EP3 (E-Prostanoid 3) Receptor Mediates Impaired Vasodilation in a Mouse Model of Salt-Sensitive Hypertension

We previously showed that impaired vasodilation in systemic and renal vessels contributes to salt-sensitive hypertension in a mouse model of impaired PPARγ (peroxisome proliferator-activated receptor gamma) function. We determined the mechanisms mediating impaired salt-induced vasodilation and whether improved vasodilation attenuates augmented hypertension in response to salt. Mice selectively expressing a PPARγ dominant negative mutation in vascular smooth muscle (S-P467L) exhibited salt-sensitive hypertension and severely impaired vasodilation in systemic and renal vessels. High-salt diet–fed S-P467L and control mice displayed comparable levels of renal oxidative stress markers. Preincubation with Tempol, a superoxide dismutase mimetic, or calphostin C, a PKC (protein kinase C) inhibitor, failed to improve salt-induced impairment of vasodilation in S-P467L mice, arguing against a role of oxidative stress or PKC activity. Inhibition of Rho kinase partially rescued impaired vasodilation in high-salt diet–fed S-P467L mice suggesting a contribution of the Ras homolog family member A (RhoA)/Rho kinase pathway. High-salt diet selectively increased synthesis of PGE2 (prostaglandin E2) in S-P467L aorta. Expression of EP3 (E-prostanoid 3) receptor mRNA was increased in aorta from chow-fed and high salt–fed S-P467L mice. Pharmacological inhibition of COX (cyclooxygenase) 2 or blockade of EP3 completely normalized the impaired vasodilation, and EP3 antagonism induced larger decreases in systolic blood pressure in high-salt diet–fed S-P467L mice. In conclusion, interference with PPARγ in vascular smooth muscle causes activation of the PGE2/EP3 signaling pathway in systemic and renal vasculature resulting in salt-induced impairment of vasodilation and salt-sensitive hypertension. PGE2/EP3 axis maybe a druggable target to prevent salt-sensitive hypertension in chronic conditions associated with decreased PPARγ activity.

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Abstract 099: Smooth Muscle PPARγ Mutation Causes Salt-sensitive Hypertension

Hypertension ◽

10.1161/hyp.70.suppl_1.099 ◽

2017 ◽

Vol 70 (suppl_1) ◽

Author(s):

Jing Wu ◽

Larry N Agbor ◽

Masashi Mukohda ◽

Anand R Nair ◽

Pablo Nakagawa ◽

...

Keyword(s):

Smooth Muscle ◽

Renal Dysfunction ◽

Vascular Dysfunction ◽

High Salt ◽

Secondary Response ◽

High Salt Diet ◽

Salt Loading ◽

Salt Diet ◽

Regular Diet ◽

Salt Sensitive Hypertension

Abnormal increase in renal salt retention is traditionally believed to be an early pathophysiological event in the causation of salt-sensitive hypertension, whereas increase in systemic vascular resistance (SVR) is a secondary response caused by autoregulation. However, recent studies show that salt-resistant subjects vasodilate and reduce SVR during salt loading, while salt-sensitive humans fail to vasodilate and exhibit salt-induced blood pressure (BP) elevation. Therefore, we tested the hypothesis that primary vascular dysfunction predisposes to salt sensitive hypertension. We used mice with smooth muscle-specific expression of a human hypertension-causing mutation in PPARγ P467L (S-P467L). S-P467L transgenic mice and non-transgenic controls (NT) were fed regular diet (0.4% salt) or high salt diet (4% salt) for 4 weeks. S-P467L mice, but not NT controls, exhibited severe impairment in acetylcholine- and sodium nitroprusside-induced vasorelaxation (31±4.9% S-P467L salt vs. 70±9.5% regular diet, maximal relaxation at 30 μM acetylcholine). This was associated with salt-induced systolic BP elevation in S-P467L mice (142±5 mmHg salt vs 127±2 mmHg regular diet), but not in NT mice (120±2.7 mmHg salt vs 115±4.0 mmHg). These changes were not due to differences in food intake, weight gain or renal sympathetic nerve activity between the two strains. In the 3 rd week of high salt diet, S-P467L mice and NT controls both had increased water intake by 3-fold compared to those on regular diet; however, S-P467L mice excreted 32% less urine and produced 36% less NO in the kidney as indicated by 24-hour urinary nitrate/nitrite. To assess renal function, mice were subjected to an acute saline challenge (10% body weight, i.p. injection). S-P467L mice exhibited a marked decline in their capacity to excrete this volume/sodium load, indicative of renal dysfunction. Of note, the impaired vasorelaxation in S-P467L occurred as early as day 3 of high salt diet, while renal dysfunction did not develop until day 10, suggesting that vascular dysfunction may serve as an initiation mechanism that reinforces salt-induced hemodynamic changes. These data supports the concept that vascular dysfunction may predispose to renal abnormalities including increased salt sensitivity.

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

International Journal of Molecular Sciences ◽

10.3390/ijms20143495 ◽

2019 ◽

Vol 20 (14) ◽

pp. 3495 ◽

Cited By ~ 1

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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Overload proteinuria is followed by salt-sensitive hypertension caused by renal infiltration of immune cells

AJP Renal Physiology ◽

10.1152/ajprenal.00199.2002 ◽

2002 ◽

Vol 283 (5) ◽

pp. F1132-F1141 ◽

Cited By ~ 69

Author(s):

Violeta Alvarez ◽

Yasmir Quiroz ◽

Mayerly Nava ◽

Héctor Pons ◽

Bernardo Rodríguez-Iturbe

Keyword(s):

Interstitial Nephritis ◽

Renal Damage ◽

High Salt ◽

High Salt Diet ◽

Salt Diet ◽

Malondialdehyde Content ◽

Induced Hypertension ◽

Salt Sensitive Hypertension ◽

And Control ◽

And Oxidative Stress

Recent evidence suggests that salt-sensitive hypertension develops as a consequence of renal infiltration with immunocompetent cells. We investigated whether proteinuria, which is known to induce interstitial nephritis, causes salt-sensitive hypertension. Female Lewis rats received 2 g of BSA intraperitoneally daily for 2 wk. After protein overload (PO), 6 wk of a high-salt diet induced hypertension [systolic blood pressure (SBP) = 156 ± 11.8 mmHg], whereas rats that remained on a normal-salt diet and control rats (without PO) on a high-salt diet were normotensive. Administration of mycophenolate mofetil (20 mg · kg−1 · day−1) during PO resulted in prevention of proteinuria-related interstitial nephritis, reduction of renal angiotensin II-positive cells and oxidative stress (superoxide-positive cells and renal malondialdehyde content), and resistance to the hypertensive effect of the high-salt diet (SBP = 129 ± 12.2 mmHg). The present studies support the participation of renal inflammatory infiltrate in the pathogenesis of salt-sensitive hypertension and provide a direct link between two risk factors of progressive renal damage: proteinuria and hypertension.

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Proximal tubule-targeted overexpression of the Cyp4a12-20-HETE synthase promotes salt-sensitive hypertension in male mice

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00089.2020 ◽

2020 ◽

Vol 319 (1) ◽

pp. R87-R95

Author(s):

Ankit Gilani ◽

Kevin Agostinucci ◽

Jonathan V. Pascale ◽

Sakib Hossain ◽

Sharath Kandhi ◽

...

Keyword(s):

Proximal Tubule ◽

Phosphoenolpyruvate Carboxykinase ◽

Fold Increase ◽

High Salt ◽

Kidney Cortex ◽

Male Mice ◽

High Salt Diet ◽

Salt Diet ◽

Renal Microvasculature ◽

Salt Sensitive Hypertension

20-Hydroxyeicosatetraenoic acid (20-HETE) has been linked to blood pressure (BP) regulation via actions on the renal microvasculature and tubules. We assessed the tubular 20-HETE contribution to hypertension by generating transgenic mice overexpressing the CYP4A12-20-HETE synthase (PT-4a12 mice) under the control of the proximal tubule (PT)-specific promoter phosphoenolpyruvate carboxykinase (PEPCK). 20-HETE levels in the kidney cortex of male (967 ± 210 vs. 249 ± 69 pg/mg protein) but not female (121 ± 15 vs. 92 ± 11 pg/mg protein) PT-4a12 mice showed a 2.5-fold increase compared with wild type (WT). Renal cortical Cyp4a12 mRNA and CYP4A12 protein in male but not female PT-4a12 mice increased by two- to threefold compared with WT. Male PT-4a12 mice displayed elevated BP (142 ± 1 vs. 111 ± 4 mmHg, P < 0.0001), whereas BP in female PT-4a12 mice was not significantly different from WT (118 ± 2 vs. 117 ± 2 mmHg; P = 0.98). In male PT-4a12 mice, BP decreased when mice were transitioned from a control-salt (0.4%) to a low-salt diet (0.075%) from 135 ± 4 to 120 ± 6 mmHg ( P < 0.01) and increased to 153 ± 5 mmHg ( P < 0.05) when mice were placed on a high-salt diet (4%). Female PT-4a12 mice did not show changes in BP on either low- or high-salt diet. In conclusion, the expression of Cyp4a12 driven by the PEPCK promoter is sex specific, probably because of its X-linkage. The salt-sensitive hypertension seen in PT-4a12 male mice suggests a potential antinatriuretic activity of 20-HETE that needs to be further explored.

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High-salt diet enhances hippocampal oxidative stress and cognitive impairment in mice

Neurobiology of Learning and Memory ◽

10.1016/j.nlm.2014.04.010 ◽

2014 ◽

Vol 114 ◽

pp. 10-15 ◽

Cited By ~ 24

Author(s):

Yun-Zi Liu ◽

Ji-Kuai Chen ◽

Zhang-Peng Li ◽

Ting Zhao ◽

Min Ni ◽

...

Keyword(s):

Oxidative Stress ◽

Cognitive Impairment ◽

High Salt ◽

High Salt Diet ◽

Salt Diet

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

Hypertension ◽

10.1161/hyp.60.suppl_1.a370 ◽

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.

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Cyperus esculentus L. (tigernut) mitigates high salt diet‐associated testicular toxicity in Wistar rats by targeting testicular steroidogenesis, oxidative stress and inflammation

Andrologia ◽

10.1111/and.13780 ◽

2020 ◽

Vol 52 (11) ◽

Author(s):

Justina Nwandimma Nwangwa ◽

Augustine Lishilinimye Udefa ◽

Ernest Atelhe Amama ◽

Inah Onete Inah ◽

Hamza Joseph Ibrahim ◽

...

Keyword(s):

Oxidative Stress ◽

Wistar Rats ◽

High Salt ◽

Testicular Toxicity ◽

Cyperus Esculentus ◽

High Salt Diet ◽

Salt Diet ◽

Testicular Steroidogenesis

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Renal arteriolar Na+/Ca2+exchange in salt-sensitive hypertension

AJP Renal Physiology ◽

10.1152/ajprenal.1999.276.4.f567 ◽

1999 ◽

Vol 276 (4) ◽

pp. F567-F573 ◽

Cited By ~ 10

Author(s):

Lawrence D. Nelson ◽

M. Tino Unlap ◽

James L. Lewis ◽

P. Darwin Bell

Keyword(s):

Cytosolic Calcium ◽

Ringer Solution ◽

High Salt ◽

High Salt Diet ◽

Salt Diet ◽

Vascular Segment ◽

Low Salt ◽

Afferent Arterioles ◽

Salt Sensitive Hypertension ◽

Exchange Activity

The present studies were performed to assess Na+/Ca2+exchange activity in afferent and efferent arterioles from Dahl/Rapp salt-resistant (R) and salt-sensitive (S) rats. Renal arterioles were obtained by microdissection from S and R rats on either a low-salt (0.3% NaCl) or high-salt (8.0% NaCl) diet. On the high-salt diet, S rats become markedly hypertensive. Cytosolic calcium concentration ([Ca2+]i) was measured in fura 2-loaded arterioles bathed in a Ringer solution in which extracellular Na (Nae) was varied from 150 to 2 mM (Na was replaced with N-methyl-d-glucamine). Baseline [Ca2+]iwas similar in afferent arterioles of R and S rats fed low- and high-salt diet. The change in [Ca2+]i(Δ[Ca2+]i) during reduction in Nae from 150 to 2 mM was 80 ± 10 and 61 ± 3 nM (not significant) in afferent arterioles from R rats fed the low- and high-salt diet, respectively. In afferent arterioles from S rats on a high-salt diet, Δ[Ca2+]iduring reductions in Nae from 150 to 2 mM was attenuated (39 ± 4 nM) relative to the Δ[Ca2+]iof 79 ± 13 nM ( P < 0.05) obtained in afferent arterioles from S rats on a low-salt diet. In efferent arterioles, baseline [Ca2+]iwas similar in R and S rats fed low- and high-salt diets, and Δ[Ca2+]iin response to reduction in Naewas also not different in efferent arterioles from R and S rats fed low- or high-salt diets. Differences in regulation of the exchanger in afferent arterioles of S and R rats were assessed by determining the effects of protein kinase C (PKC) activation by phorbol 12-myristate 13-acetate (PMA, 100 nM) on Δ[Ca2+]iin response to reductions in Naefrom 150 to 2 mM. PMA increased Δ[Ca2+]iin afferent arterioles from R rats but not from S rats. These results suggest that Na+/Ca2+exchange activity is suppressed in afferent arterioles of S rats that are on a high-salt diet. In addition, there appears to be a defect in the PKC-Na+/Ca2+exchange pathway that might contribute to altered [Ca2+]iregulation in this important renal vascular segment in salt-sensitive hypertension.

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Helicobacter pylori AdaptationIn Vivoin Response to a High-Salt Diet

Infection and Immunity ◽

10.1128/iai.00918-15 ◽

2015 ◽

Vol 83 (12) ◽

pp. 4871-4883 ◽

Cited By ~ 11

Author(s):

John T. Loh ◽

Jennifer A. Gaddy ◽

Holly M. Scott Algood ◽

Silvana Gaudieri ◽

Simon Mallal ◽

...

Keyword(s):

Oxidative Stress ◽

Helicobacter Pylori ◽

High Salt ◽

Mongolian Gerbils ◽

High Salt Diet ◽

Salt Diet ◽

Content Type ◽

Regular Diet ◽

H Pylori ◽

And Oxidative Stress

Helicobacter pyloriexhibits a high level of intraspecies genetic diversity. In this study, we investigated whether the diversification ofH. pyloriis influenced by the composition of the diet. Specifically, we investigated the effect of a high-salt diet (a known risk factor for gastric adenocarcinoma) onH. pyloridiversification within a host. We analyzedH. pyloristrains isolated from Mongolian gerbils fed either a high-salt diet or a regular diet for 4 months by proteomic and whole-genome sequencing methods. Compared to the input strain and output strains from animals fed a regular diet, the output strains from animals fed a high-salt diet produced higher levels of proteins involved in iron acquisition and oxidative-stress resistance. Several of these changes were attributable to a nonsynonymous mutation infur(fur-R88H). Further experiments indicated that this mutation conferred increased resistance to high-salt conditions and oxidative stress. We propose a model in which a high-salt diet leads to high levels of gastric inflammation and associated oxidative stress inH. pylori-infected animals and that these conditions, along with the high intraluminal concentrations of sodium chloride, lead to selection ofH. pyloristrains that are most fit for growth in this environment.

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