bluuebunny/crossref_metadata_2025_split huggingface dataset:
Involvement of Inhibitor Kappa B Kinase 2 in the Elevated Vascular Tone of Spontaneously Hypertensive Rats
Authors: Choi Soo‐Kyoung , Lim Mihwa , Kwon Youngin , Lee Young‐Ho 
Published: November 2023

IntroductionHypertension is one of the leading causes for cardiovascular disease worldwide. A contributing factor to hypertension is elevated vascular tone in small arteries and arterioles. The 20 KDa myosin light chain (MLC20) phosphorylation is determinant of vascular tone. Recently, it has been reported that inhibitor kappa B kinase 2 (IKK2) is involved in the regulation of MLC20 phosphorylation. We tested whether IKK2 is involved augmented vascular tone and increased blood pressure in spontaneously hypertensive rats (SHRs).Methods and ResultsThe vascular diameter was measured in mesenteric arteries from 16‐week old male SHRs and their control animals, wistar kyoto rats (WKYs). Western blot analysis was performed to determine changes in expression of IKK2, phosphorylation of inhibitor of kappa B alpha (IκBα), and phosphorylation of MLC20. We found that IC50 values of IKK2 inhibitor, SC‐514 were significantly higher in mesenteric arteries from SHRs compared to those from WKYs. Furthermore, expression of IKK2 is significantly increased in mesenteric arteries from SHRs, which is associated with enhanced phosphorylation of MLC20.ConclusionOur results show that IKK2 expression and activation are enhanced in the mesenteric arteries of SHRs compared to WKYs. Thus, we suggest that IKK2 contributes to increased vascular tone in SHRs.
Salt and Angiotensin II Treatment Induces Fluid Congestion and Heart Failure with Increased Mortality in Balb/C Mice but Not in C57BL/6J
Authors: Joensson Sofia Tora , Becriovic‐Agic Mediha , Hulström Michael 
Published: November 2023

Heart and kidney failure causes many hospitalizations, and is associated with high mortality rate. We have previously shown that 3% sodium diet and Angiotensin II (0.5 μg/min/kg) leads to clinical signs of heart failure with decreased blood pressure, edema and mortality in Balb/C while C57BL/6J are protected. The aim of the present investigation was to study heart function using left ventricular catheterization and to formally analyze mortality using meta‐analysis across all our studies.Mice were treated with a 3% sodium diet and AngII (0.5 μg/min/kg) using Alzet osmotic pumps for four days. Left ventricular catheterization showed lower heart rate and cardiac output in Balb/C (596±9.8 bpm, 7.1±0.74 ml/min) compared to C57BL/6J (517±6.2 bpm, 5.2±0.29 ml/min p<0.05) after Salt+AngII treatment. Stroke volume was lower in Balb/C treated with Salt+AngII compared to control treatment, but no difference was seen in C57BL/6J. The results were reproduced using echocardiography, which also showed a diastolic dysfunction. However, compliance as measured using the pressure volume relationship was not affected. This may be consistent with a fluid congestion and right heart failure as Balb/C show a lower urine output (0.24±0.04 vs. 0.46±0.02 ml/h, p<0.001) and sodium excretion (2.7±0.5 vs.3.5±0.3, p<0.05) with the combination treatment in spite of similar intake.Meta‐analysis of the mortality of 121 animals from four different experimental series showed a relative risk of 0.16 (95% CI 0.05–0.49) in favor of C57BL/6J after combination treatment with high‐sodium diet and AngII. This provides a rigorous statistical analysis of our observation that Balb/C is much more susceptible to heart failure. Similar analysis of sodium diet (n=96, RR 0.3, 95% CI 0.04–2.54), or AngII treatment alone (n= 83, RR 0.4, 95% CI 0.12–1.36) showed no significant difference.In conclusion, Balb/C mice have reduced cardiac function compared to C57BL/6J when treated with Salt and AngII, which leads to a higher mortality in Balb/C mice.Support or Funding InformationSwedish Heart‐Lung foundation, Ake Wiberg foundation, Swedish Society for Medical Research
Renal denervation normalizes blood pressure and improves glucose metabolism in obese genetically hypertensive Schlager mice
Authors: Asirvatham‐Jeyaraj Ninitha , Banek Christopher T. , Han Ruijun , Razzoli Maria , Burbach Brandon J. , Bartolomucci Alessandro , Shimizu Yoji , Osborn John W. 
Published: November 2023

Renal nerve ablation has been reported to decrease arterial pressure and improve glucose metabolism in drug‐resistant hypertensive humans, the majority of who are overweight or obese. However, the mechanism mediating these responses is unknown. The Schlager mouse (BPH/2J) is a genetically inbred strain that has chronically elevated sympathetic activity and mean arterial pressure (MAP). We used this model to assess the effect of renal denervation (RNDX) on MAP and glucose metabolism in lean and obese BPH/2J mice. In addition, since both obesity and renal efferent nerves have been shown to drive renal inflammation, we also assessed the effect of RDNX on markers of renal inflammation. Hypertensive BPH/2J and normotensive BPN mice were maintained on either a low fat (LFD; 10 KCal% from fat) or a high fat (HFD; 45 KCal% from fat) diet for 10 weeks. Radio telemeters were then implanted for measurement MAP. MAP was significantly higher in LFD BPH/2J mice (128 ± 2 mmHg) than the LFD BPN controls (107 ± 2 mmHg). Surprisingly, 10 weeks of HFD had no effect on MAP in either strain. MAP was normalized in HFD BPH/2J mice two weeks following RDNX, (~110 mmHg). In contrast, RDNX had no effect on MAP in LFD BPH/2J mice (~134 mmHg). Glucose handling was assessed by glucose tolerance tests three weeks after RDNX/Sham surgery. Glucose tolerance, as quantified by the area under the curve, was impaired to a similar extent in LFD and HFD BPH/2J mice. Moreover, RDNX improved glucose metabolism in both the LFD and HFD groups. Real time PCR was used to determine expression of MCP‐1 (monocyte chemoattractant protein‐1), a chemokine that recruits monocyte and macrophages to the site of injury, and the pro‐inflammatory renal cytokine, tumor necrosis factor alpha (TNFa). In both LF and HF fed groups MCP‐1 (135 ± 37.8 fold) and TNFa expression (56.9 ± 1.9 fold) were elevated in BPH/2J mice compared to normotensive BPN controls (2–4 fold). Results indicate that RDNX may reduce MCP‐1 expression (to 34.1 fold) in BPH/2J mice but have no effect on TNFa. These results suggest that RDNX is effective in the normalization of MAP and glucose metabolism in HFD BPN/2J mice. Future studies will focus on the assessing the mechanisms by which RDNX mediates these responses.Support or Funding InformationRO1 HL 067357‐15 and RO1 HL 116476‐02
Identification of Dipeptidyl Peptidase III as the Angiotensin‐(1–7)‐Degrading Metallopeptidase in Human Proximal Tubule Cells
Authors: Cruz‐Diaz Nildris , Wilson Bryan A , Marshall Allyson C , Pirro Nancy T , Chappell Mark C 
Published: November 2023

We previously identified a soluble metallopeptidase activity present in various compartments of the sheep including the brain medulla, cerebrospinal fluid (CSF) and renal cortex, as well as in the human proximal tubule (HK‐2) cells that efficiently metabolized Angiotensin‐(1–7) [Ang‐(1–7)], an alternative product of the renin‐angiotensin that functionally antagonizes the Ang II‐AT1 receptor axis. Indeed, peptidase activity in the CSF was markedly higher in betamethasone‐exposed sheep, a model of fetal programming‐induced hypertension. Moreover, the peptidase activity was associated with higher blood pressure and reduced CSF content of Ang‐(1–7). Since the peptidase accounted for the sole degrading activity of Ang‐(1–7) in the HK‐2 cells, we purified and sequenced the enzyme from these cells. The 100,000 xg supernatant fraction was subjected to sequential Cibacron‐blue and ion‐exchange chromatography. A single 80kDa band was revealed by both native and SDS polyacrylamide gels. The protein band exhibiting Ang‐(1–7) peptidase activity and sensitivity to the JMV‐390 inhibitor was subsequently excised from the native gel and submitted for protein sequencing by MALDI‐MS. The MS analysis revealed only one peptidase candidate identified as dipeptidyl peptidase III (DPP III, EC 3.4.14.4). Cleavage specificity of Ang‐(1–7) and sensitivity to JMV‐390 were then determined utilizing human recombinant DPP III. DPP III metabolized Ang‐(1–7) to the primary products Ang‐(3–4) and Ang‐(5–7); however, Ang‐(3–7) was a minor product. Comparison of Ang‐(1–7) and Ang‐(3–7) metabolism by recombinant DPP III revealed a ~3‐fold greater rate of hydrolysis for Ang‐(3–7) [14.8 vs. 5.5 nmol/min/ug] that is consistent with the catalytic properties of DPP III and suggests the enzyme catalyzes the sequential cleavage of Ang‐(1–7) to Ang‐(3–7) and then to Ang‐(5–7) and Ang‐(3–4). The recombinant DPP III also exhibited potent inhibition by JMV‐390 (IC50 = 1.4 ± 0.01 nM) that was comparable to the purified peptidase from HK‐2 cells (IC50 = 0.2 ± 0.01 nM). The metabolism of Ang‐(1–7) was then assessed in the HK‐2 cells following chronic treatment with a low (20 nM) and high (200 nM) dose of the JMV‐390 inhibitor over a 72 hour period. The cellular metabolism of exogenous Ang‐(1–7) was reduced at both JMV concentrations (20nM: 54 ± 7% of control, n=2; 200nM: 19 ± 5% of control, n=3, p<0.05). Moreover, the extent of the conversion of Ang I to Ang‐(1–7) was higher in the JMV‐treated HK‐2 cells (JMV 20nM: 135 ± 33% of control, n=2; JMV 200nM: 190 ± 33% of control, n=3). In summary, we identify DPP III as the Ang‐(1–7) degrading activity in human HK‐2 proximal tubule cells. We conclude that that DPP III may constitute a potential pharmacological target to enhance the intracellular levels of Ang‐(1–7) under pathological conditions.Support or Funding InformationSupported by NIH HD47584, HD‐17644 and K12‐GM102773.
Deficiency of Prorenin Renin Receptor in Adipocyte induces Liver Steatosis and increases Blood Pressure in Lean and Obese Male Mice
Authors: Wu Chia‐Hua , Moradi Shayan , Gong Ming , Nguyen Genevieve , Yiannikouris Frederique 
Published: November 2023

ObjectivesAdipose tissue is an important source of the prorenin renin receptor (PRR). During the development of obesity, the expression of PRR gene is increased in adipose tissue. However the role of adipocyte PRR during the development of obesity is not clear. The purpose of this study was to characterize a new model of adipocyte PRR deletion and define the metabolic consequences during the development of obesity related hypertension in male mice.Methods and resultsMale PRRfl/Y mice expressing Adiponectin‐driven Cre recombinase were bred to female mice PRRfl/fl to generate littermate controls (PRRfl/Y) and adipocyte‐PRR deficient mice (PRRAdi/Y). Mice were fed a low fat diet (LF, 10% kcal as fat) or a high fat diet (HF, 60% kcal as fat) for 16 weeks (n=5–8/groups). Body weight of LF fed‐PRRAdi/Y mice were decreased significantly compared to LF fed‐PRRfl/Ymice. Adipocyte PRR deficient mice were resistant to diet induced obesity (body weights: PRRfl/Y, 48 ±1 g; PRRAdi/Y, 34 ± 1 g; P<0.05). Fat mass, measured by echo‐MRI, were drastically decreased in PRRAdi/Y mice fed a LF‐or HF‐diet compared to PRRfl/Y mice (fat mass: LF: PRRfl/Y, 9 ± 1 g; PRRAdi/Y, 2 ± 0 g. HF: PRRfl/Y, 21 ± 1 g; PRRfl/Y, 3 ± 0 g. P<0.05). Surprisingly, adipocyte PRR deficiency induced an increase in lean mass in LF− and HF− fed mice. The increase in lean mass was attributed mainly by an increase of liver weights in PRRAdi/Y male mice fed a LF− or a HF‐diet compared to PRRfl/Y mice (LF: PRRfl/Y, 1.5 ± 0.1 g; PRRAdi/Y, 3.0 ± 0.4 g. HF: PRRfl/Y, 2.6 ± 0.2 g; PRRfl/Y, 3.6 ± 0.2 g. P<0.05). Microscopic examination of liver sections revealed an increase of hepatic fat accumulation in male PRRAdi/Y fed a LF‐or HF‐diet compared to control male PRRfl/Y mice. To determine the role of adipocyte PRR deficiency on glucose homeostasis, we performed an intraperitoneal glucose tolerance test (ipGTT). At 12 weeks, LF and HF‐fed PRRAdi/Y mice had an improved glucose tolerance compared to PRRfl/Y mice. At 15 weeks, we implanted radiotelemetry devices into anesthetized mice to measure blood pressure. Surprisingly, LF‐fed PRRAdi/Y mice exhibited a significant increase in systolic blood pressure compared to LF‐fed controls (LF: PRRfl/Y, 129 ± 1 mmHg; LF: PRRAdi/Y, 134 ± 2 mmHg, P< 0.05). Moreover, when challenged with HF‐feedings, adipocyte‐specific deficiency of PRR exaggerated diet induced increased‐blood pressure (HF: PRRfl/Y, 132, ± 2 mmHg ; HF: PRRAdi/Y, 138 ± 1 mmHg, P< 0.05).ConclusionOur new PRRAdi/Y mouse model provides evidence for an important link between adipocyte PRR, fat distribution and regulation of blood pressure. The mechanism by which adipocyte PRR induces increase in blood pressure is currently under investigation.Support or Funding Information13SDG17230008, COBRE P20 GM103527, pilot grant NIH CTSA UL1TR000117.
The role of Gαi2 proteins in the regulation of PVN neuronal activation in response to isotonic volume expansion in conscious rats
Authors: Carmichael Casey Y , Patel Neha M , Wipfler Rachel E , Wainford Richard D 
Published: November 2023

AimAn acute volume expansion (VE) evokes inhibition of sympathetic outflow and the paraventricular nucleus (PVN) is a key region involved in this response. Extending our prior studies demonstrating a role of CNS Gαi2 proteins in PVN neuronal activation during acute hypertonic saline challenge, we determined the role of brain Gαi2 proteins in PVN neuronal activation during an acute VE.Methods24‐h intracerebroventricular scrambled (SCR) or Gαi2 oligodeoxynucleotide (ODN; 25μg/5μl)‐pretreated conscious Sprague‐Dawley rats were IV infused with isotonic saline (0.9% w/v NaCl) equal to 10% of body weight in 10‐min, followed by a maintenance infusion of 0.5 ml/min for 90‐min, and then a physiological infusion of 20 μl/min for 20‐min. Rats were monitored for changes in cardiovascular and urine excretory parameters and sacrificed at control (C) or 120‐min post‐VE for PVN cFos IHC.ResultsIn both SCR and Gαi2 ODN pretreated rats, acute isotonic VE produced no significant change in systemic cardiovascular parameters (P>0.05). VE evoked a significant increase in urine flow rate (V) and urinary sodium excretion (UNaV) in SCR ODN pretreated rats, while the magnitude of the diuretic and natriuretic response was attenuated in Gαi2 ODN pretreated rats (peak Δ UNaV [μeq/min] SCR: 101.29±4.20 vs. Gαi2: 63.12±9.78, P<0.05). No difference in the number of PVN Fos+ cells was observed between ODN pretreated groups at control. Significant increases in the number of Fos+ PVN magnocellular and parvocellular neurons were observed post‐VE in both SCR and Gαi2 ODN groups as compared to C (P<0.05). Gαi2 ODN rats exhibited significantly less activated magnocellular (120‐min [Fos+ cells] SCR: 24±3 vs Gαi2: 16±2, P<0.05) and parvocellular neurons (120‐min [Fos+ cells] SCR: 168±6 vs Gαi2: 102±4, P<0.05) as compared to their SCR ODN counterparts following VE (P<0.05).ConclusionEndogenous brain Gαi2 proteins contribute to the activation of PVN neurons during isotonic VE to maintain body fluid homeostasis. Owing to the established sympathoinhibitory actions of PVN parvocellular neurons post VE, we speculate Gαi2 proteins are central to the activation of sympathoinhibitory parvocelluar neurons. This hypothesis is supported by our prior data demonstrating 1) CNS Gαi2 proteins are essential to facilitate the suppression of renal sympathetic nerve traffic during acute VE and 2) CNS Gαi2 proteins mediate activation of PVN parvocellular neurons and sympathoinhibition in response to an acute bolus sodium challenge. Collectively, these data highlight a novel role of PVN Gαi2 proteins in the acute neural sympathoinhibitory pathways that regulate fluid and electrolyte homeostasis. Further, impairments in these neural pathways potentially contribute to altered sympathetic outflow and sodium retention in the pathophysiology of hypertension.Support or Funding InformationNIH HL107330K02HL112718
Dopamine β‐hydroxylase Inhibition with BIA5‐1058 Normalizes the High Blood Pressure of Human GRK4g 142V Transgenic Mice
Authors: Asico Laureano D , Lin Hai , Jones John E , Soares‐da‐Silva Patricio , Jose Pedro A , Wang Xiaoyan 
Published: November 2023

Overactivity of the sympathetic nervous system is one of the mechanisms involved in the pathogenesis of human essential hypertension. However, treating hypertension by inhibiting the sympathetic nervous system is associated with adverse side effects. Reducing the biosynthesis of norepinephrine (NE) by inhibiting the enzyme that catalyzes the conversion of dopamine to NE, dopamine β‐hydroxylase (DβH), in the peripheral but not the central sympathetic nervous system may be a good drug to treat hypertension; BIA5‐1058 is such a drug. Therefore, we used BIA5‐1058 to treat the hypertension of human GRK4γ 142V transgenic (142V) mice. 142V mice and non‐transgenic (NT) littermates (7 mo old, n=4/group) were gavaged (10:00 AM) with BIA5‐1058 (30 mg/kg) or vehicle, daily for 1 week. The mice were placed in metabolic cages for 24 hr urine collection before blood pressure (BP), under anesthesia, was measured, via the femoral artery on day 7. In additional studies, BP was also monitored by telemetry in conscious mice. Food and water intake, body weight, heart rate, urine flow and sodium and serum Na+, K+, and Cl− were similar in the 4 groups. Compared with NT mice, 142V mice had increased systolic (142v mice: 120±1.5 vs. NT mice: 98.8±2.7, mm Hg) and diastolic BPs (94.8±2.7 vs. 66.5±5.1) that were normalized by BIA5‐1058 (SBP: 97±2 vs. 97.3±0.6; DBP: 70.3±4.8 vs. 70.8±2.5). In conscious mice, 30 mg/kg but not 3 and 10 mg/kg BIA5‐1058, also normalized the BPs of 142V mice. Renal protein abundance of type 1 angiotensin II receptor (AT1R) was greater in 142V than NT mice (265±56 vs. 100±18%), similar to our previous report. BIA5‐1058 also decreased renal AT1R protein in 142V but not NT mice (27±6 vs. 100±14%). Our data suggest that inhibition of DβH normalizes the BP of 142V mice, not only by decreasing the synthesis of NE but also renal AT1R protein expression.Support or Funding InformationP01HL074940P01HL068686R01HL092196R37HL023081R01DK039308
ETA Receptor Antagonism and Estrogen Replacement Prevent Ang II Hypertension in Menopausal Mice
Authors: Pollow Dennis P. , Romero‐Aleshire Melissa J. , Davies John , Nikolich‐Zugich Janko , Brooks Heddwen L. 
Published: November 2023

Cardiovascular disease, including hypertension, increases dramatically in women after menopause, however the efficacy of hormone replacement therapy (HRT) in preventing such diseases has produced controversial results. Endothelin receptor antagonists have been tested as anti‐hypertensive agents in clinical trials and may represent a promising alternative to HRT in postmenopausal women. Therefore, we sought to directly compare the anti‐hypertensive capacity of estrogen replacement (17‐b estradiol pellet, 0.1mg) vs. the ETA receptor antagonist ABT‐627 (5mg/kg, i.p., daily) in the VCD mouse model of menopause (4‐vinylcyclohexene diepoxide, VCD). Ang II (800ng/kg/min, 14d) was infused into VCD‐treated menopausal female mice alone (Meno), or with either concurrent 17‐b estradiol replacement (E2) or ETA receptor antagonism (ETAA). Premenopausal mice received sesame oil vehicle with and without subsequent Ang II (Con, Con/Ang). Ang II infusion induced a significant increase in systolic blood pressure in VCD‐treated menopausal mice compared to Ang II infusion in premenopausal mice (Con Δ2 ± 2 mmHg, Con/Ang Δ15 ± 2* mmHg, Meno/Ang Δ37 ± 6*# mmHg, *P<0.05 vs Con, #P<0.05 vs Con/Ang). Both 17‐b estradiol replacement and ETA receptor antagonism prevented the increased blood pressure response in Ang II‐infused menopausal mice (E2 Δ10 ± 6* mmHg, ETAA Δ14 ± 3* mmHg, *P<0.05 vs Meno/Ang). Splenic and renal T cell profiles were assessed via flow cytometry. 17‐b estradiol replacement increased the percentage of Foxp3+ T regulatory cells in the spleen compared to all other groups (Con 17 ± 1%, Con/Ang 18 ± 1%, Meno/Ang 18 ± 1%, E2 23 ± 1%*, ETAA 18 ± 1%, *P<0.05 vs all groups). However, no changes in T cell profiles occurred with any treatment in the kidney. Quantitative real‐time PCR demonstrated that Ang II‐induced expression of whole kidney collagen type IV in VCD‐treated menopausal mice was significantly reduced by ETA receptor antagonism, but not 17‐b estradiol replacement (ETAA 0.68 ± 0.08 fold*, E2 1.25 ± 0.05 fold*, *P<0.05 vs Meno). These data suggest that ETA receptor antagonism may be an effective treatment strategy for preventing hypertension in postmenopausal women.Support or Funding InformationAmerican Heart Association Predoctoral Fellowship (DPP), NIH DK073611 (HLB), Sarver Heart Center (DPP), ARCS Foundation (DPP)
Altered Renal and Circulating Renin‐Angiotensin System Does Not Cause Spontaneous Hypertension in the African Green Monkey
Authors: Gutierrez Alex , Goleva Slavina B , Rhoads Megan K , Weaver Chelsea Christina , Beierwaltes William H , Osborn Jeffrey L 
Published: November 2023

The renin‐angiotensin system (RAS) is important in the long‐term regulation of, sodium balance, body fluid volumes and blood pressure. The African Green Monkey, (AGM, Chlorocebus aethiops sabaeus) is a translational model of hypertension (HT) due to its close genetic similarity, behavioral activities and significant upright posture similar to humans. We hypothesized that upregulation of the RAS occurs in HT AGMs which may decrease Na+ excretion leading to Na+ retention and expansion of extracellular fluid volume. AGMs were phenotyped by systolic blood pressure (SBP) as HT (SBP>140 mmHg) or normotensive (NT, SBP<120 mmHg). Plasma and renal tissue samples were obtained from adult male AGMs with NT (n=26) having SBP of 98.2 ± 2.1 mmHg, HT AGMs (n=27) averaging 169.9 ± 6.1 mmHg. Plasma renin activity (PRA) and renal cortical renin content were determined by radioimmunoassay. Circulating PRA of NT (3.27 ± 0.36 ng AngI/ml/hr, n=15) and HT (3.34 ± 0.48 ng AngI/ml/hr, n=16) AGMs were not different (p>0.05). Renal cortex tissue was homogenized and incubated with excess renin substrate to measure renal cortical renin content (RCRC). Similar to PRA, RCRC of NT (10.73 ± 2.98 μg AngI/ml/hr/mg protein, n=11) and HT (8.94 ± 1.56 μg AngI/ml/hr/mg protein, n=13) AGMs were similar. Next, angiotensinogen (AGT) expression was assessed from renal cortex, outer medulla and liver using qRT‐PCR from extracted tissue RNA. Gene expression was normalized using RPS32 for kidney and RPS13A for liver. AGT expression was similar between NT and HT AGMs in the renal cortex (NT; 1 ± 0.55 vs HT; 1.74 ± 0.91), in the renal outer medulla (NT; 1 ± 0.16 vs HT; 0.59 ± 0.21) and liver (NT; 1 ± 0.14 vs HT; 1.19 ± 0.17, p > 0.05 for all tissues). To assess renal Na+ handling in HT (n=4) and NT (n=3) AGMs, animals were housed individually in pens and urine collected at 24 hour intervals for 5 consecutive days. Daily urinary sodium excretion of HT AGM's was greater than that of NT animals (HT; 2.86±0.40 mmol/day vs NT; 1.17±0.16 mmol/day, p<0.05) but urine osmolality was not different. The similar quantities of plasma and tissue renin, combined with unchanged gene expression of AGT, indicate that renin activity and renin substrate (angiotensinogen) in the RAS do not contribute to hypertension in the AGM. Thus, the long term altered blood pressure regulation and hypertension may result from elevated peripheral resistance due to other pressor mechanisms, as our data rules out any abnormal expression or activity of the renin‐angiotensin system in this nonhuman primate model of heritable, genetic hypertension.Support or Funding InformationSupported by American Physiological Society, National Heart, Lung and Blood Institute (NHLBI; 1 R25 HL115473‐01), and Biomedical Science Research Group, LLC.