Abstract 138: High Salt Intake Augments Excitability of Pre-sympathetic PVN Neurons Through Dysfunction of the Endoplasmic Reticulum Ca2+ ATPase

High salt (HS) intake sensitizes pre-sympathetic neurons in the hypothalamic paraventricular nucleus (PVN) leading to augmented neuronal excitability. Recently, we reported that dysfunction of Ca 2+ dependent K + channels in the PVN contributes to HS intake induced sympathoexcitation. The endoplasmic reticulum (ER) acts as a Ca 2+ store and plays an important role in regulating intracellular Ca 2+ homeostasis. The ER Ca 2+ ATPase is responsible for maintaining the high level of ER Ca 2+ and loss of function would deplete the Ca 2+ store contributing to the reduced activity of Ca 2+ dependent K + channels. We hypothesized that a 2% (NaCl) HS diet for 5 weeks would reduce function of the ER Ca 2+ ATPase and augment excitability of PVN neurons with axon projections to the rostral ventrolateral medulla (PVN-RVLM) identified by retrograde label. In whole cell current-clamp recordings from PVN-RVLM neurons, graded current injections evoked graded increases in spike frequency. Maximum discharge was evoked by +200 pA injections and averaged 22±2 Hz (n=6) in normal salt (NS) control and was significantly augmented (p<0.05) by HS diet 34±5 Hz (n=8). Bath application of thapsigargin (TG) (0.5 μM), the ER Ca 2+ ATPase inhibitor, augmented excitability of PVN-RVLM neurons in NS (32±4 Hz, n=5, p<0.05), yet had no significant effect in HS rats (32±6 Hz, n=6). ER Ca 2+ ATPase function was assessed in whole animal preparations by bilateral PVN microinjection of TG in anesthetized rats. PVN microinjection of TG (0.15, 0.3 0.75 and 1.5 nmol/100nl) increased sympathetic nerve activity (SNA) and mean arterial pressure (MAP) in a dose-dependent manner in NS rats. Maximum increases in splanchnic SNA (SSNA), renal SNA (RSNA) and MAP elicited by PVN TG (0.75 nmol/100nl; n=5) were 93±7%, 75±7%, and 11±2mmHg, respectively. In contrast, sympathoexcitatory responses to PVN TG (0.75 nmol/100nl; n=5) were attenuated in HS treated rats (SSNA 41±8%, RSNA 22±5%, p<0.05 vs. NS) while MAP responses demonstrated no significant difference (+8±2 mmHg, p>0.05 vs NS). Our data indicate that a HS diet reduces ER Ca 2+ ATPase activity and augments excitability of PVN-RVLM neurons in vitro. Altered ER Ca 2+ homeostasis may contribute to sympathoexcitation through loss of Ca 2+ dependent K + channel activity in the PVN.

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Abstract P201: Enhanced Upregulation of (Pro)renin Receptor Expression by High Salt Intake in the Kidney of Dahl Salt-sensitive Rats

Hypertension ◽

10.1161/hyp.68.suppl_1.p201 ◽

2016 ◽

Vol 68 (suppl_1) ◽

Author(s):

Seiko Yamakoshi ◽

Osamu Ito ◽

Rong Rong ◽

Yusuke Ohsaki ◽

Yoshikazu Muroya ◽

...

Keyword(s):

Salt Intake ◽

Immunohistochemical Analysis ◽

High Salt ◽

Receptor Expression ◽

Dependent Manner ◽

Sprague Dawley ◽

Independent Manner ◽

Nephron Segments ◽

High Salt Intake ◽

Distal Tubules

We recently reported that high salt (HS) intake increased the (pro)renin receptor ((P)RR) expression by 3-5 fold in several nephron segments of Sprague-Dawley rats (Peptides 63: 156-162, 2015). The preset study examined the effects of HS intake on the renal (P)RR expression in Dahl-Salt sensitive (DS) rats. Male DS rats were fed a normal salt (NS) diet (0.6%NaCl) and a HS diet (8%NaCl) for 4weeks. A part of the rats fed the HS diet were treated orally with angiotensin II type 1 receptor (AT 1 R) antagonist, candesartan (Can,3mg/kg/day) or mineralocorticoid receptor (MR) antagonist, spironolactone (Spi, 100mg/kg/day). The (P)RR expression in nephron segments was examined by immunoblot and immunohistochemical analyses. HS intake increased the blood pressure, which did not significantly affected by Can or Spi. (P)RR was expressed in the all kidney sections, glomeruli, proximal tubules (PT), medullary thick ascending limbs and inner medullary collecting ducts. HS intake increased the (P)RR expression in the cortex by 22.6 fold (p<0.001) and the PT by 4.9 fold (p<0.01), but did not change it in the other sections or segments. Can inhibited the HS intake-increased (P)RR expression in the cortex by 32% (p<0.05), Spi inhibited it by 89% (p<0.001), but neither drug did not inhibit the HS intake-increased (P)RR expression in the PT. Immunohistochemical analysis also revealed that HS intake increased the (P)RR expression in the PT and distal tubules, and that Can and Spi inhibited the HS intake-increased (P)RR expression in the distal tubules. Additionally, deoxycorticosterone acetate (DOCA, 50mg/kg/week) administered to rats fed the NS diet for 4 weeks increased the (P)RR expression in the cortex by 80% (p<0.001) and distal tubules, but not in the PT. These results indicate that HS intake-increased (P)RR expression is enhanced in the PT and distal tubules of DS rats. The mechanisms of HS intake-increased (P)RR expression may be AT 1 R and MR-dependent manner in the distal tubules, but AT 1 R or MR-independent manner in the PT.

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Abstract P207: High Salt Intake desynchronizes the Molecular Clock in Rats

Hypertension ◽

10.1161/hyp.68.suppl_1.p207 ◽

2016 ◽

Vol 68 (suppl_1) ◽

Author(s):

Joshua S Speed ◽

Kelly A Hyndman ◽

Kaehler A Roth ◽

Malgorzata Kasztan ◽

Jermaine G Johnston ◽

...

Keyword(s):

Molecular Clock ◽

Salt Intake ◽

Receptor Activation ◽

High Salt ◽

Dietary Sodium ◽

Expression Control ◽

High Salt Intake ◽

Significant Difference ◽

A Cell ◽

Peripheral Clocks

Circadian rhythms in physiologic functions are driven, at the molecular level, by a group of transcription factors that oscillate over a 24 hour period, collectively termed the molecular clock. Within the kidney, it has been shown that the molecular clock directly influences transcription of Na + transporters and channels, including ENaC. ENaC is regulated by endothelin-1 (ET-1), via ET B receptor activation, in response to high salt intake. Thus, we hypothesized that increases in dietary sodium regulate the renal molecular clock (which in turn would facilitate Na+ homeostasis) through an ET B dependent mechanism. To address this question, we examined the effect of high salt (HS) intake on renal clock gene ( Bmal1, Cry1, Per1, Per2 ) expression. Control and ET B receptor deficient (ET B def) rats (a model of elevated renal ENaC) were placed on either HS or normal salt (NS) for two weeks and euthanized every 4 hours beginning at Zeitgeber Time 0 (Lights on). In the inner medulla, HS causes a phase delay in Bmal1 (Fig 1A) expression in control but not ET B def rats (Fig 1B). In addition, HS suppressed the expression of Cry1 , and Per2 during the respective acrophase in both control and ET B def rats (Fig 1C-1F) with no significant effect on Per1 . In contrast, no significant difference in the expression of Bmal1, Cry1, Per2, or Per1 (Fig 1I-1P) was found in response to HS in the renal cortex of either control or ET B def. These data indicate that HS feeding desynchronizes the molecular clock within the kidney and provides evidence that peripheral clocks are regulated in a cell type specific manner, even within the same organ.

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High Salt Intake Augments Excitability of PVN Neurons in Rats: Role of the Endoplasmic Reticulum Ca2+ Store

Frontiers in Neuroscience ◽

10.3389/fnins.2017.00182 ◽

2017 ◽

Vol 11 ◽

Cited By ~ 2

Author(s):

Robert A. Larson ◽

Andrew D. Chapp ◽

Le Gui ◽

Michael J. Huber ◽

Zixi Jack Cheng ◽

...

Keyword(s):

Endoplasmic Reticulum ◽

Salt Intake ◽

High Salt ◽

High Salt Intake

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High Salt Diet Impacts the Risk of Sarcopenia Associated with Reduction of Skeletal Muscle Performance in the Japanese Population

Nutrients ◽

10.3390/nu12113474 ◽

2020 ◽

Vol 12 (11) ◽

pp. 3474

Author(s):

Yasuko Yoshida ◽

Keisei Kosaki ◽

Takehito Sugasawa ◽

Masahiro Matsui ◽

Masaki Yoshioka ◽

...

Keyword(s):

Older People ◽

Salt Intake ◽

Handgrip Strength ◽

High Salt ◽

Muscle Performance ◽

World Health ◽

Fat Percentage ◽

High Salt Intake ◽

Significant Difference ◽

Low Salt

The World Health Organization has recommended 5 g/day as dietary reference intakes for salt. In Japan, the averages for men and women were 11.0 g/day and 9.3 g/day, respectively. Recently, it was reported that amounts of sodium accumulation in skeletal muscles of older people were significantly higher than those in younger people. The purpose of this study was to investigate whether the risk of sarcopenia with decreased muscle mass and strength was related to the amount of salt intake. In addition, we investigated its involvement with renalase. Four groups based on age and salt intake (“younger low-salt,” “younger high-salt,” “older low-salt,” and “older high-salt”) were compared. Stratifying by age category, body fat percentage significantly increased in high-salt groups in both younger and older people. Handgrip strength/body weight and chair rise tests of the older high-salt group showed significant reduction compared to the older low-salt group. However, there was no significant difference in renalase concentrations in plasma. The results suggest that high-salt intake may lead to fat accumulation and muscle weakness associated with sarcopenia. Therefore, efforts to reduce salt intake may prevent sarcopenia.

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Randomized Controlled Trial of Simple Salt Reduction Instructions by Physician for Patients with Type 2 Diabetes Consuming Excessive Salt

International Journal of Environmental Research and Public Health ◽

10.3390/ijerph18136913 ◽

2021 ◽

Vol 18 (13) ◽

pp. 6913

Author(s):

Chikako Oyabu ◽

Emi Ushigome ◽

Yuriko Ono ◽

Ayaka Kobayashi ◽

Yoshitaka Hashimoto ◽

...

Keyword(s):

Type 2 Diabetes ◽

Randomized Controlled Trial ◽

Salt Intake ◽

Controlled Trial ◽

High Salt ◽

Salt Reduction ◽

Randomized Controlled ◽

High Salt Intake ◽

Significant Difference

Objectives: We verified the clinical usefulness of an approach method in which a physician gives simple salt reduction instructions during outpatient visits to patients with type 2 diabetes. Methods: This study was an open-blind, randomized controlled trial. Subjects were outpatients with type 2 diabetes whose estimated salt intake using spot morning urine sample exceeded the target of salt intake. The control group (CG) was notified only of the current salt intake, whereas the intervention group (IG) was given the brief salt reduction instruction by a physician in addition to the information regarding their current salt intake. Results: The change in estimated salt intake was −0.6 g (from 10.1 to 9.5 g, p = 0.029) in the CG after 8 weeks, and −0.9 g (from 10.1 to 9.2 g, p = 0.001) in the IG, although there were no significant differences between them (p = 0.47). After 24 weeks, both groups no longer differed significantly from the baseline. In addition, multivariate linear regression analyses indicated that high salt intake and low estimated glomerular filtration rate at baseline were significantly associated with salt reduction after 8 weeks. Conclusions: Salt-reducing effects were observed after 8 weeks in both the IG and CG, but no significant difference was observed. Moreover, patients with high salt intake and renal disfunction may be more effective in accepting salt reduction instructions. Making patients aware of the importance of salt reduction through a physician is effective for continuous salt reduction, and it is important to continue regular and repetitive guidance.

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Long-Term High Salt Intake Involves Reduced SK Currents and Increased Excitability of PVN Neurons with Projections to the Rostral Ventrolateral Medulla in Rats

Neural Plasticity ◽

10.1155/2017/7282834 ◽

2017 ◽

Vol 2017 ◽

pp. 1-10 ◽

Cited By ~ 2

Author(s):

Andrew D. Chapp ◽

Renjun Wang ◽

Zixi (Jack) Cheng ◽

Zhiying Shan ◽

Qing-Hui Chen

Keyword(s):

Neuronal Excitability ◽

Salt Intake ◽

Cell Voltage ◽

High Salt ◽

Ventrolateral Medulla ◽

Sk Channel ◽

High Salt Intake ◽

Salt Sensitive Hypertension ◽

Small Conductance

Evidence indicates that high salt (HS) intake activates presympathetic paraventricular nucleus (PVN) neurons, which contributes to sympathoexcitation of salt-sensitive hypertension. The present study determined whether 5 weeks of HS (2% NaCl) intake alters the small conductance Ca2+-activated potassium channel (SK) current in presympathetic PVN neurons and whether this change affects the neuronal excitability. In whole-cell voltage-clamp recordings, HS-treated rats had significantly decreased SK currents compared to rats with normal salt (NS, 0.4% NaCl) intake in PVN neurons. The sensitivity of PVN neuronal excitability in response to current injections was greater in HS group compared to NS controls. The SK channel blocker apamin augmented the neuronal excitability in both groups but had less effect on the sensitivity of the neuronal excitability in HS group compared to NS controls. In the HS group, the interspike interval (ISI) was significantly shorter than that in NS controls. Apamin significantly shortened the ISI in NS controls but had less effect in the HS group. This data suggests that HS intake reduces SK currents, which contributes to increased PVN neuronal excitability at least in part through a decrease in spike frequency adaptation and may be a precursor to the development of salt-sensitive hypertension.

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Regulation of the cardioprotective adiponectin and its receptor AdipoR1 by salt

Canadian Journal of Physiology and Pharmacology ◽

10.1139/cjpp-2016-0570 ◽

2017 ◽

Vol 95 (3) ◽

pp. 305-309

Author(s):

Nicholas Arnold ◽

Abuzar Mahmood ◽

Maya Ramdas ◽

Paul P. Ehlinger ◽

Lakshmi Pulakat

Keyword(s):

Salt Intake ◽

High Salt ◽

Dependent Manner ◽

H9c2 Cells ◽

Mitochondrial Complex ◽

Improve Insulin Sensitivity ◽

High Salt Intake ◽

Cardioprotective Effects ◽

First Time ◽

Dose Dependent

Both circulating adiponectin (APN) and cardiac APN exert cardioprotective effects and improve insulin sensitivity and mitochondrial function. Low circulating APN serves as a biomarker for cardiovascular risk. Ablation of adiponectin receptor 1 (AdipoR1) causes myocardial mitochondrial dysfunction. Although high salt intake is a contributor to cardiovascular disease, how it modulates the expression of APN or AdipoR1 in cardiomyocytes is not known. We report that APN mRNA expression was attenuated in a dose-dependent manner in mouse cardiomyocyte cell line HL-1 exposed to salt concentrations ranging from 0.75% to 1.5% for 12 h. High-salt exposure (0.88% and 1.25% for 12 h) also suppressed APN and AdipoR1 protein expression significantly in rat cardiac muscle H9c2 cells. Co-immunostaining for AdipoR1 and mitochondrial complex 1 indicated that AdipoR1 may be co-localized with mitochondria. These data show for the first time that high salt is an important suppressor of cardiovascular protective APN and AdipoR1.

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Flow-dependent arteriolar dilation in normotensive rats fed low- or high-salt diets

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.1995.269.4.h1407 ◽

1995 ◽

Vol 269 (4) ◽

pp. H1407-H1414 ◽

Cited By ~ 22

Author(s):

M. A. Boegehold

Keyword(s):

Salt Intake ◽

High Salt ◽

Vessel Occlusion ◽

High Salt Intake ◽

Significant Difference ◽

Low Salt ◽

No Release ◽

Luminal Flow ◽

Arteriolar Tone

Ingestion of a high-salt diet has previously been shown to suppress the endogenous influence of nitric oxide (NO) on arteriolar tone in hypertension-resistant, salt-resistant Dahl (SR/Jr) rats. Because luminal blood flow can be an important stimulus for endothelial NO release, this study was undertaken to determine whether high salt intake can also lead to a deficit in the direct flow-dependent regulation of arteriolar diameter. The spinotrapezius muscle microvasculature was studied by in vivo microscopy in SR/Jr rats fed low (0.45%)- or high (7%)-salt diets for 2 wk, and arcade arteriole responses to increased luminal flow (via parallel vessel occlusion) were studied in both dietary groups. There was no significant difference between groups in arterial pressure or in resting arteriolar diameters, volume flows, or wall shear rates. In low-salt SR/Jr, a 36% increase in luminal flow produced an average arteriolar dilation of 38% that was significantly reduced by the NO synthase inhibitor NG-monomethyl-L-arginine (L-NMMA). In high-salt SR/Jr, a similar flow increase produced an average dilation of only 16% (P < 0.05 vs. low-salt SR/Jr), and this response was unaffected by L-NMMA. Inhibition of cyclooxygenase activity with meclofenamate had no effect on this response in either group. These findings suggest that NO release mediates a portion of flow-dependent arteriolar dilation in rat spinotrapezius muscle and that high salt intake, in the absence of hypertension, can attenuate this response via a suppression of NO activity.

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High Salt Intake–Increased (Pro)renin Receptor Expression Is Exaggerated in the Kidney of Dahl Salt-Sensitive Rats

Hypertension ◽

10.1161/hypertensionaha.119.13905 ◽

2020 ◽

Vol 75 (6) ◽

pp. 1447-1454

Author(s):

Seiko Yamakoshi ◽

Osamu Ito ◽

Rong Rong ◽

Yusuke Ohsaki ◽

Takahiro Nakamura ◽

...

Keyword(s):

Renal Cortex ◽

Salt Intake ◽

High Salt ◽

Proximal Tubules ◽

Receptor Expression ◽

Dependent Manner ◽

Mineralocorticoid Receptor Antagonist ◽

Salt Diet ◽

High Salt Intake ◽

Distal Tubules

The (P)RR ([pro]renin receptor) was identified as a new component of the renin-angiotensin system. We previously reported that high salt (HS) intake increased the (P)RR expression in several nephron segments of Sprague-Dawley rats. Other studies reported HS intake increased the XO (xanthine oxidase) activity and an MR (mineralocorticoid receptor) antagonist inhibited HS intake–increased (P)RR expression in the kidneys of Dahl salt-sensitive (DS) rats. The present study examined the effects of HS intake on (P)RR expression in the kidney of DS rats. Male DS rats were fed a normal salt diet or an HS diet for 4 weeks. Some of the rats fed on the HS diet were treated with the XO inhibitor, febuxostat, and the MR antagonist, spironolactone. Immunoblot and immunohistochemical analyses showed that HS intake increased (P)RR expression in the renal cortex by 22.6-fold, the proximal tubules by 4.9-fold and the distal tubules, respectively. Both febuxostat and spironolactone inhibited HS intake–increased (P)RR expression in the renal cortex. Febuxostat inhibited HS intake–increased (P)RR expression in the proximal tubules, whereas spironolactone inhibited HS intake–increased (P)RR expression in the distal tubules. Additionally, deoxycorticosterone acetate increased (P)RR expression in the renal cortex and distal tubules but not in the proximal tubules of DS rats fed the normal salt diet. These results indicate that HS intake greatly increases (P)RR expression in the renal cortex of DS rats. The mechanisms of HS intake–increased (P)RR expression may work in an XO-dependent manner in the proximal tubules and an MR-dependent manner in the distal tubules.

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