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

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.

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Abstract 10: Mouse Recombinant Soluble PRR-induced Increase Of Blood Pressure Is Sex-dependant In High Fat-fed Mice

Hypertension ◽

10.1161/hyp.76.suppl_1.10 ◽

2020 ◽

Vol 76 (Suppl_1) ◽

Author(s):

Audrey A Poupeau ◽

Eva Gatineau ◽

Gertrude Arthur ◽

Wen Su ◽

Ming C Gong ◽

...

Keyword(s):

Blood Pressure ◽

Renin Angiotensin System ◽

The Body ◽

Soluble Form ◽

Dependent Manner ◽

High Fat ◽

Female Mice ◽

Prorenin Receptor ◽

Atropine Treatment ◽

Fat Feeding

Obesity is a major risk factor for hypertension. Although the renin-angiotensin system (RAS) contributes to the sex difference of blood pressure (BP) control, whether the prorenin receptor (PRR) and its soluble form (sPRR) play a role in the sexual dimorphism of BP is not clear. We previously demonstrated that, in high fat (HF)-fed male C57BL/6 mice, the infusion of mouse recombinant sPRR increased systolic blood pressure (SBP) by the sympatho-excitatory effects of leptin on BP. Therefore, in the present study, we aim to address whether mouse recombinant sPRR influences the BP in HF-fed female mice. To test this hypothesis, C57BL/6 female mice were fed a HF diet for 32 weeks and were implanted with radiotelemetry transmitter. After 24 weeks of high fat feeding, female mice (5-6/group) were implanted with osmotic pumps and infused with either saline (veh) or sPRR for 3 to 4 weeks. In contrast to male mice, the infusion of sPRR (30 μg/kg/day) did not change significantly the SBP (24hSBP; veh: 135 ± 7; sPRR: 134 ± 4 mmHg; P>0.05) and the baroreflex sensitivity. The decrease in BP mediated by chlorisondamine treatment was not significantly different between female mice infused with vehicle or sPRR (ΔSBP; veh: -11 ± 9; sPRR: -16 ± 7 mmHg; P>0.05). In addition, sPRR infusion did not affect the bradycardic or tachycardic responses after propranolol or atropine treatment respectively. Moreover, the decrease of SBP induced by losartan was similar in mice infused with vehicle or sPRR (ΔSBP; veh: -9 ± 4; sPRR: -10 ± 3 mmHg; P>0.05). Similar results were obtained using higher dose of sPRR (60 μg/kg/day). In female mice, sPRR infusion did not increase significantly the body weight (veh: 32.7 ± 2.5 g; sPRR: 35.8 ± 4.2 g; P>0.05), the white adipose tissue weight (WAT; veh: 3.0 ± 0.7g; sPRR: 3.7 ± 1.6 g; P>0.05) or circulating leptin levels (veh: 12.0 ± 7.6 ng/ml; sPRR: 15.5 ± 9.5 ng/ml; P>0.05). In conclusion, in contrast to male, female mice are protected from sPRR-induced increase in BP. sPRR did not increase circulating leptin suggesting that sPRR-induced leptin increase is regulated in a sex-dependent manner. Other pathways could participate to the protection against sPRR-induced increase in BP in female mice such as the vasodilator arm of the RAS and/or the hormonal status of the female mice.

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Renin-angiotensin System (RAS)-mediated Antiobesity and Antihypertensive Effects of Korean Traditional Soybean Paste (Doenjang) in Rat Model of Diet-induced Obesity (P08-097-19)

Current Developments in Nutrition ◽

10.1093/cdn/nzz044.p08-097-19 ◽

2019 ◽

Vol 3 (Supplement_1) ◽

Author(s):

Hayoung Woo ◽

Jung Eun Park ◽

Youn-soo Cha

Keyword(s):

Blood Pressure ◽

Systolic Blood Pressure ◽

High Fat Diet ◽

Health Benefits ◽

Renin Angiotensin System ◽

Serum Chemistry ◽

Table Salt ◽

High Fat ◽

Angiotensin System ◽

Renin Angiotensin

Abstract Objectives Hypertension is becoming more prevalent and one of the main cause is found in the increase of excessive dietary sodium intake. It is also risk factors for cardiovascular and kidney disease. Korean Traditional Fermented Food, doenjang, is made with high salt, so many of them are thinking that there is a lot of relation to hypertension despite reporting many health benefits. Our previous studies reported that doenjang have been associated effect of anti-obesity in human and animal study. Therefore, we expected that doenjang may have different effects on blood pressure and lipid metabolism compared to same concentrations of salt. Methods In this study, Sprague-Dawley rats divided into four groups, normal diet (ND), high fat diet (HD), high fat diet with 8% table salt (HDS), high fat diet with Doenjang contains 8% table salt (HDJ) for 13 weeks. The systolic blood pressure (SBP), serum chemistry, Na+ and K+ concentrations, liver and renal gene expressions were measured. Results Doenjang decreased systolic blood pressure (SBP), body weight and hepatic lipids. Serum chemistry, leptin and aldosterone levels were increased in HD and HDS groups while decreased in HDJ group. Results from analysing feces and urine, Na+, Ca+ and K+concentrations were changed by Doenjang. Furthermore, fatty acid synthesis-related genes expression was decreased in liver and downregulated the renin, AT1 receptor and ACE in renal cortex of doenjang treatment group. Conclusions These results suggest that doenjang may have anti-obesity and anti-hypertension through regulation of the renin angiotensin system. We believed that it is an important result of demonstrating that doenjang has health benefits regardless of salt content. Funding Sources This work was supported by the Korea Science and Engineering Foundation (KOSEF) grant funded by the Korea government (MEST) (No. 2018R1A2B6006477).

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EFFECT OF SEQUENTIAL NEPHRON BLOCKING IN COMPARISON WITH THE DOUBLE BLOCKADE OF THE RENIN- ANGIOTENSIN SYSTEM + BISOPROLOL ON CENTRAL SYSTOLIC BLOOD PRESSURE AND ARTERIAL STIFFNESS

Journal of Hypertension ◽

10.1097/01.hjh.0000748620.90653.e8 ◽

2021 ◽

Vol 39 (Supplement 1) ◽

pp. e354

Author(s):

Elizabeth do Espirito Santo Cestari ◽

Priscilla Galisteu de Mello ◽

Tatiane de Azevedo Rubio ◽

Maira Regina de Souza ◽

Eliangela Gianini Gonzales ◽

...

Keyword(s):

Blood Pressure ◽

Arterial Stiffness ◽

Systolic Blood Pressure ◽

Renin Angiotensin System ◽

Angiotensin System ◽

Renin Angiotensin ◽

Central Systolic Blood Pressure

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Abolition of long-term vascular influence of renin-angiotensin system

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.1990.259.2.h543 ◽

1990 ◽

Vol 259 (2) ◽

pp. H543-H553

Author(s):

R. D. Randall ◽

B. G. Zimmerman

Keyword(s):

Blood Pressure ◽

Vascular Tissue ◽

Renin Angiotensin System ◽

Ace Inhibition ◽

Ang Ii ◽

Flow Measurements ◽

Angiotensin System ◽

Renin Angiotensin ◽

Normal Controls

Rabbits were bilaterally nephrectomized for 24 h or received an angiotensin-converting enzyme (ACE) inhibitor chronically (5 days) before an acute experiment. Conductance responses to sympathetic nerve stimulation (SNS) (0.25, 0.75, and 2.25 Hz) and norepinephrine (NE) administration (0.2, 0.6, and 1.8 micrograms ia) were determined from simultaneous blood pressure and iliac blood flow measurements. Conductance responses to SNS were significantly reduced in nephrectomized (44, 26, and 20%) and chronic ACE inhibition (39, 31, and 24%) groups compared with normal controls, whereas conductance responses to NE were unchanged. Continuous infusion of angiotensin II (ANG II) for 24 h restored the depressed responses to SNS in nephrectomized and chronic ACE inhibition groups compared with normal controls but did not change conductance responses to NE. Acute ACE inhibition did not affect the conductance responses to SNS or NE compared with controls. Vascular tissue ACE activity was inhibited to a similar degree (50%) in both acute and chronic ACE inhibition groups compared with normal rabbits. Sodium depletion increased the conductance responses to SNS (30 and 24% at 0.25 and 0.75 Hz, respectively), but responses to NE were not affected. Chronic ACE inhibition significantly attenuated the conductance responses to SNS and slightly decreased responses to NE in sodium-depleted rabbits. Thus, in the anesthetized rabbit, the renin-angiotensin system potentiates the effect of SNS, presumably by ANG II acting at a prejunctional site, and this effect of ANG II appears to be long term in nature. Therefore, the renin-angiotensin system exerts a physiological role in the control of blood pressure in addition to the ability of this system to support arterial pressure in pathophysiological states.

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Involvement of the Intrarenal Renin-Angiotensin System in Experimental Models of Glomerulonephritis

Journal of Biomedicine and Biotechnology ◽

10.1155/2012/601786 ◽

2012 ◽

Vol 2012 ◽

pp. 1-6 ◽

Cited By ~ 12

Author(s):

Maki Urushihara ◽

Yukiko Kinoshita ◽

Shuji Kondo ◽

Shoji Kagami

Keyword(s):

Blood Pressure ◽

Intracellular Signaling ◽

Renin Angiotensin System ◽

Experimental Models ◽

At1 Receptor ◽

Biologically Active ◽

Ang Ii ◽

Angiotensin System ◽

Renin Angiotensin ◽

Proinflammatory Mediators

The intrarenal renin-angiotensin system (RAS) has several pathophysiologic functions not only in blood pressure regulation but also in the development of glomerulonephritis (GN). Angiotensin II (Ang II) is the biologically active product of the RAS. Locally produced Ang II induces inflammation, renal cell growth, mitogenesis, apoptosis, migration, and differentiation, regulates the gene expression of bioactive substances, and activates multiple intracellular signaling pathways, leading to tissue damage. Activation of the Ang II type 1 (AT1) receptor pathway results in the production of proinflammatory mediators, cell proliferation, and extracellular matrix synthesis, which facilitates glomerular injury. Previous studies have shown that angiotensin-converting enzyme inhibitors and/or AT1 receptor blockers have beneficial effects in experimental GN models and humans with various types of GN, and that these effects are more significant than their suppressive effects on blood pressure. In this paper, we focus on intrarenal RAS activation in the pathophysiology of experimental models of GN.

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Role of neurons and glia in the CNS actions of the renin-angiotensin system in cardiovascular control

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00078.2015 ◽

2015 ◽

Vol 309 (5) ◽

pp. R444-R458 ◽

Cited By ~ 29

Author(s):

Annette D. de Kloet ◽

Meng Liu ◽

Vermalí Rodríguez ◽

Eric G. Krause ◽

Colin Sumners

Keyword(s):

Blood Pressure ◽

Glial Cell ◽

Renin Angiotensin System ◽

Cardiovascular Control ◽

Health Concern ◽

Ang Ii ◽

Ongoing Research ◽

Angiotensin System ◽

Renin Angiotensin

Despite tremendous research efforts, hypertension remains an epidemic health concern, leading often to the development of cardiovascular disease. It is well established that in many instances, the brain plays an important role in the onset and progression of hypertension via activation of the sympathetic nervous system. Further, the activity of the renin-angiotensin system (RAS) and of glial cell-mediated proinflammatory processes have independently been linked to this neural control and are, as a consequence, both attractive targets for the development of antihypertensive therapeutics. Although it is clear that the predominant effector peptide of the RAS, ANG II, activates its type-1 receptor on neurons to mediate some of its hypertensive actions, additional nuances of this brain RAS control of blood pressure are constantly being uncovered. One of these complexities is that the RAS is now thought to impact cardiovascular control, in part, via facilitating a glial cell-dependent proinflammatory milieu within cardiovascular control centers. Another complexity is that the newly characterized antihypertensive limbs of the RAS are now recognized to, in many cases, antagonize the prohypertensive ANG II type 1 receptor (AT1R)-mediated effects. That being said, the mechanism by which the RAS, glia, and neurons interact to regulate blood pressure is an active area of ongoing research. Here, we review the current understanding of these interactions and present a hypothetical model of how these exchanges may ultimately regulate cardiovascular function.

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Differential effect of tetradecythioacetic acid on the renin-angiotensin system and blood pressure in SHR and 2-kidney, 1-clip hypertension

AJP Renal Physiology ◽

10.1152/ajprenal.00140.2007 ◽

2007 ◽

Vol 293 (3) ◽

pp. F839-F845 ◽

Cited By ~ 1

Author(s):

Liliana Monica Bivol ◽

Rolf Kristian Berge ◽

Bjarne Magnus Iversen

Keyword(s):

Blood Pressure ◽

Blood Pressure Reduction ◽

Kidney Tissue ◽

Renin Angiotensin System ◽

Minor Effect ◽

Ang Ii ◽

Hypertensive Rats ◽

Blood Pressure Lowering Effect ◽

Angiotensin System ◽

Renin Angiotensin

The tetradecythioacetic acid (TTA) is a modified fatty acid known to exhibit pleiotropic effects. First, we compared the effect of TTA on the blood pressure in spontaneously hypertensive rats (SHR) with two-kidney, one-clip (2K1C)-hypertensive rats. Second, we examined mechanisms involved in the blood pressure reduction. TTA had minor effect on systolic blood pressure (SBP) in young SHR up to 8 wk of age. In 2K1C we confirmed the blood pressure-lowering effect of TTA (SBP: 173 ± 4 before vs. 138 ± 3 mmHg after TTA, P < 0.001). No effect on SBP was seen in Wistar-Kyoto rat (WKY) controls. Plasma renin activity (PRA) was low in SHR and WKY controls and TTA did not change it. PRA decreased from 22.9 ± 1.3 to 16.2 ± 2.2 ng·ml−1·h−1 ( P = 0.02) in 2K1C. Plasma ANG II concentration declined from 101 ± 3 to 81 ± 5 fmol/l after TTA treatment ( P = 0.005). In the clipped kidney, tissue ANG I concentration decreased from 933 ± 68 to 518 ± 60 fmol/g tissue ( P = 0.001), and ANG II decreased from 527 ± 38 to 149 ± 21 fmol/g tissue ( P < 0.001) after TTA treatment. In the nonclipped kidney, TTA did not change ANG I and moderately reduced ANG II levels. The renal blood flow response to injection of ANG II into the nonclipped kidney was blunted compared with controls and normalized with TTA treatment (10 ± 2 before vs. 20 ± 2%, P < 0.001). The results indicate that TTA downregulates the renin-angiotensin system in high renin animals but has no effect in low renin models.

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Cardiovascular hypertrophy in diabetic spontaneously hypertensive rats: optimizing blockade of the renin–angiotensin system

Clinical Science ◽

10.1042/cs1040341 ◽

2003 ◽

Vol 104 (4) ◽

pp. 341-347 ◽

Cited By ~ 1

Author(s):

Markus LASSILA ◽

Belinda J. DAVIS ◽

Terri J. ALLEN ◽

Louise M. BURRELL ◽

Mark E. COOPER ◽

...

Keyword(s):

Blood Pressure ◽

Systolic Blood Pressure ◽

Calcium Channel ◽

Spontaneously Hypertensive Rats ◽

Renin Angiotensin System ◽

At1 Receptor ◽

Hypertensive Rats ◽

Angiotensin System ◽

Spontaneously Hypertensive ◽

Renin Angiotensin

The aim of the present study was to compare the antihypertrophic effects of blockade of the renin–angiotensin system (RAS), vasopeptidase inhibition and calcium channel antagonism on cardiac and vascular hypertrophy in diabetic spontaneously hypertensive rats (SHR). SHR with streptozotocin-induced diabetes were treated with one of the following therapies for 32 weeks: the angiotensin-converting enzyme (ACE) inhibitor captopril (100mg/kg); the angiotensin AT1 receptor antagonist valsartan (30mg/kg); a combination of captopril with valsartan; the vasopeptidase inhibitor mixanpril (100mg/kg); or the calcium channel antagonist amlodipine (6mg/kg). Systolic blood pressure and cardiac and mesenteric artery hypertrophy were assessed. Mean systolic blood pressure in diabetic SHR (200±5mmHg) was reduced by captopril (162±5mmHg), valsartan (173±5mmHg), mixanpril (176±2mmHg) and amlodipine (159±4mmHg), and was further reduced by the combination of captopril with valsartan (131±5mmHg). Captopril, valsartan and mixanpril reduced heart and left ventricle weights by approx. 10%. The combination of captopril and valsartan further reduced heart weight (-24%) and left ventricular weight (-29%). Amlodipine did not affect cardiac hypertrophy. Only mixanpril and the combination of captopril and valsartan significantly reduced mesenteric weight. The mesenteric wall/lumen ratio was reduced by all drugs, and to a greater extent by the combination of captopril and valsartan. We conclude that optimizing the blockade of vasoconstrictive pathways such as the RAS, particularly with the combination of ACE inhibition and AT1 receptor antagonism, is associated with antitrophic effects in the context of diabetes and hypertension. In contrast, calcium channel blockade, despite similar effects on blood pressure, confers less antitrophic effects in the diabetic heart and blood vessels.

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From Rat to Human: Regulation of Renin-Angiotensin System Genes by Sry

International Journal of Hypertension ◽

10.1155/2012/724240 ◽

2012 ◽

Vol 2012 ◽

pp. 1-7 ◽

Cited By ~ 10

Author(s):

Jeremy W. Prokop ◽

Ingrid Kazue Mizuno Watanabe ◽

Monte E. Turner ◽

Adam C. Underwood ◽

Almir S. Martins ◽

...

Keyword(s):

Blood Pressure ◽

Amino Acid ◽

Promoter Activity ◽

Renin Angiotensin System ◽

Pressure Variation ◽

Ang Ii ◽

Angiotensin System ◽

Renin Angiotensin ◽

Blood Pressure Variation ◽

Testis Determination

The testis determining protein, Sry, has functions outside of testis determination. Multiple Sry loci are found on the Y-chromosome. Proteins from these loci have differential activity on promoters of renin-angiotensin system genes, possibly contributing to elevation of blood pressure. Variation at amino acid 76 accounts for the majority of differential effects by rat proteins Sry1 and Sry3. Human SRY regulated rat promoters in the same manner as rat Sry, elevatingAgt, Ren, andAcepromoter activity while downregulatingAce 2. Human SRY significantly regulated human promoters ofAGT, REN, ACE2, AT2,andMAScompared to control levels, elevatingAGTandRENpromoter activity while decreasingACE2, AT2,andMAS. While the effect of human SRY on individual genes is often modest, we show that many different genes participating in the renin-angiotensin system can be affected by SRY, apparently in coordinated fashion, to produce more Ang II and less Ang-(1–7).

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