Abstract 513: Evaluation of Proinflammatory Effects of Low Dose Angiotensin II Infusion in Intact Female Mice and Adiponectin Deficient Mice

2015 ◽  
Vol 35 (suppl_1) ◽  
Author(s):  
Esther Yu ◽  
Xia Wang ◽  
Jaya Pamidimukkala
Keyword(s):  
Angiotensin Ii ◽  
Mrna Expression ◽  
Adhesion Molecules ◽  
Endothelial Activation ◽  
Tissue Expression ◽  
Renal Tissue ◽  
Protective Effects ◽  
Ang Ii ◽  
Female Mice ◽  
Deficient Mice

Circulating vasoactive peptide Angiotensin II (ANGII) has a well-known role in the development of hypertension and other cardiovascular diseases. In addition it has significant proinflammatory actions in the vascular wall inducing the production of reactive oxygen species, inflammatory cytokines and adhesion molecules. It has been previously shown that estrogen in female mice protects against ANGII mediated hypertension and against proinflammatory effects. It is not clear if the protective effects of estrogen extend to adiponectin deficient mice. Adiponectin is one of the few peptides secreted by fat to have anti-inflammatory properties. The present study evaluates the effect of chronic ANGII infusion on expression of cytokines in female C57BL/6J and adiponectin deficient mice (adipo-/-). Female mice (24- 28wks), were implanted with osmotic pump containing either ANG II (800 ng/Kg /min) or saline. Blood samples and tissue were collected at the end of 14 days. Plasma levels of TNFalpha and IL6 were measured using enzyme linked immunoabsorbent assay. Renal tissue expression of the cytokines were quantified using real-time PCR (Eppendorf Realplex 4 mastercycler) and SYBR Green ROX mastermix. Plasma TNFα levels were similar in saline infused C57Bl/6J(11±1 pg/ml) and adiponectin deficient mice(10± 1 pg/ml). ANGII did not significantly increase TNFα in the control(14±3 pg/ml) or adipo-/- mice(13+1 pg/ml). Plasma IL6 levels were also not significantly different in the two groups. A microarray for mRNA expression of markers of endothelial activation and adhesion molecules was also performed in the renal tissue. Preliminary data show that TNFalpha mRNA expression levels were not increased by ANG II infusion and IL6 expression was undetectable. ANGII also did not alter E-Selectin,VCAM1, Collagen1a1 and eNOS expression. In conclusion, ANGII infusion did not result in a proinflammatory milieu in both female C57BL/6J and Adipo -/- mice.

Abstract 505: Effect of Angiotensin II Infusion on Renal TNFα and IL6 mRNA Expression in Male Adiponectin Deficient Mice

2015 ◽  
Vol 35 (suppl_1) ◽  
Author(s):  
Jayabala Pamidimukkala ◽  
Xia Wang ◽  
Esther Yu ◽  
Joy Phan
Keyword(s):  
Angiotensin Ii ◽  
Mrna Expression ◽  
Endothelial Activation ◽  
Renal Tissue ◽  
Tissue Samples ◽  
Markers Of Inflammation ◽  
Lower Baseline ◽  
Dose Infusion ◽  
Blood Pressures ◽  
Lower Expression

Adiponectin is a well-known adipokine with insulin sensitizing and anti-inflammatory actions. Low circulating levels of adiponectin are associated with a proinflammatory milieu leading to the development of cardiovascular and metabolic disorders. We have previously shown that male adiponectin deficient (adipo-/-) mice have lower baseline blood pressures but are more susceptible to prohypertensive effect of Angiotensin II (ANGII). In addition to being a vasoconstrictor, ANGII is also known to stimulate proinflammatory cytokine expression in cardiovascular & renal tissue. However, low dose infusion of ANGII for 14 days did not increase plasma TNFα or IL6 appreciably in the adipo -/- mice. The present study evaluates the expression of these proinflammatory cytokines in renal tissue. Briefly, male wild type C57Bl/6J and adiponectin deficient (adipo-/-) mice (24-28wk, ~30g) were implanted with osmotic pumps containing Angiotensin II (ANGII, 800ng/Kg body weight/min) or Saline. At the end of 14 days infusion, the mice were euthanized to obtain blood and tissue samples. The kidneys were snap frozen in liquid nitrogen and the total RNA was extracted using RNA mini kit (Qiagen). Quantitative real-time PCR was performed with Eppendorf Realplex 4 mastercycler and SYBR Green ROX Mastermix. TNFα mRNA expression normalized to GAPDH was similar in adipo-/- and C57Bl/6J mice. TNFα mRNA expression levels were not increased by ANGII infusion. IL6 expression was undetectable in all groups (n=3 animals/group). We also carried out additional microarray analysis of markers of endothelial activation and adhesion molecules. Preliminary data show that ANGII increases expression of E-Selectin, VCAM1, Collagen1a1 and eNOS by two fold in the C57BL/6J mice. The saline treated adipo-/- had lower expression of eNOS, VCAM-1 and Collagen1a1. Interestingly, ANGII infusion increased expression of E-Selectin, VCAM1 and Collagen 1a1 in these mice but eNOS expression was unchanged. The data suggest that chronic ANGII infusion did not change renal expression of cytokines appreciably but downstream markers of inflammation and fibrosis were increased.

Estrogen receptor-α mediates estrogen protection from angiotensin II-induced hypertension in conscious female mice

2007 ◽  
Vol 292 (4) ◽  
pp. H1770-H1776 ◽  
Author(s):  
Baojian Xue ◽  
Jaya Pamidimukkala ◽  
Dennis B. Lubahn ◽  
Meredith Hay
Keyword(s):  
Estrogen Receptor ◽  
Angiotensin Ii ◽  
Estrogen Receptor Α ◽  
Protective Role ◽  
Protective Effects ◽  
Pressor Effect ◽  
Ang Ii ◽  
Female Mice ◽  
Female Sex Hormones ◽  
Induced Hypertension

It has been shown that the female sex hormones have a protective role in the development of angiotensin II (ANG II)-induced hypertension. The present study tested the hypotheses that 1) the estrogen receptor-α (ERα) is involved in the protective effects of estrogen against ANG II-induced hypertension and 2) central ERs are involved. Blood pressure (BP) was measured in female mice with the use of telemetry implants. ANG II (800 ng·kg−1·min−1) was administered subcutaneously via an osmotic pump. Baseline BP in the intact, ovariectomized (OVX) wild-type (WT) and ERα knockout (ERαKO) mice was similar; however, the increase in BP induced by ANG II was greater in OVX WT (23.0 ± 1.0 mmHg) and ERαKO mice (23.8 ± 2.5 mmHg) than in intact WT mice (10.1 ± 4.5 mmHg). In OVX WT mice, central infusion of 17β-estradiol (E2; 30 μg·kg−1·day−1) attenuated the pressor effect of ANG II (7.0 ± 0.4 mmHg), and this protective effect of E2 was prevented by coadministration of ICI-182,780 (ICI; 1.5 μg·kg−1·day−1, 18.8 ± 1.5 mmHg), a nonselective ER antagonist. Furthermore, central, but not peripheral, infusions of ICI augmented the pressor effects of ANG II in intact WT mice (17.8 ± 4.2 mmHg). In contrast, the pressor effect of ANG II was unchanged in either central E2-treated OVX ERαKO mice (19.0 ± 1.1 mmHg) or central ICI-treated intact ERαKO mice (19.6 ± 1.6 mmHg). Lastly, ganglionic blockade on day 7 after ANG II infusions resulted in a greater reduction in BP in OVX WT, central ER antagonist-treated intact WT, central E2 + ICI-treated OVX WT, ERαKO, and central E2- or ICI-treated ERαKO mice compared with that in intact WT mice given just ANG II. Together, these data indicate that ERα, especially central expression of the ER, mediates the protective effects of estrogen against ANG II-induced hypertension.

Pharmacological blockage of ICAM-1 improves angiotensin II-induced cardiac remodeling by inhibiting adhesion of LFA-1+ monocytes

2019 ◽  
Vol 317 (6) ◽  
pp. H1301-H1311 ◽  
Author(s):  
Qiu-Yue Lin ◽  
Ping-Ping Lang ◽  
Yun-Long Zhang ◽  
Xiao-Lei Yang ◽  
Yun-Long Xia ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Cardiovascular Diseases ◽  
Adhesion Molecules ◽  
Vascular Endothelium ◽  
Cardiac Remodeling ◽  
Leukocyte Adhesion ◽  
Neutralizing Antibody ◽  
Ang Ii ◽  
Cardiac Contractile ◽  
And Migration

Intercellular adhesion molecule-1 (ICAM-1) is a member of an immunoglobulin-like superfamily of adhesion molecules that mediate leukocyte adhesion to vascular endothelium and are involved in several cardiovascular diseases, including ischemia-reperfusion injury, myocardial infarction, and atherosclerosis. However, the role of ICAM-1 in angiotensin II (ANG II)-induced cardiac remodeling in mice remains unclear. Wild-type mice were administered an IgG control or ICAM-1 neutralizing antibody (1 and 2 mg/mouse, respectively) and ANG II (1,000 ng·kg−1·min−1) for up to 14 days. Cardiac contractile function and structure were detected by echocardiography. Hypertrophy, fibrosis, and inflammation were assessed by histological examination. The infiltration of lymphocyte function-associated antigen-1 (LFA-1+) monocytes/macrophages was assessed by immunostaining. The mRNA expression of genes was evaluated by quantitative RT-PCR analysis. Protein levels were tested by immunoblotting. We found that ICAM-1 expression in ANG II-infused hearts and ICAM-1 levels in serum from human patients with heart failure were significantly increased. Moreover, ANG II infusion markedly enhanced ANG II-induced hypertension, caused cardiac contractile dysfunction, and promoted cardiac hypertrophy, fibrosis, and LFA-1+ macrophage infiltration. Conversely, blockage of ICAM-1 with a neutralizing antibody dose-dependently attenuated these effects. Moreover, our in vitro data further demonstrated that blocking ICAM-1 inhibited ANG II-induced LFA-1+ macrophage adhesion to endothelial cells and migration. In conclusion, these results provide novel evidence that blocking ICAM-1 exerts a protective effect in ANG II-induced cardiac remodeling at least in part through the modulation of adhesion and infiltration of LFA-1+ macrophages in the heart. Inhibition of ICAM-1 may represent a new therapeutic approach for hypertrophic heart diseases. NEW & NOTEWORTHY Leukocyte adhesion to vascular endothelium is a critical step in cardiovascular diseases. ICAM-1 is a member of immunoglobulin-like superfamily of adhesion molecules that binds LFA-1 to mediate leukocytes adhesion and migration. However, the significance of ICAM-1 in ANG II-induced cardiac remodeling remains unclear. This study reveals that blocking of ICAM-1 prevents ANG II-induced cardiac remodeling via modulating adhesion and migration of LFA-1+ monocytes, may serve as a novel therapeutic target for hypertensive cardiac diseases.

Reactive Oxygen Species-Mediated Homologous Downregulation of Angiotensin II Type 1 Receptor Mrna by Angiotensin II

Hypertension ◽  
2000 ◽  
Vol 36 (suppl_1) ◽  
pp. 688-688
Author(s):  
Toshihiro Ichiki ◽  
Kotaro Takeda ◽  
Akira Takeshita
Keyword(s):  
Reactive Oxygen Species ◽  
Angiotensin Ii ◽  
Nadph Oxidase ◽  
Mrna Expression ◽  
Crucial Role ◽  
Oxygen Species ◽  
Ang Ii ◽  
Stimulation Of

58 Recent studies suggest a crucial role of reactive oxygen species (ROS) for the signaling of Angiotensin II (Ang II) through type 1 Ang II receptor (AT1-R). However, the role of ROS in the regulation of AT1-R expression has not been explored. In this study, we examined the effect of an antioxidant on the homologous downregulation of AT1-R by Ang II. Ang II (10 -6 mol/L) decreased AT1-R mRNA with a peak suppression at 6 hours of stimulation in rat aortic vascular smooth muscle cells (VSMC). Ang II dose-dependently (10 -8 -10 -6 ) suppressed AT1-R mRNA at 6 hours of stimulation. Preincubation of VSMC with N-acetylcysteine (NAC), a potent antioxidant, almost completely inhibited the Ang II-induced downregulation of AT1-R mRNA. The effect of NAC was due to stabilization of the AT1-R mRNA that was destabilized by Ang II. Ang II did not affect the promoter activity of AT1-R gene. Diphenylene iodonium (DPI), an inhibitor of NADH/NADPH oxidase failed to inhibit the Ang II-induced AT1-R mRNA downregulation. The Ang II-induced AT1-R mRNA downregulation was also blocked by PD98059, an extracellular signal-regulated protein kinase (ERK) kinase inhibitor. Ang II-induced ERK activation was inhibited by NAC as well as PD98059 whereas DPI did not inhibit it. To confirm the role of ROS in the regulation of AT1-R mRNA expression, VSMC were stimulated with H 2 O 2 . H 2 O 2 suppressed the AT1-R mRNA expression and activated ERK. These results suggest that production of ROS and activation of ERK are critical for downregulation of AT1-R mRNA. The differential effect of NAC and DPI on the downregulation of AT1-R mRNA may suggest the presence of other sources than NADH/NADPH oxidase pathway for ROS in Ang II signaling. Generation of ROS through stimulation of AT1-R not only mediates signaling of Ang II but may play a crucial role in the adaptation process of AT1-R to the sustained stimulation of Ang II.

scholarly journals Alpha-Asarone Protects Endothelial Cells from Injury by Angiotensin II

2014 ◽  
Vol 2014 ◽  
pp. 1-7 ◽  
Author(s):  
Hai-Xia Shi ◽  
Jiajun Yang ◽  
Tao Yang ◽  
Yong-Liang Xue ◽  
Jun Liu ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Endothelial Cells ◽  
Angiotensin Ii ◽  
Cell Injury ◽  
Fluorescent Dyes ◽  
Umbilical Vein ◽  
Protective Effects ◽  
Ang Ii ◽  
Versus Model

α-Asarone is the major therapeutical constituent ofAcorus tatarinowiiSchott. In this study, the potential protective effects ofα-asarone against endothelial cell injury induced by angiotensin II were investigatedin vitro. The EA.hy926 cell line derived from human umbilical vein endothelial cells was pretreated withα-asarone (10, 50, 100 µmol/L) for 1 h, followed by coincubation with Ang II (0.1 µmol/L) for 24 h. Intracellular nitric oxide (NO) and reactive oxygen species (ROS) were detected by fluorescent dyes, and phosphorylation of endothelial nitric oxide synthase (eNOS) atSer1177was determined by Western blotting.α-Asarone dose-dependently mitigated the Ang II-induced intracellular NO reduction (P<0.01versus model) and ROS production (P<0.01versus model). Furthermore, eNOS phosphorylation (Ser1177) by acetylcholine was significantly inhibited by Ang II, while pretreatment for 1 h withα-asarone partially prevented this effect (P<0.05versus model). Additionally, cell viability determined by the MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] assay (105~114.5% versus control,P>0.05) was not affected after 24 h of incubation withα-asarone at 1–100 µmol/L. Therefore,α-asarone protects against Ang II-mediated damage of endothelial cells and may be developed to prevent injury to cardiovascular tissues.

Hexarelin protects rat cardiomyocytes from angiotensin II-induced apoptosis in vitro

2004 ◽  
Vol 286 (3) ◽  
pp. H1063-H1069 ◽  
Author(s):  
Jin-Jiang Pang ◽  
Rong-Kun Xu ◽  
Xiang-Bin Xu ◽  
Ji-Min Cao ◽  
Chao Ni ◽  
...  
Keyword(s):  
Heart Failure ◽  
Angiotensin Ii ◽  
Caspase 3 ◽  
Cardiomyocyte Apoptosis ◽  
Protective Effects ◽  
Ang Ii ◽  
Growth Hormone Secretagogue Receptor ◽  
Growth Hormone Secretagogue ◽  
Rat Cardiomyocytes ◽  
Induced Apoptosis

Loss of cardiomyocytes by apoptosis is proposed to cause heart failure. Angiotensin II (ANG II), an important neurohormonal factor during heart failure, can induce cardiomyocyte apoptosis. Inasmuch as hexarelin has been reported to have protective effects in this process, we examined whether hexarelin can prevent cardiomyocytes from ANG II-induced cell death. Cultured cardiomyocytes from neonatal rats were stimulated with ANG II. Apoptosis was evaluated using fluorescence microscopy, TdT-mediated dUTP nick-end labeling (TUNEL) method, flow cytometry, DNA laddering, and analysis of cell viability by (3,4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT). It was found that incubation with 0.1 μmol/l ANG II for 48 h increased cardiomyocyte apoptosis. Administration of 0.1 μmol/l hexarelin significantly decreased this ANG II-induced apoptosis and DNA fragmentation and increased myocyte viability. To further investigate the underlying mechanisms, caspase-3 activity assay and mRNA expression of Bax, Bcl-2, and growth hormone secretagogue receptor (GHS-R; the supposed hexarelin binding site) were examined. GHS-R mRNA was abundantly expressed in cardiomyocytes and was upregulated after administration of hexarelin. These results suggest that hexarelin abates cardiomyocytes from ANG II-induced apoptosis possibly via inhibiting the increased caspase-3 activity and Bax expression induced by ANG II and by increasing the expression of Bcl-2, which is depressed by ANG II. Whether the upregulated expression of GHS-R induced by hexarelin is associated with this antiapoptotic effect deserves further investigation.

β-Pro7Ang III is a novel highly selective angiotensin II type 2 receptor (AT2R) agonist, which acts as a vasodepressor agent via the AT2R in conscious spontaneously hypertensive rats

2015 ◽  
Vol 129 (6) ◽  
pp. 505-513 ◽  
Author(s):  
Mark Del Borgo ◽  
Yan Wang ◽  
Sanja Bosnyak ◽  
Morimer Khan ◽  
Pia Walters ◽  
...  
Keyword(s):  
Cardiovascular Disease ◽  
Angiotensin Ii ◽  
Protein Binding ◽  
Binding Site ◽  
Spontaneously Hypertensive Rats ◽  
Protective Effects ◽  
Ang Ii ◽  
Hypertensive Rats ◽  
Spontaneously Hypertensive

We have synthesized a highly selective compound that is able to target a protein-binding site [called angiotensin (Ang) II type 2 receptor, AT2R] in the cardiovascular system. This research tool will enhance our ability to stimulate AT2R to produce protective effects against cardiovascular disease.

Embryonic lethality in Dear gene-deficient mice: new player in angiogenesis

2005 ◽  
Vol 23 (3) ◽  
pp. 257-268 ◽  
Author(s):  
Victoria L. M. Herrera ◽  
Lorenz R. B. Ponce ◽  
Pia D. Bagamasbad ◽  
Benjamin D. VanPelt ◽  
Tamara Didishvili ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Embryonic Lethality ◽  
Female Rats ◽  
Ang Ii ◽  
Sprague Dawley ◽  
Angiotensin Ii Receptor ◽  
Endothelin 1 ◽  
Receptor Isoforms ◽  
Age Range ◽  
Deficient Mice

The dual endothelin-1/angiotensin II receptor (Dear) binds endothelin-1 (ET-1) and angiotensin II (ANG II) with equal affinities in the Dahl S/JRHS rat strain. To elucidate its physiological significance within the context of multiple receptor isoforms and diverse ET-1 and ANG II functions spanning blood pressure regulation, tumor proliferation, and angiogenesis, we characterized mouse Dear and Dear-deficient mice. Unlike null mutant models of ET-1, ANG II, and all other ET-1 and ANG II receptors, Dear−/− deficiency results in impaired angiogenesis, dysregulated neuroepithelial development, and embryonic lethality by embryonic day 12.5. Interestingly, mouse Dear does not bind ANG II, similar to Dahl R/JRHS rat Dear, but binds ET-1 and vascular endothelial growth factor (VEGF) signal peptide (VEGFsp) with equal affinities, suggesting a putative novel multifunction for VEGFsp and a parsimonious mechanism for coordination of VEGF-induced and Dear-mediated pathways. Consistent with its developmental angiogenic role, Dear inhibition results in decreased tumor growth in B16-F10 melanoma cell-induced subcutaneous tumor in female Dear+/−/C57BL6BC10 mice, but not in males (age 3.5 mo), and in 127Cs radiation-induced orthotopic mammary tumors in Sprague-Dawley female rats (age range 3–6.5 mo). Altogether, the data identify Dear as a new player in angiogenesis during development downstream to, and nonredundant with, VEGF-mediated pathways, as well as a putative modulator of tumor angiogenesis acting within a gender-specific paradigm.

Abstract P363: Annexin-A1 Deficiency Exaggerates Cardiac Remodeling In Angiotensin II-induced Hypertension

2021 ◽  
Vol 129 (Suppl_1) ◽  
Author(s):  
Kristy Jackson ◽  
Jaideep Singh ◽  
Yen Zhi Ng ◽  
Cheng Peng ◽  
Anida Velagic ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Angiotensin Ii ◽  
Cardiac Remodeling ◽  
Physiological Role ◽  
Preclinical Model ◽  
Annexin A1 ◽  
Ang Ii ◽  
Cardiac Damage ◽  
Induced Hypertension ◽  
Deficient Mice

Introduction: We have previously demonstrated that the naturally-occurring anti-inflammatory and pro-resolving protein Annexin-A1 (Anx-A1) limits the acute inflammatory response post myocardial infarction, but its impact on chronic inflammation, such as hypertension, has not been explored. This study aims to investigate the role of Anx-A1 in a preclinical model of hypertension, induced by angiotensin-II (Ang-II). Methods: 15-week-old male C57BL/6 or ANXA1 -/- were anesthetized (isoflurane, 2-4% v/v) and implanted with an osmotic minipump randomly assigned to receive Ang-II (0.7mg/kg/day) or vehicle (saline). Radiotelemetry recordings of blood pressure were taken at 10 intermittent timepoints from baseline to the end of the 29-day infusion period. Animals were euthanized with pentobarbitone (100mg/kg; i.p.) at endpoint and organ weights recorded and normalized to bodyweight. Left ventricle (LV) samples were stained with picrosirius red to assess total LV collagen deposition. Results: Ang II-induced mice at the end of the study had elevated mean arterial pressure (MAP), cardiac hypertrophy and fibrosis compared to normotensive mice (Table). Anx-A1 deficient mice given Ang II had an even greater increase in MAP and cardiac remodeling compared to WT. Interestingly, MAP of Anx-A1 deficient mice at baseline is significantly higher compare to C57BL/6 counterparts (Table). Conclusion: This is the first study to demonstrate that deficiency of Anx-A1 exaggerates cardiac remodeling in AngII-induced hypertension, suggesting that endogenous Anx-A1 might play previously unappreciated physiological role in regulating blood pressure. This supports the development of Anx-A1 based pharmacotherapy against hypertension-induced cardiac damage.

Abstract 7: Angiotensin II Type 2 Receptor Deficiency Increases Renal ACE/ACE2 Ratio-Ang II-AT1R Expression In Male but not in Female Mice

Hypertension ◽  
2012 ◽  
Vol 60 (suppl_1) ◽  
Author(s):  
Quaisar Ali ◽  
Yonnie Wu ◽  
Tadashi Inagami ◽  
Tahir Hussain
Keyword(s):  
Blood Pressure ◽  
Renal Function ◽  
Angiotensin Ii ◽  
Renin Activity ◽  
Ang Ii ◽  
Male And Female ◽  
Female Mice ◽  
Gender Specific

Angiotensin II acting via Angiotensin II type 2 receptors (AT2Rs) is believed to be protective against blood pressure increase and affects renal function under pathophysiological condition. Recently we have observed that stimulation of AT2Rs in male obese Zucker rats has shifted the two opposing arms of renin angiotensin system (RAS) i.e. ACE-Ang II-AT1 vs ACE2/Ang-(1-7)-Mas. Evidence suggests that estrogen regulates RAS, including AT2R in female mice. We hypothesized that AT2R has a gender specific regulation of RAS. In the present study, we investigated the role of AT2Rs in regulating RAS components in male and female mice. Kidney cortex from AT2R knockout (AT2RKO) male and female mice and wild type (WT) with similar background (C57BL/6) of 20 weeks of age were used in the study. The cortical ACE expression (ng ACE/μg tissue) was significantly increased in AT2RKO mice (3±0.02) compared to WT males (1.9±0.02). LC/MS analysis of cortical tissue revealed that Ang II was also significantly increased in AT2RKO mice (WT: 31±3, AT2RKO: 47±3 fmoles/mg tissue). Deletion of AT2R significantly increased AT1R (204%, 204 of 100) expression and had no effect on renin activity compared to WT males. The cortical expression of ACE2 activity (WT: 113±8, AT2RKO: 40±11, RFU/min), Ang-(1-7) levels (WT: 7.3±1.4, AT2RKO: 3±0.8 fmoles/mg tissue) and Mas receptor (AT2RKO: 54±15, % of WT) was significantly decreased in AT2RKO males compared to WT. The cortical expression of the AT2R and MasR was 2-fold greater in WT females compared to WT male. The renin activity (WT: 32±2, AT2RKO: 21±0.3, RFU/min) and MasR expression (WT: 187.5±55, AT2KO: 47±9) was significantly decreased in AT2RKO females compared to the female WT. Interestingly, Ang-(1-7) level (WT: 5.7±0.7, AT2RKO 2.6±0.7 fmoles/mg tissue) was decreased but no changes in ACE or ACE2 activity was observed in AT2KO females compared to their WT, suggesting a role of non-ACE2 pathway. This study suggests that AT2R regulates ACE/ACE2 ratio-Ang II-AT1R expression negatively only in males, whereas in females, it regulates Ang-(1-7) potentially via non-ACE2 pathway. Such changes indicate a gender specific mechanisms potentially associated with AT2R-mediated regulation of renal function and blood pressure control.

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