The Potential Detrimental Role of High Salt Diet in Promoting Exaggerated Th-17 Responses in COVID-19 Patients, an Intriguing Hypothesis

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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Role of high-salt diet in non-alcoholic fatty liver disease: a mini-review of the evidence

European Journal of Clinical Nutrition ◽

10.1038/s41430-021-01044-8 ◽

2021 ◽

Author(s):

Jing Xu ◽

Fei Mao

Keyword(s):

Liver Disease ◽

Fatty Liver ◽

Fatty Liver Disease ◽

High Salt ◽

High Salt Diet ◽

Alcoholic Fatty Liver ◽

Salt Diet ◽

Alcoholic Fatty Liver Disease

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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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Role of Endothelin B Receptors in Enhancing Endothelium-Dependent Nitric Oxide–Mediated Vascular Relaxation During High Salt Diet

Hypertension ◽

10.1161/01.hyp.37.2.516 ◽

2001 ◽

Vol 37 (2) ◽

pp. 516-523 ◽

Cited By ~ 35

Author(s):

Jena B. Giardina ◽

GaChavis M. Green ◽

Anna N. Rinewalt ◽

Joey P. Granger ◽

Raouf A. Khalil

Keyword(s):

Nitric Oxide ◽

High Salt ◽

Vascular Relaxation ◽

High Salt Diet ◽

Salt Diet ◽

Endothelin B

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Role of central nervous system aldosterone synthase and mineralocorticoid receptors in salt-induced hypertension in Dahl salt-sensitive rats

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.90903.2008 ◽

2009 ◽

Vol 296 (4) ◽

pp. R994-R1000 ◽

Cited By ~ 66

Author(s):

Bing S. Huang ◽

Roselyn A. White ◽

Arco Y. Jeng ◽

Frans H. H. Leenen

Keyword(s):

Salt Intake ◽

High Salt ◽

High Salt Diet ◽

Salt Diet ◽

Aldosterone Synthase ◽

High Salt Intake ◽

Induced Hypertension ◽

Synthase Inhibitor ◽

The Brain

In Dahl salt-sensitive (S) rats, high salt intake increases cerebrospinal fluid (CSF) Na+ concentration ([Na+]) and blood pressure (BP). Intracerebroventricular (ICV) infusion of a mineralocorticoid receptor (MR) blocker prevents the hypertension. To assess the role of aldosterone locally produced in the brain, we evaluated the effects of chronic central blockade with the aldosterone synthase inhibitor FAD286 and the MR blocker spironolactone on changes in aldosterone and corticosterone content in the hypothalamus and the increase in CSF [Na+] and hypertension induced by high salt intake in Dahl S rats. After 4 wk of high salt intake, plasma aldosterone and corticosterone were not changed, but hypothalamic aldosterone increased by ∼35% and corticosterone tended to increase in Dahl S rats, whereas both steroids decreased by ∼65% in Dahl salt-resistant rats. In Dahl S rats fed the high-salt diet, ICV infusion of FAD286 or spironolactone did not affect the increase in CSF [Na+]. ICV infusion of FAD286 prevented the increase in hypothalamic aldosterone and 30 mmHg of the 50-mmHg BP increase induced by high salt intake. ICV infusion of spironolactone fully prevented the salt-induced hypertension. These results suggest that, in Dahl S rats, high salt intake increases aldosterone synthesis in the hypothalamus and aldosterone acts as the main MR agonist activating central pathways contributing to salt-induced hypertension.

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The role of high salt diet in left ventricular remodeling and telmisartan intervention in Wistar rats

International Journal of Cardiology ◽

10.1016/j.ijcard.2011.08.813 ◽

2011 ◽

Vol 152 ◽

pp. S105

Author(s):

Qianhui Shang ◽

Genghui Shi ◽

Qin Wu ◽

Chan Liu

Keyword(s):

Wistar Rats ◽

Ventricular Remodeling ◽

Left Ventricular Remodeling ◽

Left Ventricular ◽

High Salt ◽

High Salt Diet ◽

Salt Diet

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Effects of high-salt diet on CYP450-4A ω-hydroxylase expression and active tone in mesenteric resistance arteries

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00755.2004 ◽

2005 ◽

Vol 288 (4) ◽

pp. H1557-H1565 ◽

Cited By ~ 24

Author(s):

Jingli Wang ◽

Richard J. Roman ◽

John R. Falck ◽

Lourdes de la Cruz ◽

Julian H. Lombard

Keyword(s):

Salt Intake ◽

High Salt ◽

Resistance Arteries ◽

Dietary Salt ◽

High Salt Diet ◽

Salt Diet ◽

Dietary Salt Intake ◽

Vasoconstrictor Response ◽

Cytochrome P 450

This study investigated the role of changes in the expression of the cytochrome P-450 4A (CYP450-4A) enzymes that produce 20-hydroxyeicosatetraenoic acid (20-HETE) in modulating the responses of rat mesenteric resistance arteries to norepinephrine (NE) and reduced Po2 after short-term (3-day) changes in dietary salt intake. The CYP450-4A2, -4A3, and -4A8 isoforms were all detected by RT-PCR in arteries obtained from rats fed a high-salt (HS, 4% NaCl) diet, whereas only the CYP450-4A3 isoform was detected in vessels from rats fed a low-salt (LS, 0.4% NaCl) diet. Expression of the 51-kDa CYP450-4A protein was significantly increased by a HS diet. Inhibiting 20-HETE synthesis with 30 μM N-methylsulfonyl-12,12-dibromododec-11-enamide (DDMS) reduced the vasoconstrictor response to NE in arteries obtained from rats fed either a LS or HS diet, but NE sensitivity after DDMS treatment was significantly lower in vessels from rats on a HS diet. DDMS treatment also restored the vasodilator response to reduced Po2 that was impaired in arteries from rats on a HS diet. These findings suggest that 1) a HS diet increases the expression of CYP450-4A enzymes in the mesenteric vasculature, 2) 20-HETE contributes to the vasoconstrictor response to NE in mesenteric resistance arteries, 3) the contribution of 20-HETE to the vasoconstrictor response to NE is greater in rats fed a HS diet than in rats fed a LS diet, and 4) upregulation of the production of 20-HETE contributes to the impaired dilation of mesenteric resistance arteries in response to hypoxia in rats fed a HS diet.

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Abstract 294: Evaluation of the Role of the NAD(P)H Oxidase Subunit p67phox in the Regulation of Glomerular Filtration Rate in Dahl Salt-sensitive Rats

Hypertension ◽

10.1161/hyp.62.suppl_1.a294 ◽

2013 ◽

Vol 62 (suppl_1) ◽

Author(s):

Louise C Evans ◽

Robert P Ryan ◽

Terry Kurth ◽

Meredith Skelton ◽

Allen W Cowley

Keyword(s):

Nadph Oxidase ◽

Pressor Response ◽

High Salt ◽

Null Mutation ◽

High Salt Diet ◽

Salt Diet ◽

Low Salt ◽

Species Production ◽

Stable Control

Studies were performed in male Dahl salt-sensitive (SS) rats with a null mutation in the p67 phox gene (SSp67 phox -/-) and wild type littermates (SS-WT) aged 10-12 weeks (n=5/6 /group). In previous studies we have shown that this important subunit of NADPH oxidase is upregulated in the SS rat. A new method for sequential measurement of GFR in conscious rats was applied during the consumption of a high salt diet. Utilizing a miniaturized device, disappearance curves of fluorescein isothiocynate (FITC)-sinistrin were determined by transcutaneous excitation and real time detection of the emitted light through the skin. The rats were surgically prepared with femoral venous catheters for the administration of (FITC)-sinistrin and carotid catheters for MAP measurement by telemetry. Baseline measurement of GFR and MAP were made daily to obtain 2 stable control days on low salt (LS, 0.4% NaCl). High salt (HS, 4.0% NaCl) measurements were made on day 2,5,7,14 and 21. In SS-WT rats, HS resulted in a progressive and significant increase in MAP (from 126±2 mmHg during LS to 158±11 mmHg by d21 HS). GFR decreased significantly from 1.50±0.03 ml/min/100g bwgt during LS to 1.26±0.02 by d21 HS. Notably, a significant increase in blood pressure was observed at d7 HS in the SS-WT preceeding the reduction in GFR which did not occur until d14 HS. In rats with the null mutation of the p67 phox gene, the pressor response to HS was blunted, MAP averaged 131±5 mmHg by d21, and there was no significant change in GFR (LS values 1.54±0.07 ml/min/100g bwgt comparable to d21 HS values of 1.41±0.04). In summary, when p67 phox is not functional in the SS rat, the hypertensive response to HS is blunted and GFR is maintained. We conclude that reactive oxygen species production via NADPH oxidase plays a major role in the eventual reduction of GFR in SS rats following the development of hypertension.

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Renal denervation attenuates hypertension but not salt sensitivity in ETB receptor-deficient rats

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00174.2017 ◽

2017 ◽

Vol 313 (4) ◽

pp. R425-R437 ◽

Cited By ~ 6

Author(s):

Bryan K. Becker ◽

Amanda C. Feagans ◽

Daian Chen ◽

Malgorzata Kasztan ◽

Chunhua Jin ◽

...

Keyword(s):

Blood Pressure ◽

Low Frequency ◽

Sympathetic Nerves ◽

Salt Sensitivity ◽

High Salt ◽

High Salt Diet ◽

Salt Diet ◽

Etb Receptor ◽

Renal Sympathetic

Hypertension is a prevalent pathology that increases risk for numerous cardiovascular diseases. Because the etiology of hypertension varies across patients, specific and effective therapeutic approaches are needed. The role of renal sympathetic nerves is established in numerous forms of hypertension, but their contribution to salt sensitivity and interaction with factors such as endothelin-1 are poorly understood. Rats deficient of functional ETB receptors (ETB-def) on all tissues except sympathetic nerves are hypertensive and exhibit salt-sensitive increases in blood pressure. We hypothesized that renal sympathetic nerves contribute to hypertension and salt sensitivity in ETB-def rats. The hypothesis was tested through bilateral renal sympathetic nerve denervation and measuring blood pressure during normal salt (0.49% NaCl) and high-salt (4.0% NaCl) diets. Denervation reduced mean arterial pressure in ETB-def rats compared with sham-operated controls by 12 ± 3 (SE) mmHg; however, denervation did not affect the increase in blood pressure after 2 wk of high-salt diet (+19 ± 3 vs. +16 ± 3 mmHg relative to normal salt diet; denervated vs. sham, respectively). Denervation reduced cardiac sympathetic-to-parasympathetic tone [low frequency-high frequency (LF/HF)] during normal salt diet and vasomotor LF/HF tone during high-salt diet in ETB-def rats. We conclude that the renal sympathetic nerves contribute to the hypertension but not to salt sensitivity of ETB-def rats.

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