney via a type 1 (AT1) receptor-mediated mechanism, but it is not known which AT1 receptor is involved in this process in rodents. We tested the hypothesis that AT1a receptor-deficient mice (Agtr1a−/−) are unable to accumulate ANG II intracellularly in the kidney because of the absence of AT1a receptor-mediated endocytosis. Adult male wild-type (Agtr1a+/+), heterozygous (Agtr1a+/−), and Agtr1a−/− were treated with vehicle, ANG II (40 ng/min ip via osmotic minipump), or ANG II plus the AT1 antagonist losartan (10 mg·kg−1·day−1 po) for 2 wk. In wild-type mice, ANG II induced hypertension (168 ± 4 vs. 113 ± 3 mmHg, P < 0.001), increased kidney-to-body weight ratio ( P < 0.01), caused pressure natriuresis ( P < 0.05), and elevated plasma and whole kidney ANG II levels ( P < 0.001). Concurrent administration of ANG II with losartan attenuated these responses to ANG II. In contrast, Agtr1a−/− mice had lower basal systolic pressures ( P < 0.001), smaller kidneys with much fewer AT1b receptors ( P < 0.001), higher basal 24-h urinary sodium excretion ( P < 0.01), as well as basal plasma and whole kidney ANG II levels ( P < 0.01). However, intracellular ANG II levels in the kidney were lower in Agtr1a−/− mice. In Agtr1a−/− mice, ANG II slightly increased systolic pressure ( P < 0.05) but had no effect on the kidney weight, urinary sodium excretion, and whole kidney ANG II levels. Losartan restored systolic pressure to basal levels and decreased whole kidney ANG II levels by ∼20% ( P < 0.05). These results demonstrate a predominant role of AT1a receptors in blood pressure regulation and in the renal responses to long-term ANG II administration, that AT1b receptors may play a limited role in blood pressure control and mediating intrarenal ANG II accumulation in the absence of AT1a receptors.

Abstract P617: Angiotensin II-induced Hypertension And Vascular Injury Is Mediated By Gamma/delta T Cells

Hypertension ◽  
2015 ◽  
Vol 66 (suppl_1) ◽  
Author(s):  
Antoine Caillon ◽  
Muhammad Oneeb Rehman Mian ◽  
Tlili Barhoumi ◽  
Pierre Paradis ◽  
Ernesto L. Schiffrin
Keyword(s):  
Blood Pressure ◽  
T Cells ◽  
T Cell ◽  
Vascular Injury ◽  
Mesenteric Artery ◽  
Gamma Delta T Cells ◽  
Ang Ii ◽  
Wild Type ◽  
Gamma Delta ◽  
Adaptive Immune

Objective: Both innate antigen presenting cells and the adaptive immune system have been shown to play a role in the development of hypertension. Nevertheless, the T cell subset involved in the pathophysiology of hypertension remains unclear. There is a small subset of “innate-like” T cells expressing gamma/delta T cell receptor (TCR) rather than the alpha/beta TCR that could play a role in bridging between the innate and adaptive immune systems. However, it is unknown whether gamma/delta T cells contribute to development of hypertension. Method/Results: Thirteen to 15 week-old male C57BL/6 wild-type and Tcrd-/- mice, which are devoid of gamma/delta T cells, were infused or not with angiotensin (Ang) II (490 ng/kg/min, SC) for 7 or 14 days (n=4-9). Telemetric blood pressure, mesenteric artery endothelial function and vascular remodeling by pressurized myography and spleen T cell profile by flow cytometry were evaluated. Fourteen days of Ang II increased systolic blood pressure (167±4 vs 125±2 mmHg, P≤0.01) in wild-type compared to control mice. The frequency of gamma/delta T cells (6±1% vs 3±1%, P≤0.05) and activated (CD69+) gamma/delta T cells (11±1% vs 7±1%) was increased after 7 days of Ang II, and 7 days later were respectively unchanged or further increased (24±2% vs 10±1%) in wild-type compared to control mice. Ang II decreased mesenteric artery relaxation responses to acetylcholine (51±5% vs 88±3%, P≤0.01) and increased media/lumen (5±1 vs 3±0%, P≤0.01) in wild-type mice compare to controls. No gamma/delta T cells were detected in Tcrd-/- treated or not with Ang II. All the above Ang II effects were abrogated in Tcrd-/- mice. Conclusion: These data suggest that gamma/delta T cells mediate Ang II-induced blood pressure rise and vascular injury. Gamma/delta T cells could be key immune cells bridging innate and adaptive immune responses during the development of hypertension.

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