scholarly journals Studies of Salt and Stress Sensitivity on Arterial Pressure in Renin-b Deficient Mice

2021 ◽  
Author(s):  
Pablo Nakagawa ◽  
Javier Gomez ◽  
Ko-Ting Lu ◽  
Justin L. Grobe ◽  
Curt D. Sigmund
Keyword(s):  
Blood Pressure ◽  
Restraint Stress ◽  
Sodium Intake ◽  
High Salt ◽  
Ventrolateral Medulla ◽  
High Salt Diet ◽  
Blood Pressure Elevation ◽  
Salt Diet ◽  
The Brain ◽  
Deficient Mice

AbstractExcessive sodium intake is known to increase the risk for hypertension, heart disease, and stroke. Individuals who are more susceptible to the effects of high salt are at higher risk for cardiovascular diseases even independent of their blood pressure status. Local activation of the renin-angiotensin system (RAS) in the brain, among other mechanisms, has been hypothesized to play a key role in contributing to salt balance. We have previously shown that deletion of the alternative renin isoform termed renin-b disinhibits the classical renin-a encoding preprorenin in the brain resulting in elevated brain RAS activity. Thus, we hypothesized that renin-b deficiency results in higher susceptibility to salt-induced elevation in blood pressure. Telemetry implanted Ren-bNull and wildtype littermate mice were first offered a low salt diet for a week and subsequently a high salt diet for another week. A high salt diet induced a mild blood pressure elevation in both Ren-bNull and wildtype mice, but mice lacking renin-b did not exhibit an exaggerated pressor response. When renin-b deficient mice were exposed to a high salt diet for a longer duration (4 weeks), was a trend for increased myocardial enlargement in Ren-bNull mice when compared with control mice. Multiple studies have also demonstrated the association of chronic and acute environmental stress with hypertension. Activation of the RAS in the rostral ventrolateral medulla and the hypothalamus is required for stress-induced hypertension. Thus, we next questioned whether the lack of renin-b would result in exacerbated response to an acute restraint-stress. Wildtype and Ren-bNull mice equally exhibited elevated blood pressure in response to restraint-stress, which was similar in mice fed either a low or high salt diet. These studies highlight a complex mechanism that masks/unmasks roles for renin-b in cardiovascular physiology.

scholarly journals Studies of salt and stress sensitivity on arterial pressure in renin-b deficient mice

PLoS ONE ◽  
2021 ◽  
Vol 16 (7) ◽  
pp. e0250807
Author(s):  
Pablo Nakagawa ◽  
Javier Gomez ◽  
Ko-Ting Lu ◽  
Justin L. Grobe ◽  
Curt D. Sigmund
Keyword(s):  
Blood Pressure ◽  
Restraint Stress ◽  
Statistical Significance ◽  
High Salt ◽  
Ventrolateral Medulla ◽  
High Salt Diet ◽  
Blood Pressure Elevation ◽  
Salt Diet ◽  
The Brain ◽  
Deficient Mice

Excessive sodium intake is known to increase the risk for hypertension, heart disease, and stroke. Individuals who are more susceptible to the effects of high salt are at higher risk for cardiovascular diseases even independent of their blood pressure status. Local activation of the renin-angiotensin system (RAS) in the brain, among other mechanisms, has been hypothesized to play a key role in contributing to salt balance. We have previously shown that deletion of the alternative renin isoform termed renin-b disinhibits the classical renin-a encoding preprorenin in the brain resulting in elevated brain RAS activity. Thus, we hypothesized that renin-b deficiency results in higher susceptibility to salt-induced elevation in blood pressure. Telemetry implanted Ren-bNull and wildtype littermate mice were first offered a low salt diet for a week and subsequently a high salt diet for another week. A high salt diet induced a mild blood pressure elevation in both Ren-bNull and wildtype mice, but mice lacking renin-b did not exhibit an exaggerated pressor response. When renin-b deficient mice were exposed to a high salt diet for a longer duration (4 weeks), there was a trend for increased myocardial enlargement in Ren-bNull mice when compared with control mice, but this did not reach statistical significance. Multiple studies have also demonstrated the association of environmental stress with hypertension. Activation of the RAS in the rostral ventrolateral medulla and the hypothalamus is required for stress-induced hypertension. Thus, we next questioned whether the lack of renin-b would result in exacerbated response to an acute restraint-stress. Wildtype and Ren-bNull mice equally exhibited elevated blood pressure in response to restraint-stress, which was similar in mice fed either a low or high salt diet. These studies suggest that mechanisms unrelated to salt and acute stress alter the cardiovascular phenotype in mice lacking renin-b.

Abstract 370: Upregulation of Renal D5 Dopamine Receptor Ameliorates Hypertension in D3 Deficient Mice

Hypertension ◽  
2012 ◽  
Vol 60 (suppl_1) ◽  
Author(s):  
Xiaoyan Wang ◽  
Crisanto S Escano ◽  
Laureano Asico ◽  
John E Jones ◽  
Alan Barte ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Blood Pressure ◽  
Nadph Oxidase ◽  
Protein Expression ◽  
Dopamine Receptors ◽  
Dopamine Receptor ◽  
High Salt ◽  
High Salt Diet ◽  
Salt Diet ◽  
Deficient Mice

D 3 dopamine receptor (D 3 R) deficient mice have renin-dependent hypertension but the hypertension is mild and is not associated with oxidative stress. In order to determine if any compensatory mechanism in the kidney is involved in the regulation of blood pressure with disruption of D 3 R, we measured the renal protein expression of dopamine receptors in D 3 R homozygous (D 3 -/-) and heterozygous (D 3 +/-) knockout mice and their wild type (D 3 +/+) littermates. D 5 dopamine receptor (D 5 R) (169±23%, reported as % of D 3 +/+, n=5/group) expression was increased but D 4 dopamine receptors protein expression (59±8%) was decreased, while no significant changes were found with D 1 and D 2 dopamine receptors. Immunocytochemistry showed a stronger renal staining of D 5 R but without a change in renal tubule cell distribution in D 3 -/- relative to D 3 +/+ mice. D 5 R abundance was also increased in D 3 +/- (205±30%, n=5/group) relative to D 3 +/+ mice, while D 1 R abundance was similar between D 3 +/- and D 3 +/+ mice. The increase in D 5 R expression was abolished while blood pressure was increased further in D 3 -/- mice fed a high salt diet. Treatment of the D 1 -like (including D 1 and D 5 receptors) antagonist, SCH23390 , increased the blood pressure to a greater extent in anesthetized D 3 -/- mice than in D 3 +/+ mice (n=4/group), suggesting that the upregulation of D 5 R may modulate the hypertension in mice caused by the disruption of D 3 R. Since dopamine inhibits the NADPH oxidase-induced production of reactive oxygen species (ROS) via the D 5 R, we also measured the protein expression of NOXs in the kidney and isoprostane in the urine. No NADPH oxidase subunit was increased in D 3 -/- and D 3 +/- mice relative to D 3 +/+ mice fed a normal or salt high salt diet, and urinary isoprostane excretion was also similar in D 3 -/- and D 3 +/+ mice. Our findings suggest that the upregulation of D 5 R may minimize the hypertension and prevent oxidative stress in D 3 -/- mice.

scholarly journals Fetal programming effects of pentaerythritol tetranitrate in a rat model of superimposed preeclampsia

2020 ◽  
Vol 98 (9) ◽  
pp. 1287-1299
Author(s):  
Andy W. C. Man ◽  
Min Chen ◽  
Yawen Zhou ◽  
Zhixiong Wu ◽  
Gisela Reifenberg ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Glucose Tolerance ◽  
Fetal Growth ◽  
Rat Model ◽  
High Salt ◽  
Pentaerythritol Tetranitrate ◽  
High Salt Diet ◽  
Blood Pressure Elevation ◽  
Salt Diet ◽  
Normal Chow

Abstract Preeclampsia is a common medical condition during pregnancy and a major cause of maternal and prenatal mortality. The present study was conducted to investigate the effects of maternal treatment with pentaerythritol tetranitrate (PETN) in Dahl salt-sensitive rats (DSSR), a model of superimposed preeclampsia. F0 parental DSSR were treated with PETN (50 mg/kg) from the time point of mating to the end of lactation. Maternal PETN treatment improved fetal growth and had no effect on blood pressure in DSSR offspring fed with normal chow or high-salt diet. Upon high-fat diet (HFD) feeding, offspring from PETN-treated mother showed improved glucose tolerance despite similar weight gain. Unexpectedly, maternal PETN treatment significantly potentiated the HFD-induced blood pressure elevation in male DSSR offspring. Endothelium-derived hyperpolarization factor (EDHF)-mediated vasodilation was similar between NCD-fed and HFD-fed control offspring but was markedly reduced in HFD-fed PETN offspring. EDHF genes were downregulated in the vasculature of HFD-fed PETN offspring, which was associated with epigenetic changes in histone modifications. In conclusion, maternal PETN treatment in DSSR shows both beneficial and unfavorable effects. It improves fetal growth and ameliorates glucose tolerance in the offspring. Although maternal PETN treatment has no effect on blood pressure in offspring fed with normal chow or high-salt diet, the offspring is at higher risk to develop HFD-induced hypertension. PETN may potentiate the blood pressure response to HFD by epigenetic modifications of EDHF genes. Key messages The core findings of this article suggest that maternal PETN treatment of DSSR, a rat model of a spontaneous superimposed preeclampsia, leads to • Improvement of fetal growth; • No changes of maternal blood pressure or markers of preeclampsia; • Amelioration of HFD-induced glucose intolerance in adult offspring; • No changes in blood pressure development of the offspring on normal chow or high salt-diet; • Potentiation of blood pressure elevation of the offspring on HFD.

Salt-sensitive hypertension develops after transient induction of ANG II-dependent hypertension in Cyp1a1-Ren2 transgenic rats

2005 ◽  
Vol 288 (4) ◽  
pp. F810-F815 ◽  
Author(s):  
Laura L. Howard ◽  
Matthew E. Patterson ◽  
John J. Mullins ◽  
Kenneth D. Mitchell
Keyword(s):  
Blood Pressure ◽  
Renal Plasma Flow ◽  
Systolic Pressure ◽  
High Salt ◽  
Ang Ii ◽  
Transgenic Rats ◽  
High Salt Diet ◽  
Blood Pressure Elevation ◽  
Salt Diet ◽  
Salt Sensitive Hypertension

Transient exposure to ANG II results in the development of salt-sensitive hypertension in rats. This study was performed to determine whether a transient hypertensive episode can induce salt-sensitive hypertension in transgenic rats with inducible expression of the mouse Ren2 renin gene [strain name TGR(Cyp1a1-Ren2)]. Systolic blood pressures were measured in conscious male Cyp1a1-Ren2 rats ( n = 6) during control conditions and during dietary administration of indole-3-carbinol (I3C; 0.15%, wt/wt), for 14 days. Systolic pressure increased from 135 ± 5 to 233 ± 7 mmHg by day 14. I3C administration was terminated and blood pressure returned to normal levels (137 ± 5 mmHg) within 10 days. Subsequently, the rats were placed on a high-salt diet (8% NaCl) for 10 days. Systolic pressure increased by 34 ± 2 mmHg throughout 10 days of the high-salt diet. Neither glomerular filtration rate nor renal plasma flow was altered in Cyp1a1-Ren2 rats with salt-sensitive hypertension. In a separate group of male Cyp1a1-Ren2 rats ( n = 6) transiently induced with 0.15% I3C for 14 days, administration of the superoxide dismutase mimetic tempol (4-hydroxy-2,2,6,6-tetramethyl piperidinoxyl, 2 mM) attenuated the increase in systolic pressure induced by high salt. Systolic pressure increased by only 11 ± 1 mmHg throughout 8 days of a high-salt diet and tempol administration. Thus transient induction of ANG II-dependent hypertension via activation of the Cyp1a1-Ren2 transgene induces salt-sensitive hypertension in these transgenic rats. The attenuation by tempol of the high salt-induced blood pressure elevation indicates that ANG II-induced production of superoxide anion contributes to the development of salt-sensitive hypertension after transient induction of ANG II-dependent hypertension.

scholarly journals Sex dependent compensatory mechanisms to preserve blood pressure homeostasis in PGI2 receptor deficient mice

2020 ◽  
Author(s):  
Soon Yew Tang ◽  
Seán T. Anderson ◽  
Hu Meng ◽  
Dimitra Sarantopoulou ◽  
Emanuela Ricciotti ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Oxidant Stress ◽  
High Salt ◽  
Prostaglandin E ◽  
High Salt Diet ◽  
Salt Loading ◽  
Salt Diet ◽  
Female Mice ◽  
The Impact ◽  
Deficient Mice

AbstractInhibitors of microsomal prostaglandin E synthase-1 (mPges-1) are in the early phase of clinical development. Deletion of mPges-1 confers analgesia, restrains atherogenesis and fails to accelerate thrombogenesis, while suppressing prostaglandin (PG) E2, but increasing biosynthesis of prostacyclin (PGI2). In hyperlipidemic mice, this last effect represents the dominant mechanism by which mPges-1 deletion restrains thrombogenesis, while suppression of PGE2 accounts for its anti-atherogenic effect. However, the impact of mPges-1 depletion on blood pressure (BP) in this setting remains unknown.To address how differential effects on PGE2 and PGI2 might modulate salt-evoked BP responses in the absence of mPges-1, we generated mice lacking the I prostanoid (Ipr) receptor or mPges-1 on a hyperlipidemic background caused by deletion of the low density lipoprotein receptor (Ldlr KOs). Here, mPges-1 depletion significantly increased the BP response to salt loading in male Ldlr KO mice, whereas, despite the direct vasodilator properties of PGI2, Ipr deletion suppressed it. Furthermore, combined deletion of the Ipr abrogated the exaggerated BP response in male mPges-1 KO mice. Suppression of PGE2 biosynthesis was enough to explain the exaggerated BP response to salt loading by either mPges-1/Ldlr depletion or by an MPGES-1 inhibitor in mice expressing human mPGES-1. However, the lack of a hypertensive response to salt in Ipr-deficient mice was attributable to reactive activation of the atrial natriuretic peptide pathway. Interestingly, these unexpected BP phenotypes were not observed in female mice fed a high salt diet. This is attributable to the protective effect of estrogen in Ldlr KO mice and in Ipr /Ldlr DKOs. Thus, estrogen compensates for a deficiency in PGI2 to maintain BP homeostasis in response to high salt in hyperlipidemic female mice. In males, by contrast, augmented formation of ANP plays a similar compensatory role, restraining hypertension and oxidant stress in the setting of Ipr depletion. Hyperlipidemic males on a high salt diet might be at risk of a hypertensive response to mPGES-1 inhibitors.

scholarly journals Alpha2B-Adrenergic Receptor Overexpression in the Brain Potentiate Air Pollution-induced Behavior and Blood Pressure Changes

2019 ◽  
Vol 169 (1) ◽  
pp. 95-107 ◽  
Author(s):  
Xiaoquan Rao ◽  
Laureano D Asico ◽  
Panos Zanos ◽  
Ganapati H Mahabeleshwar ◽  
Roopesh Singh Gangwar ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Air Pollution ◽  
High Salt ◽  
Behavioral Changes ◽  
Wild Type ◽  
High Salt Diet ◽  
Blood Pressure Elevation ◽  
Pressure Elevation ◽  
Pollution Exposure ◽  
The Brain

AbstractFine ambient particulate matter (PM2.5) is able to induce sympathetic activation and inflammation in the brain. However, direct evidence demonstrating an essential role of sympathetic activation in PM2.5-associated disease progression is lacking. We assess the contribution of α2B-adrenergic receptor (Adra2b) in air pollution-associated hypertension and behavioral changes in this study. Wild-type mice and Adra2b-transgenic mice overexpressing Adra2b in the brain (Adra2bTg) were exposed to concentrated PM2.5 or filtered air for 3 months via a versatile aerosol concentrator exposure system. Mice were fed with a high salt diet (4.0% NaCl) for 1 week at week 11 of exposure to induce blood pressure elevation. Intra-arterial blood pressure was monitored by radio-telemetry and behavior changes were assessed by open field, light-dark, and prepulse inhibition tests. PM2.5 exposure increased Adra2b in the brain of wild-type mice. Adra2b overexpression enhanced the anxiety-like behavior and high salt diet-induced blood pressure elevation in response to air pollution but not filtered air exposure. Adra2b overexpression induced upregulation of inflammatory genes such as TLR2, TLR4, and IL-6 in the brain exposed to PM2.5. In addition, there were increased frequencies of activated effector T cells and increased expression of oxidative stress-related genes, such as SOD1, NQO1, Nrf2, and Gclm in Adra2bTg mice compared with wild-type mice. Our results provide new evidence of distinct behavioral changes consistent with anxiety and blood pressure elevation in response to high salt intake and air pollution exposure, highlighting the importance of centrally expressed Adra2b in the vulnerability to air pollution exposure.

scholarly journals Cerebral Aβ40 and systemic hypertension

2017 ◽  
Vol 38 (11) ◽  
pp. 1993-2005 ◽  
Author(s):  
Hannah M Tayler ◽  
Jennifer C Palmer ◽  
Taya L Thomas ◽  
Patrick G Kehoe ◽  
Julian FR Paton ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Blood Pressure ◽  
Alzheimer's Disease ◽  
Arterial Pressure ◽  
High Salt ◽  
Systemic Hypertension ◽  
High Salt Diet ◽  
Salt Diet ◽  
Intracerebroventricular Infusion ◽  
The Brain

Mid-life hypertension and cerebral hypoperfusion may be preclinical abnormalities in people who later develop Alzheimer’s disease. Although accumulation of amyloid-beta (Aβ) is characteristic of Alzheimer’s disease and is associated with upregulation of the vasoconstrictor peptide endothelin-1 within the brain, it is unclear how this affects systemic arterial pressure. We have investigated whether infusion of Aβ40 into ventricular cerebrospinal fluid modulates blood pressure in the Dahl salt-sensitive rat. The Dahl salt-sensitive rat develops hypertension if given a high-salt diet. Intracerebroventricular infusion of Aβ induced a progressive rise in blood pressure in rats with pre-existing hypertension produced by a high-salt diet ( p < 0.0001), but no change in blood pressure in normotensive rats. The elevation in arterial pressure in high-salt rats was associated with an increase in low frequency spectral density in systolic blood pressure, suggesting autonomic imbalance, and reduced cardiac baroreflex gain. Our results demonstrate the potential for intracerebral Aβ to exacerbate hypertension, through modulation of autonomic activity. Present findings raise the possibility that mid-life hypertension in people who subsequently develop Alzheimer’s disease may in some cases be a physiological response to reduced cerebral perfusion complicating the accumulation of Aβ within the brain.

Pregnancy prevents hypertensive remodeling and decreases myogenic reactivity in posterior cerebral arteries from Dahl salt-sensitive rats: a role in eclampsia?

2007 ◽  
Vol 292 (2) ◽  
pp. H1071-H1076 ◽  
Author(s):  
Annet M. Aukes ◽  
Lisa Vitullo ◽  
Gerda G. Zeeman ◽  
Marilyn J. Cipolla
Keyword(s):  
Blood Pressure ◽  
Structural Changes ◽  
Cerebral Arteries ◽  
High Salt ◽  
Third Order ◽  
High Salt Diet ◽  
Salt Diet ◽  
Protein Gene Product ◽  
Oxide Synthase ◽  
The Brain

Previous studies have demonstrated that pregnancy prevents protective hypertension-induced remodeling of cerebral arteries using nitric oxide synthase (NOS) inhibition to raise mean arterial pressure (MAP). In the present study, we investigated whether this effect of pregnancy was specific to NOS inhibition by using the Dahl salt-sensitive (SS) rat as a model of hypertension. Nonpregnant ( n = 16) and late-pregnant ( n = 17) Dahl SS rats were fed either a high-salt diet (8% NaCl) to raise blood pressure or a low-salt diet (<0.7% NaCl). Third-order posterior cerebral arteries were isolated and pressurized in an arteriograph chamber to measure active responses to pressure and passive remodeling. Several vessels from each group were stained for protein gene product 9.5 to determine perivascular nerve density. Blood pressure was elevated in both groups on high salt. The elevated MAP was associated with significantly smaller active and passive diameters ( P < 0.05) and inward remodeling in the nonpregnant hypertensive group only. Whereas no structural changes were observed in the late-pregnant hypertensive animals, both late-pregnant groups had diminished myogenic reactivity ( P < 0.05). Nerve density in both the late-pregnant groups was significantly greater when compared with the nonpregnant groups, suggesting that pregnancy has a trophic influence on perivascular innervation of the posterior cerebral artery. However, hypertension lowered the nerve density in both nonpregnant and late-pregnant animals. It therefore appears that pregnancy has an overall effect to prevent hypertension-induced remodeling regardless of the mode of hypertension. This effect may predispose the brain to autoregulatory breakthrough, hyperperfusion, and eclampsia when MAP is elevated.

scholarly journals Metabolic Syndrome and Salt-Sensitive Hypertension in Polygenic Obese TALLYHO/JngJ Mice: Role of Na/K-ATPase Signaling

2019 ◽  
Vol 20 (14) ◽  
pp. 3495 ◽  
Author(s):  
Yanling Yan ◽  
Jiayan Wang ◽  
Muhammad A. Chaudhry ◽  
Ying Nie ◽  
Shuyan Sun ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Renal Function ◽  
Significant Rise ◽  
Protein Carbonylation ◽  
High Salt ◽  
Kidney Cortex ◽  
High Salt Diet ◽  
Salt Diet ◽  
Salt Sensitive Hypertension

We have demonstrated that Na/K-ATPase acts as a receptor for reactive oxygen species (ROS), regulating renal Na+ handling and blood pressure. TALLYHO/JngJ (TH) mice are believed to mimic the state of obesity in humans with a polygenic background of type 2 diabetes. This present work is to investigate the role of Na/K-ATPase signaling in TH mice, focusing on susceptibility to hypertension due to chronic excess salt ingestion. Age-matched male TH and the control C57BL/6J (B6) mice were fed either normal diet or high salt diet (HS: 2, 4, and 8% NaCl) to construct the renal function curve. Na/K-ATPase signaling including c-Src and ERK1/2 phosphorylation, as well as protein carbonylation (a commonly used marker for enhanced ROS production), were assessed in the kidney cortex tissues by Western blot. Urinary and plasma Na+ levels were measured by flame photometry. When compared to B6 mice, TH mice developed salt-sensitive hypertension and responded to a high salt diet with a significant rise in systolic blood pressure indicative of a blunted pressure-natriuresis relationship. These findings were evidenced by a decrease in total and fractional Na+ excretion and a right-shifted renal function curve with a reduced slope. This salt-sensitive hypertension correlated with changes in the Na/K-ATPase signaling. Specifically, Na/K-ATPase signaling was not able to be stimulated by HS due to the activated baseline protein carbonylation, phosphorylation of c-Src and ERK1/2. These findings support the emerging view that Na/K-ATPase signaling contributes to metabolic disease and suggest that malfunction of the Na/K-ATPase signaling may promote the development of salt-sensitive hypertension in obesity. The increased basal level of renal Na/K-ATPase-dependent redox signaling may be responsible for the development of salt-sensitive hypertension in polygenic obese TH mice.

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