Endothelin B receptors impair baroreflex function and increase blood pressure variability during high salt diet

Independent studies of renal sympathetic nerves and the endothelin (ET) system have demonstrated important contributions of each in the progression of hypertension. Very few studies, however, have investigated the interaction between the ET system and renal nerves in relation to blood pressure control and electrolyte homeostasis. Although endothelin B (ETB) receptors in the renal medulla promote natriuresis, ETB receptors on sympathetic neurons are thought to increase neuronal activity. We hypothesized that renal denervation reduces blood pressure in a salt-sensitive, hypertensive model of ET dysfunction, the ETB-deficient (ETB-def) rat, which lacks functional ETB receptors in all tissues except neurons. After bilateral renal sympathetic denervation (Dnx) or sham operation of ETB-def and transgenic control (TG) rats, baseline blood pressure was recorded via telemetry for 5 days on a normal salt (0.49% NaCl) diet followed by a high salt (4.0%) diet. At baseline, ETB-def Dnx rats had a lower 24-hr systolic blood pressure (SBP) (152.6 ± 3.6 mmHg) relative to ETB-def sham (167.8 ± 2.6 mmHg; p < 0.005; n = 7/group). Denervation did not significantly affect TG rats relative to sham on normal salt (138.8 ± 2.5 vs. 144.7 ± 0.5 mmHg respectively; p = 0.53; n = 6/group). Following 10 days of high salt diet, ETB-def sham rats had an increased 24-hr SBP (+10.59 ± 2.8 mmHg relative to baseline; p < 0.005). There was a similar increase in SBP in ETB-def Dnx rats (+10.03 ± 2.3 mmHg relative to baseline; p < 0.005), although the ETB-def Dnx group remained lower than ETB-def sham. High salt had no effect on TG sham or Dnx animals (-2.2 ± 1.3 and -0.6 ± 2.8 mmHg relative to baseline). Preliminary evidence from a subset of the animals in this experiment indicated a dramatically reduced inner medullary ET-1 content in ETB-def sham rats vs. TG sham (97.9 ± 15.4 vs. 327.0 ± 25.4 ng/mg total protein; p < 0.005; n = 3-4/group) in both ETB-def and TG groups, Dnx tended to increase inner medullary ET-1 content (181.8 ± 75.8 and 402.7 ± 19.6 ng/mg total protein respectively). We conclude that in a model of ET dysfunction, the renal nerves are integral mediators of hypertension during normal salt diet, but do not mediate the increase in pressure following high salt diet in this model of salt-sensitive hypertension.

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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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Abstract 16835: Targeted Disruption of Paraoxonase 3 in a Dahl Salt-Sensitive Rat Model of Chronic Kidney Disease Increases Renal Cortical Pro-Inflammatory Eicosanoids

Circulation ◽

10.1161/circ.142.suppl_3.16835 ◽

2020 ◽

Vol 142 (Suppl_3) ◽

Author(s):

Chrysan J Mohammed ◽

Fatimah K Khalaf ◽

Prabhatchandra Dube ◽

Tyler J Reid ◽

Jacob A Connolly ◽

...

Keyword(s):

Blood Pressure ◽

Renal Injury ◽

Renal Cortex ◽

High Salt ◽

High Density Lipoproteins ◽

Wild Type ◽

Targeted Disruption ◽

High Salt Diet ◽

Salt Diet ◽

Mediators Of Inflammation

Background: Paraoxonase 3 (Pon3), is one of the three isoforms of the paraoxonase gene family. While Pon1 and Pon2 are widely studied, there is a paucity of knowledge regarding Pon3. Pon3 is synthesized in the liver and can circulate bound to high-density lipoproteins. There is significant expression in the kidney also. Pon3 has the ability to metabolize eicosanoids, which can act as signaling molecules and have known roles in the pathophysiology of some renal diseases. Decreased Pon activity is associated with elevated levels of eicosanoid metabolites and adverse clinical outcomes. We tested the hypothesis that targeted disruption of Pon3 results in elevated levels of pro-inflammatory eicosanoids and progression of renal injury. Methods/ Results: Ten week old male Dahl salt-sensitive (SS rats) and Pon3 mutant rats (SS Pon3 KO) were maintained on 8% high salt diet for eight weeks, to initiate salt-sensitive hypertensive renal disease. Previously we observed that SS Pon3 KO rats on eight weeks high salt diet demonstrated significantly increased phenotypic renal injury and mortality. In the current study, we noted that SS Pon3 KO had significantly decreased (p<0.05) glomerular filtration rate compared to SS wild type. Blood pressure (radiotelemetry) as well as plasma angiotensin and aldosterone (LC-MS/MS) were not different between the two groups after high salt diet. We used targeted lipidomic profiling to determine eicosanoid content in renal cortex from SS Pon3 KO and SS wild type rats at the end of eight weeks of high salt diet. We found that hydroxyl fatty acids 5-HEPE and 5-HETE (5-lipoxygenase dependent arachidonic acid metabolites) were significantly (p<0.05) elevated in the renal cortex of SS Pon3 KO compared to SS wild type rats. In addition to being mediators of inflammation, these metabolites are associated with renal cell injury and death. Furthermore, prostaglandin 6-keto-PGF 1α , which has known links to renal inflammation, was significantly (p<0.05) increased in renal cortex of SS- Pon3 KO compared to SS wild type rats. Conclusion: These findings suggest that targeted deletion of Pon3 increases pro-inflammatory eicosanoids (5-HETE and 5-HEPE) and prostaglandins (6-keto-PGF 1α ), as well as increases renal damage independent of blood pressure.

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Abstract 096: Leptin and High Salt Diet Induce Greater Increases in Blood Pressure in Female than Male Mice

Hypertension ◽

10.1161/hyp.68.suppl_1.096 ◽

2016 ◽

Vol 68 (suppl_1) ◽

Author(s):

Jessica L Faulkner ◽

Eric J Belin de Chantemele

Keyword(s):

Blood Pressure ◽

Recovery Period ◽

Pressure Rise ◽

High Salt ◽

High Salt Diet ◽

Salt Diet ◽

Male And Female ◽

Female Mice ◽

Males And Females ◽

Blood Pressure Responses

Recent studies by our group demonstrated that leptin is a direct regulator of aldosterone secretion and increases blood pressure via sex-specific mechanisms involving leptin-mediated activation of the aldosterone-mineralocorticoid receptor signaling pathway in females and sympatho-activation in males. Although it is well accepted that females secrete more leptin and aldosterone than males, it is unknown whether leptin infusion raises blood pressure similarly in male and female mice and whether higher aldosterone levels sensitize females to salt-induced hypertension. We hypothesized that female mice would be more sensitive to leptin than males and also have a potentiated blood pressure rise in response to high salt diet compared to males. Male and female Balb/C mice were implanted with radiotelemeters for continuous measurement of mean arterial pressure (MAP) at 10 weeks of age. MAP was measured for seven days prior to feeding with a high-salt diet (HS, 4%NaCl) for seven days. Following a recovery period, animals were then implanted with osmotic minipumps containing leptin (0.9mg/kg/day) recorded for seven days. Baseline MAP was similar between males and females (101.3±2.9 vs 99.3±3.7 mmHg, n=4 and 5, respectively), however, HS diet resulted in a greater MAP increase in females (15.0±2.6 mmHg) compared to males (3.1±4.5 mmHg, P<0.05). MAP with leptin treatment was increased with leptin in females moreso than in males, however, this did not reach significance (6.8±5.8 vs 1.8±5.9 mmHg, respectively). This potential sex difference in blood pressure responses to leptin was not associated with changes in body weight (0.07±0.44 vs -0.22±0.2 g, respectively) nor changes in blood glucose (-19.67±15.06 vs -15.4±11.4 mg/dl, respectively) in males and females in response to leptin. In summary, female mice are more sensitive to HS diet-induced blood pressure increases than males. Females may be more sensitive to leptin-mediated blood pressure increases than males. Further investigation is needed to determine whether these sex differences in blood pressure responses to HS diet and leptin are mediated by aldosterone or other mechanisms.

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Abstract 9: Endothelin B Receptors Protect Against Hypertension Induced by Chronic Angiotensin II in Female Rats

Hypertension ◽

10.1161/hyp.60.suppl_1.a9 ◽

2012 ◽

Vol 60 (suppl_1) ◽

Author(s):

Wararat Kittikulsuth ◽

David M Pollock

Keyword(s):

Blood Pressure ◽

High Salt ◽

Female Rats ◽

Male Rats ◽

Ang Ii ◽

Hypertensive Rats ◽

High Salt Diet ◽

Male And Female ◽

Male And Female Rats ◽

Endothelin B

Endothelin B (ET B ) receptors mediate vasodilation, anti-inflammation and natriuresis, which ultimately contribute to blood pressure control. We previously showed that renal medullary ET B receptor function is maintained in female angiotensin (Ang) II hypertensive rats, while male Ang II hypertensive rats have blunted ET B -induced natriuretic responses. Because female rats are more resistance to blood pressure elevation induced by high salt intake and/or Ang II infusion, we hypothesized that ET B receptors protect female rats against the hypertensive response and renal injury induced by a high salt diet and chronic Ang II infusion compared to males. Male and female rats received Ang II infusion (150 ng/kg/min; sc.) with 4% NaCl for 4 weeks; blood pressure was measured by telemetry. After a week of Ang II infusion with a high salt diet, subsets of both male and female rats received the ET B antagonist, A-192621, at three doses on consecutive weeks (1, 3, and 10 mg/kg/d in food). Male rats had a significantly higher blood pressure compared to females after 4 weeks of Ang II (178±10 vs. 138±10 mmHg; p<0.05). A-192621 resulted in a dose-dependent increase in blood pressure in female Ang II hypertensive rats (167±8 mmHg at 10 mg/kg/d; p<0.05); the increase produced by A-192621 in male Ang II hypertensive rats was not statistically significant (193±10 mmHg). After 4 weeks of Ang II infusion, the level of proteinuria and nephrinuria was higher in male rats compared to female. A-192621 did not further increase urinary excretion of protein or nephrin in both male and female Ang II hypertensive rats. In conclusion, these results support the hypothesis that ET B receptors provide more protection against hypertension during chronic Ang II infusion in female rats compared to male.

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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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Effects of a chronic high-salt diet on large artery structure: role of endogenous bradykinin

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.1998.274.5.h1423 ◽

1998 ◽

Vol 274 (5) ◽

pp. H1423-H1428 ◽

Cited By ~ 5

Author(s):

Chohreh Partovian ◽

Athanase Benetos ◽

Jean-Pierre Pommiès ◽

Willy Mischler ◽

Michel E. Safar

Keyword(s):

Blood Pressure ◽

High Salt ◽

Large Artery ◽

High Salt Diet ◽

Salt Diet ◽

Wky Rats ◽

Arterial Blood ◽

Arterial Structure ◽

Hoe 140

Bradykinin activity could explain the blood pressure increase during NaCl loading in hypertensive animals, but its contribution on vascular structure was not evaluated. We determined cardiac mass and large artery structure after a chronic, 4-mo, high-salt diet in combination with bradykinin B2-receptor blockade by Hoe-140. Four-week-old rats were divided into eight groups according to strain [spontaneously hypertensive rats (SHR) vs. Wistar-Kyoto (WKY) rats], diet (0.4 vs. 7% NaCl), and treatment (Hoe-140 vs. placebo). In WKY rats, a high-salt diet significantly increased intra-arterial blood pressure with minor changes in arterial structure independently of Hoe-140. In SHR, blood pressure remained stable but 1) the high-salt diet was significantly associated with cardiovascular hypertrophy and increased arterial elastin and collagen, and 2) Hoe-140 alone induced carotid hypertrophy. A high-salt diet plus Hoe-140 acted synergistically on carotid hypertrophy and elastin content in SHR, suggesting that the role of endogenous bradykinin on arterial structure was amplified in the presence of a high-salt diet.

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Association of a Disrupted Dipping Pattern of Blood Pressure with Progression of Renal Injury during the Development of Salt-Dependent Hypertension in Rats

International Journal of Molecular Sciences ◽

10.3390/ijms21062248 ◽

2020 ◽

Vol 21 (6) ◽

pp. 2248 ◽

Cited By ~ 1

Author(s):

Abu Sufiun ◽

Asadur Rahman ◽

Kazi Rafiq ◽

Yoshihide Fujisawa ◽

Daisuke Nakano ◽

...

Keyword(s):

Blood Pressure ◽

Circadian Rhythm ◽

Renal Injury ◽

Tissue Injury ◽

Renal Tissue ◽

High Salt ◽

Hypertensive Rats ◽

High Salt Diet ◽

Salt Diet ◽

The Difference

The aim of the present study is to investigate whether a disruption of the dipping pattern of blood pressure (BP) is associated with the progression of renal injury in Dahl salt-sensitive (DSS) hypertensive rats. Seven-week-old DSS rats were fed a high salt diet (HSD; 8% NaCl) for 10 weeks, followed by a transition to a normal salt diet (NSD; 0.3% NaCl) for 4 weeks. At baseline, NSD-fed DSS rats showed a dipper-type circadian rhythm of BP. By contrast, HSD for 5 days caused a significant increase in the difference between the active and inactive periods of BP with an extreme dipper type of BP, while proteinuria and renal tissue injury were not observed. Interestingly, HSD feeding for 10 weeks developed hypertension with a non-dipper pattern of BP, which was associated with obvious proteinuria and renal tissue injury. Four weeks after switching to an NSD, BP and proteinuria were significantly decreased, and the BP circadian rhythm returned to the normal dipper pattern. These data suggest that the non-dipper pattern of BP is associated with the progression of renal injury during the development of salt-dependent hypertension.

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