A8062 Effects of long-term high-salt diet on blood pressure variability in Wistar rats

P111 We have previously shown that inhibition of inducible nitric oxide synthase (NOS II) evokes a salt-sensitive increase in blood pressure in Dahl salt-resistant rats when given a high salt (8% NaCl) diet for 7 days. To determine whether or not the effect of NOS II inhibition is short-lived, we continued the high salt diet for an additional 3 weeks following the discontinuation of the NOS II inhibitor. DR rats were given one of two NOS II selective inhibitors, AMT (300 nmoles/hr) and 1400W (35 nmoles/hr) for 2 weeks. A high salt diet was initiated after the first week of NOS II inhibition and continued for an additional 3 weeks for a total of 4 weeks of high salt treatment. Control DR rats received high salt alone for 4 weeks. Systolic blood pressure was taken at baseline and once weekly for the treatment period. Blood pressure significantly increased in DR rats after 1 week of high salt following NOS II inhibition. The blood pressure remained elevated throughout the 4-week period of high salt treatment despite the discontinuation of NOS II inhibitors 1 week following the initiation of the high salt diet. There was no significant change in blood pressure in DR rats on high salt diet alone. These data suggest that salt-sensitive hypertension can be evoked by transient NOS II inhibitor exposure. We conclude that tranisent NOS II inhibition may initiate events or processes that high salt maintains leading to sustained elevation in systolic blood pressure.

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Endocannabinoid Regulates Blood Pressure via Activation of the Transient Receptor Potential Vanilloid Type 1 in Wistar Rats Fed a High-Salt Diet

Journal of Pharmacology and Experimental Therapeutics ◽

10.1124/jpet.106.112904 ◽

2007 ◽

Vol 321 (2) ◽

pp. 763-769 ◽

Cited By ~ 29

Author(s):

Youping Wang ◽

Norbert E. Kaminski ◽

Donna H. Wang

Keyword(s):

Blood Pressure ◽

Wistar Rats ◽

Transient Receptor Potential ◽

Receptor Potential ◽

High Salt ◽

Transient Receptor Potential Vanilloid ◽

High Salt Diet ◽

Salt Diet ◽

Transient Receptor

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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 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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