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.

Angiotensin II, interstitial inflammation, and the pathogenesis of salt-sensitive hypertension

2006 ◽  
Vol 291 (6) ◽  
pp. F1281-F1287 ◽  
Author(s):  
Martha Franco ◽  
Flavio Martínez ◽  
Bernardo Rodríguez-Iturbe ◽  
Richard J. Johnson ◽  
José Santamaría ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Inflammatory Cells ◽  
Acute Effect ◽  
High Salt ◽  
Acute Administration ◽  
Ang Ii ◽  
High Salt Diet ◽  
Salt Diet ◽  
Interstitial Inflammation ◽  
Salt Sensitive Hypertension

Transient administration of ANG II causes persistent salt-sensitive hypertension associated with arteriolopathy, interstitial inflammation, and cortical vasoconstriction; blocking the vascular and inflammatory changes with mycophenolate mofetil (MMF) prevents vasoconstriction. While infiltrating leukocytes during the salt-sensitive hypertension phase express ANG II, the functional role of ANG II during this phase is not known. We examined the acute effect of candesartan on renal hemodynamics during the established salt-sensitive hypertensive phase and related these findings to direct measurement of intrarenal ANG II and inflammatory cells in rats previously exposed to ANG II with or without MMF treatment. Sham controls were also examined. The administration of ANG II, followed by exposure to high-salt diet, resulted in hypertension, cortical vasoconstriction, an increase in interstitial inflammatory cells (44.8 ± 1.3 lymphocytes/mm2, and 30.8 ± 1.2 macrophages/mm2 ANG II vs. 19.6 ± 2 lymphocytes/mm2, and 22 ± 0.7 macrophages/mm2 Sham), and increase in renal ANG II levels (1,358 ± 74.6 pg/ml ANG II vs. 194 ± 9.28 pg/ml Sham). Treatment with MMF during the administration of exogenous ANG II resulted in reduction in renal interstitial inflammation (19.7 ± 0.9 lymphocytes/mm2 and 15.9 ± 0.8 machophages/mm2), ANG II levels (436.9 ± 52.29 pg/ml), cortical vasoconstriction, and stable blood pressure levels during the subsequent challenge with a high-salt diet. Acute administration of candesartan similarly reduced renal vasoconstriction and blood pressure. We conclude that the cortical vasoconstriction occurring with salt-sensitive hypertension following exposure to ANG II is mediated by intrarenal ANG II, related, at least in part, to the interstitial inflammation.

AT1 receptor regulation in salt-sensitive hypertension

1999 ◽  
Vol 277 (5) ◽  
pp. H1701-H1707 ◽  
Author(s):  
Kerstin Strehlow ◽  
Georg Nickenig ◽  
Jörg Roeling ◽  
Sven Wassmann ◽  
Oliver Zolk ◽  
...  
Keyword(s):  
Blood Pressure ◽  
High Salt ◽  
Receptor Regulation ◽  
Ang Ii ◽  
Receptor Density ◽  
Pressure Regulation ◽  
High Salt Diet ◽  
Salt Diet ◽  
Receptor Mrna ◽  
Salt Sensitive Hypertension

The molecular events governing salt-sensitive hypertension are currently unknown. Because the renin-ANG system plays a central role in blood pressure regulation and electrolyte balance, it may be closely involved in the phenomenon of salt sensitivity. Therefore, we examined the effect of a high-salt diet (8%) and a low-salt diet (0.4%) on ANG II-caused vascular constriction and ANG II type 1 (AT1) receptor expression in aorta, brain, and kidney of Dahl S (salt-sensitive) and Dahl R (salt-resistant) rats by means of radioligand binding assays and quantitative PCR. NaCl diet at 8% led to a significant increase of blood pressure in Dahl S but not in Dahl R rats. High-sodium intake caused a profound decrease of ANG II-induced aortic vasoconstriction in both Dahl R and Dahl S rats. The underlying mechanism was a downregulation of aortic AT1receptor density and AT1 receptor mRNA. AT1 receptor mRNA was downregulated to 57.8% in Dahl R and 59.0% in Dahl S rats by an 8% NaCl diet compared with a 0.4% NaCl diet ( P < 0.05). There was a similar decrease in aortic AT1 receptor density. Additionally, AT1receptor mRNA was also downregulated in the kidney but upregulated the brain of Dahl R and S rats on a high-salt diet. Thus high NaCl intake causes organ-specific AT1 receptor regulation in Dahl R and in Dahl S rats despite the differential blood pressure regulation in these animal models in response to a high-salt diet. These findings suggest that the regulation of vascular AT1 receptors is influenced by numerous factors such as the renin-ANG system and obviously by various other events that are currently only partly understood.

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.

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.

scholarly journals Time course of decompensation after angiotensin II and high-salt diet in Balb/CJ mice suggests pulmonary hypertension-induced cardiorenal syndrome

2019 ◽  
Vol 316 (5) ◽  
pp. R563-R570 ◽  
Author(s):  
Mediha Becirovic-Agic ◽  
Sofia Jönsson ◽  
Maria K. Tveitarås ◽  
Trude Skogstrand ◽  
Tine V. Karlsen ◽  
...  
Keyword(s):  
Cardiac Output ◽  
Angiotensin Ii ◽  
Cardiac Function ◽  
Systolic Pressure ◽  
Left Ventricular ◽  
High Salt ◽  
Ang Ii ◽  
Salt Treatment ◽  
High Salt Diet ◽  
Salt Diet

The genetic background of a mouse strain determines its susceptibility to disease. C57BL/6J and Balb/CJ are two widely used inbred mouse strains that we found react dramatically differently to angiotensin II and high-salt diet (ANG II + Salt). Balb/CJ show increased mortality associated with anuria and edema formation while C57BL/6J develop arterial hypertension but do not decompensate and die. Clinical symptoms of heart failure in Balb/CJ mice gave the hypothesis that ANG II + Salt impairs cardiac function and induces cardiac remodeling in male Balb/CJ but not in male C57BL/6J mice. To test this hypothesis, we measured cardiac function using echocardiography before treatment and every day for 7 days during treatment with ANG II + Salt. Interestingly, pulsed wave Doppler of pulmonary artery flow indicated increased pulmonary vascular resistance and right ventricle systolic pressure in Balb/CJ mice, already 24 h after ANG II + Salt treatment was started. In addition, Balb/CJ mice showed abnormal diastolic filling indicated by reduced early and late filling and increased isovolumic relaxation time. Furthermore, Balb/CJ exhibited lower cardiac output compared with C57BL/6J even though they retained more sodium and water, as assessed using metabolic cages. Left posterior wall thickness increased during ANG II + Salt treatment but did not differ between the strains. In conclusion, ANG II + Salt treatment causes early restriction of pulmonary flow and reduced left ventricular filling and cardiac output in Balb/CJ, which results in fluid retention and peripheral edema. This makes Balb/CJ a potential model to study the adaptive capacity of the heart for identifying new disease mechanisms and drug targets.

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.

Dietary Salt Modifies the Blood Pressure Response to Renin-Angiotensin Inhibition in Experimental Chronic Kidney Disease

2021 ◽  
Author(s):  
Dominique M Bovee ◽  
Estrellita Uijl ◽  
David Severs ◽  
Eloisa Rubio-Beltrán ◽  
Richard van Veghel ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
High Salt ◽  
Dietary Salt ◽  
High Salt Diet ◽  
Salt Diet ◽  
Renin Angiotensin ◽  
Water Accumulation ◽  
Salt Sensitive Hypertension

Chronic kidney disease (CKD) contributes to hypertension, but the mechanisms are incompletely understood. To address this, we applied the 5/6th nephrectomy rat model to characterize hypertension and the response to dietary salt and renin-angiotensin inhibition. 5/6th nephrectomy caused low-renin, salt-sensitive hypertension with hyperkalemia and unsuppressed aldosterone. Compared to sham, 5/6Nx rats had lower NHE3, NKCC2, NCC, a-ENaC and Kir4.1, but higher SKG1, prostasin, g-ENaC, and Kir5.1. These differences correlated with plasma renin, aldosterone, and/or potassium. On a normal salt diet, adrenalectomy (0 ± 9 mmHg) and spironolactone (-11 ± 10 mmHg) prevented a progressive rise in blood pressure (10 ± 8 mmHg), and this was enhanced in combination with losartan (-41 ± 12 mmHg and -43 ± 9 mmHg). A high salt diet caused skin sodium and water accumulation and aggravated hypertension that could only be attenuated by spironolactone (-16 ± 7 mmHg) and in which the additive effect of losartan was lost. Spironolactone also increased natriuresis, reduced skin water accumulation and restored vasorelaxation. In summary, in the 5/6th nephrectomy rat CKD model, salt-sensitive hypertension develops with a selective increase in g-ENaC and despite appropriate transporter adaptations to low renin and hyperkalemia. With a normal salt diet, hypertension in 5/6th nephrectomy depends on angiotensin II and aldosterone, while a high salt diet causes more severe hypertension mediated through the mineralocorticoid receptor.

Abstract 446: Deletion of Il-6 Prevents Development of Cardiac Damage and Dysfunction in Chronic Ang Ii-salt-induced Hypertension

Hypertension ◽  
2012 ◽  
Vol 60 (suppl_1) ◽  
Author(s):  
Germán E González ◽  
Nour-Eddine Rhaleb ◽  
Pablo Nakagawa ◽  
Yun-He Liu ◽  
Oscar A Carretero
Keyword(s):  
Blood Pressure ◽  
Cardiac Dysfunction ◽  
High Salt ◽  
Myocardial Inflammation ◽  
Pressure Measurements ◽  
Ang Ii ◽  
Cardiac Damage ◽  
High Salt Diet ◽  
Salt Diet ◽  
Induced Hypertension

IL-6 knockout (KO) mice were reported to spontaneously develop cardiac dysfunction and fibrosis. These KO mice also develop less hypertension when fed high salt and infused with angiotensin II (Ang II). We tested the hypothesis that in IL-6-KO mice the attenuated hypertension in response to Ang II-salt is due to the development of cardiac dysfunction. Male C57Bl/6J and IL-6-/- mice (B6.129S6- Il6 tm1Kopf ) were implanted with telemetry devices for blood pressure measurements, infused with vehicle (V) or Ang II (90 ng/min/mouse subcutaneously) and feed a high salt diet (4% salt diet, HS) for 8 weeks (W). We studied 4 experimental groups: 1) C57BL/6J + V (n=9); 2) IL6-KO + V (n=9); 3) C57BL/6J + Ang II (n=8) and 4) IL6-KO + Ang II (n=6). Blood pressure and echocardiography data were collected before starting the HS diet and Ang II infusion (baseline) and 8 weeks after HS alone or combined with Ang II. Results (Mean±SEM) Conclusion: Our results do not support our hypothesis and shows that the lack of IL-6 does not affect development of hypertension or cardiac hypertrophy but rather prevents cardiac dysfunction, LV dilation, myocardial inflammation and fibrosis in Ang II-salt-induced hypertension, suggesting that IL-6 plays an important role in cardiac dysfunction associated with hypertension.

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