Salt Induces Adipogenesis/Lipogenesis and Inflammatory Adipocytokines Secretion in Adipocytes

It is well known that high salt intake is associated with cardiovascular diseases including hypertension. However, the research on the mechanism of obesity due to high salt intake is rare. To evaluate the roles of salt on obesity prevalence, the gene expression of adipogenesis/lipogenesis and adipocytokines secretion according to adipocyte dysfunction were investigated in salt-loading adipocytes. High salt dose-dependently increased the expression of adipogenic/lipogenic genes, such as PPAR-γ, C/EBPα, SREBP1c, ACC, FAS, and aP2, but decreased the gene of lipolysis like AMPK, ultimately resulting in fat accumulation. With SIK-2 and Na+/K+-ATPase activation, salt increased the metabolites involved in the renin-angiotensin-aldosterone system (RAAS) such as ADD1, CYP11β2, and MCR. Increasing insulin dependent insulin receptor substrate (IRS)-signaling, resulting in the insulin resistance, mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) and Akt-mTOR were activated but AMPK(Thr172) was depressed in salt-loading adipocytes. The expression of pro-inflammatory adipocytokines, TNFα, MCP-1, COX-2, IL-17A, IL-6, leptin, and leptin to adiponectin ratio (LAR) were dose-dependently increased by salt treatment. Using the inhibitors of MAPK/ERK, U0126, we found that the crosstalk among the signaling pathways of MAPK/ERK, Akt-mTOR, and the inflammatory adipogenesis can be the possible mechanism of salt-linked obesity. The possibilities of whether the defense mechanisms against high dose of intracellular salts provoke signaling for adipocytes differentiation or interact with surrounding tissues through other pathways will be explored in future research.

Download Full-text

Thromboxane A2 Receptor Antagonist (ONO-8809) Attenuates the Renal Disorders Caused by Salt-Overload in Stroke-Prone Spontaneously Hypertensive Rats

10.20944/preprints202101.0319.v1 ◽

2021 ◽

Author(s):

Yusuke Nagatani ◽

Toshihide Higashino ◽

Kosho Kinoshita ◽

Hideaki Higashino

Keyword(s):

Gene Expression ◽

Spontaneously Hypertensive Rats ◽

Salt Intake ◽

Thromboxane A2 ◽

High Salt ◽

Hypertensive Rats ◽

Salt Loading ◽

Spontaneously Hypertensive ◽

Oxidative Stresses ◽

High Salt Intake

Background. Epidemiological and clinical studies demonstrated that excessive salt intake causes severe hypertension and exacerbated organ derangement such as chronic kidney disease (CKD). In this study, we focused on evaluating histological and gene-expression findings in the kidney using stroke-prone spontaneously hypertensive rats (SHRSP) with high-salt intake and thromboxane A2/ prostaglandin H2 receptor (TPR) blocker ONO-8809. Methods. SHRSP aged 6 weeks were divided into three groups eating normal chow containing 0.4% NaCl, 2.0%NaCl, or 2.0%NaCl +ONO-8809 (0.6mg/kg p.o. daily). Histological analyses with immunohistochemistry and a gene-expression assay with a DNA kidney microarray were performed after 8 weeks. Results. The following changes were observed with high-salt intake. Glomerular sclerotic changes were remarkably observed in the juxtaglomerular cortex areas. ED1, MCP-1, nitrotyrosine, and HIF-1α staining areas were increased in the glomeruli and interstitial portion. Tbxa2r which encodes TPR, Prcp, and Car7 were significantly underexpressed in the kidney. The plasma 8-isoprostane level was significantly elevated, and was attenuated with ONO-8809 treatment. Conclusion. TXA2 and oxidative stresses exaggerated renal dysfunction in salt-loading SHRSP, and ONO-8809 as a TPR blocker suppressed these changes. Therefore, ONO-8809 is a candidate drug to prevent CKD for hypertensive patients associated with high-salt intake.

Download Full-text

Dissociation between right atrial pressure and plasma atrial natriuretic factor following prolonged high salt intake

Canadian Journal of Physiology and Pharmacology ◽

10.1139/y90-057 ◽

1990 ◽

Vol 68 (3) ◽

pp. 408-412

Author(s):

Jiri Widimsky Jr. ◽

Otto Kuchel ◽

Waldemar Debinski ◽

Gaétan Thibault

Keyword(s):

Atrial Natriuretic Factor ◽

Salt Intake ◽

High Salt ◽

Atrial Pressure ◽

Right Atrial ◽

Right Atrial Pressure ◽

Salt Loading ◽

Natriuretic Factor ◽

High Salt Intake ◽

Atrial Natriuretic

The influence of prolonged high salt intake on intravascular volume, right atrial pressure, plasma atrial natriuretic factor, and extra-atrial tissue (lung, kidney, and liver) COOH- and NH2-terminal atrial natriuretic factor content was investigated in normotensive rats. Despite prolonged high salt (8% NaCl) intake for 5 weeks, total intravascular volume was not impaired. However, right atrial pressure was increased by 54% (p < 0.01) after salt loading. Although this increment in right atrial pressure should favor atrial natriuretic factor release after NaCl intake, plasma atrial natriuretic factor (COOH-terminal) concentrations markedly decreased from 97.8 ± 27 to 38.9 ± 8 pg/mL. Sodium and circulatory homeostasis was, however, well preserved. The lungs contained the highest levels of COOH- and NH2-terminal atrial natriuretic factor. Salt loading resulted in increased concentrations of low as well as high molecular weight atrial natriuretic factor in the lung but not in the kidney or the liver. Our study indicates a limited role of atrial natriuretic factor in adaptation to prolonged salt consumption in rats. Dissociation between right atrial pressure and plasma atrial natriuretic factor after salt intake implicates other factors regulating circulating peptide levels. Prolonged salt intake increases lung generation of atrial natriuretic factor.Key words: atrial natriuretic factor, volume, atrial pressure, high salt diet.

Download Full-text

Salt loading augments vascular responses to indomethacin in stroke-prone SHR

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.1982.243.3.h360 ◽

1982 ◽

Vol 243 (3) ◽

pp. H360-H364

Author(s):

T. Imaizumi ◽

A. Takeshita ◽

T. Ashihara ◽

M. Nakamura

Keyword(s):

Vascular Resistance ◽

Prostaglandin E1 ◽

Salt Intake ◽

High Salt ◽

Salt Loading ◽

Salt Diet ◽

Spontaneously Hypertensive ◽

High Salt Intake ◽

Endogenous Prostaglandins ◽

Wistar Kyoto

We examined whether endogenous prostaglandins (PGs) participated in control of hindquarters vascular resistance during salt loading in stroke-prone spontaneously hypertensive rates (SHR-SP). SHR-SP and Wistar-Kyoto rats (WKY) were fed either a normal (0.3% NaCl) or high (8% NaCl) salt diet for 5 wk. High salt increased blood pressure and hindquarter vascular resistance (VR) in SHR-SP (P less than 0.01) but not in WKY. Indomethacin given intravenously increased hindquarter VR in SHR-SP during high salt as well as during normal salt (P less than 0.01) but not in either group of WKY. In SHR-SP the increase in hindquarter VR by PG synthesis inhibitors were two times greater during high salt than during normal salt (P less than 0.01). In addition, hindquarter vasodilatation by bradykinin was greater (P less than 0.05) in SHR-SP during high salt than that during normal salt, but vasodilatation by prostaglandin E1 or nitroglycerin was not different between the two groups. These results suggest that vascular synthesis of endogenous PGs was greater in SHR-SP during high salt than that during normal salt. Increased endogenous PGs may play an important role in the regulation of hindquarter VR during high salt intake in SHR-SP.

Download Full-text

Salt loading enhances rat renal TxA2/PGH2 receptor expression and TGF response to U-46,619

AJP Renal Physiology ◽

10.1152/ajprenal.1997.273.6.f976 ◽

1997 ◽

Vol 273 (6) ◽

pp. F976-F983 ◽

Cited By ~ 11

Author(s):

William J. Welch ◽

Bo Peng ◽

Kazuhisa Takeuchi ◽

Keishi Abe ◽

Christopher S. Wilcox

Keyword(s):

Salt Intake ◽

Receptor Activation ◽

High Salt ◽

Receptor Expression ◽

Tubuloglomerular Feedback ◽

Kidney Cortex ◽

Salt Loading ◽

Receptor Mrna ◽

High Salt Intake ◽

Low Salt

The tubuloglomerular feedback (TGF) response is potentiated by thromboxane A2(TxA2) and/or prostaglandin endoperoxide (PGH2) acting on specific receptors. Infusion of the TxA2/PGH2mimetic, U-46,619, into conscious rats leads to hypertension that is potentiated by a high-salt intake. Therefore, we tested the hypothesis that a high-salt intake enhances the expression of transcripts for TxA2/PGH2receptors in the kidney and glomeruli and enhances the response of TGF to TxA2/PGH2receptor stimulation. Groups of rats were accommodated to a low-salt (LS), normal salt (NS), or high-salt (HS) diet for 8–10 days. TxA2/PGH2receptor mRNA was detected by reverse transcription-polymerase chain reaction in kidney cortex, isolated glomeruli, and abdominal aorta. TxA2/PGH2mRNA abundance was significantly ( P< 0.001) increased during intake of high-salt compared with low-salt diets in the kidney cortex (1.34 ± 0.10 vs. 0.84 ± 0.04 arbitrary units) and isolated outer cortical glomeruli (0.68 ± 0.04 vs. 0.32 ± 0.03 arbitrary units), but there was no effect of salt on TxA2/PGH2receptor mRNA expression in the aorta. Maximal TGF responses were assessed from the increase in proximal stop flow pressure (an index of glomerular capillary pressure) during increases in loop of Henle perfusion with artificial tubular fluid from 0 to 40 nl/min. Compared with vehicle, the enhancement of maximal TGF with U-46,619 (10−6 M) added to the perfusate was greater in rats adapted to high-salt than normal salt (HS: +9.6 ± 1.1 vs. NS: +5.1 ± 0.4 mmHg; P < 0.001) or low-salt (LS: +3.8 ± 1.3 mmHg; P < 0.001) intakes. Responses to U-46,619 at each level of salt intake were blocked by >70% by the TxA2/PGH2receptor antagonist ifetroban. In contrast, enhancement of TGF by peritubular capillary perfusion of arginine vasopressin (AVP; 10−7 M) was similar in high-salt and low-salt rats (HS: +1.5 ± 0.6 vs. LS: +1.6 ± 0.5 mmHg; not significant). We conclude that salt loading increases selectively the abundance of TxA2/PGH2receptor transcripts in the kidney cortex and glomerulus, relative to the aorta, and enhances selectively TGF responses to TxA2/PGH2receptor activation but not to AVP.

Download Full-text

Adipocytes initiate an adipose-cerebral-peripheral sympathetic reflex to induce insulin resistance during high-fat feeding

Clinical Science ◽

10.1042/cs20190412 ◽

2019 ◽

Vol 133 (17) ◽

pp. 1883-1899 ◽

Cited By ~ 5

Author(s):

Wei Cao ◽

Meng Shi ◽

Liling Wu ◽

Jiaxin Li ◽

Zhichen Yang ◽

...

Keyword(s):

Insulin Resistance ◽

Adipose Tissue ◽

Glucose Uptake ◽

White Adipose Tissue ◽

Salt Intake ◽

High Salt ◽

High Fat ◽

Efferent Nerve ◽

Salt Loading ◽

High Salt Intake

Abstract The underlying mechanism by which amassing of white adipose tissue in obesity regulates sympathetic nerve system (SNS) drive to the tissues responsible for glucose disposal, and causes insulin resistance (IR), remains unknown. We tested the hypothesis that high-fat (HF) feeding increases afferent impulses from white adipose tissue that reflexively elevate efferent nerve activity to skeletal muscle (SM) and adipose tissue to impair their local glucose uptake. We also investigated how salt-intake can enhance IR. HF-fed rats received a normal salt (0.4%) or high salt (4%) diet for 3 weeks. High-salt intake in HF fed rats decreased insulin-stimulated 2-deoxyglucose uptake by over 30% in white adipose tissue and SM, exacerbated inflammation, and impaired their insulin signaling and glucose transporter 4 (Glut4) trafficking. Dietary salt in HF fed rats also increased the activity of the adipose-cerebral-muscle renin–angiotensin system (RAS) axes, SNS, and reactive oxygen species (ROS). Insulin sensitivity was reduced by 32% in HF rats during high-salt intake, but was improved by over 62% by interruption of central RAS and SNS drive, and by over 45% by denervation or deafferentation of epididymal fat (all P<0.05). Our study suggest that a HF diet engages a sympathetic reflex from the white adipose tissue that activates adipose-cerebral-muscle RAS/ROS axes and coordinates a reduction in peripheral glucose uptake. These are all enhanced by salt-loading. These findings provide new insight into the role of a reflex initiated in adipose tissue in the regulation of glucose homeostasis during HF feeding that could lead to new therapeutic approaches to IR.

Download Full-text

Nephron-Specific Disruption of Polycystin-1 Induces Cyclooxygenase-2–Mediated Blood Pressure Reduction Independent of Cystogenesis

Journal of the American Society of Nephrology ◽

10.1681/asn.2019090934 ◽

2020 ◽

Vol 31 (6) ◽

pp. 1243-1254

Author(s):

Jayalakshmi Lakshmipathi ◽

Yang Gao ◽

Chunyan Hu ◽

Deborah Stuart ◽

Jonathan Genzen ◽

...

Keyword(s):

Cell Proliferation ◽

Arterial Pressure ◽

Knockout Mice ◽

Salt Intake ◽

Blood Pressure Reduction ◽

Cyclooxygenase 2 ◽

High Salt ◽

Salt Loading ◽

High Salt Intake ◽

And Control

BackgroundHypertension often occurs before renal function deteriorates in autosomal dominant polycystic kidney disease (ADPKD). It is unknown whether the Pkd1 gene product polycystin-1—the predominant causal factor in ADPKD—itself contributes to ADPKD hypertension independent of cystogenesis.MethodsWe induced nephron-specific disruption of the Pkd1 gene in 3-month-old mice and examined them at 4–5 months of age.ResultsKidneys from the Pkd1 knockout mice showed no apparent renal cysts, tubule dilation, or increased cell proliferation. Compared with control mice, Pkd1 knockout mice exhibited reduced arterial pressure during high salt intake; this associated with an increased natriuretic, diuretic, and kaliuretic response during the first 2–3 days of salt loading. The lower arterial pressure and enhanced natriuresis during high salt loading in Pkd1 knockout mice were associated with lower urinary nitrite/nitrate excretion and markedly increased urinary PGE2 excretion, whereas GFR, plasma renin concentration, and urinary endothelin-1 excretion were similar between knockout and control mice. Kidney cyclooxygenase-2 protein levels were increased in Pkd1 knockout mice during high salt intake; administration of NS-398, a selective cyclooxygenase-2 inhibitor, abolished the arterial pressure difference between the knockout and control mice during high salt intake. Total kidney Na+/K+/2Cl− cotransporter isoform 2 (NKCC2) levels were greatly reduced in Pkd1 knockout mice fed a high salt diet compared with controls.ConclusionsThese studies suggest that nephron polycystin-1 deficiency does not itself contribute to ADPKD hypertension and that it may, in fact, exert a relative salt-wasting effect. The work seems to comprise the first in vivo studies to describe a potential physiologic role for nephron polycystin-1 in the absence of cysts, tubule dilation, or enhanced cell proliferation.

Download Full-text

Congenic strains provide evidence that four mapped loci in chromosomes 2, 4, and 16 influence hypertension in the SHR

Physiological Genomics ◽

10.1152/physiolgenomics.90299.2008 ◽

2009 ◽

Vol 37 (1) ◽

pp. 52-57 ◽

Cited By ~ 15

Author(s):

Ivy Aneas ◽

Mariliza V. Rodrigues ◽

Bianca A. Pauletti ◽

Gustavo J. J. Silva ◽

Renata Carmona ◽

...

Keyword(s):

Salt Intake ◽

Spontaneously Hypertensive Rat ◽

High Salt ◽

Brown Norway ◽

Chromosome 4 ◽

Chromosome 16 ◽

Salt Loading ◽

Norway Rat ◽

Spontaneously Hypertensive ◽

High Salt Intake

To dissect the genetic architecture controlling blood pressure (BP) regulation in the spontaneously hypertensive rat (SHR) we derived congenic rat strains for four previously mapped BP quantitative trait loci (QTLs) in chromosomes 2, 4, and 16. Target chromosomal regions from the Brown Norway rat (BN) averaging 13–29 cM were introgressed by marker-assisted breeding onto the SHR genome in 12 or 13 generations. Under normal salt intake, QTLs on chromosomes 2a, 2c, and 4 were associated with significant changes in systolic BP (13, 20, and 15 mmHg, respectively), whereas the QTL on chromosome 16 had no measurable effect. On high salt intake (1% NaCl in drinking water for 2 wk), the chromosome 16 QTL had a marked impact on SBP, as did the QTLs on chromosome 2a and 2c (18, 17, and 19 mmHg, respectively), but not the QTL on chromosome 4. Thus these four QTLs affected BP phenotypes differently: 1) in the presence of high salt intake (chromosome 16), 2) only associated with normal salt intake (chromosome 4), and 3) regardless of salt intake (chromosome 2c and 2a). Moreover, salt sensitivity was abrogated in congenics SHR.BN2a and SHR.BN16. Finally, we provide evidence for the influence of genetic background on the expression of the mapped QTLs individually or as a group. Collectively, these data reveal previously unsuspected nuances of the physiological roles of each of the four mapped BP QTLs in the SHR under basal and/or salt loading conditions unforeseen by the analysis of the F2 cross.

Download Full-text

Expression and function of COX isoforms in renal medulla: evidence for regulation of salt sensitivity and blood pressure

AJP Renal Physiology ◽

10.1152/ajprenal.00232.2005 ◽

2006 ◽

Vol 290 (2) ◽

pp. F542-F549 ◽

Cited By ~ 54

Author(s):

Wenling Ye ◽

Hui Zhang ◽

Elaine Hillas ◽

Donald E. Kohan ◽

R. Lance Miller ◽

...

Keyword(s):

Blood Pressure ◽

Salt Intake ◽

Renal Medulla ◽

Interstitial Cells ◽

High Salt ◽

Salt Loading ◽

Arterial Blood ◽

High Salt Intake ◽

Cox 2 ◽

Cox 1

Expression of cyclooxygenase (COX)-2, but not COX-1, in the renal medulla is stimulated by chronic salt loading; yet the functional implication of this phenomenon is incompletely understood. The present study examined the cellular localization and antihypertensive function of high-salt-induced COX-2 expression in the renal medulla, with a parallel assessment of the function of COX-1. COX-2 protein expression in response to high-salt loading, assessed by immunostaining, was found predominantly in inner medullary interstitial cells, whereas COX-1 protein was abundant in collecting duct (CD) and inner medullary interstitial cells and was not affected by high salt. We compared mRNA expressions of COX-1 and COX-2 in CD vs. non-CD cells isolated from aquaporin 2-green fluorescent protein transgenic mice. A low level of COX-2 mRNA, but a high level of COX-1 mRNA, as determined by real-time RT-PCR, was detected in CD compared with non-CD segments. During high-salt intake, chronic infusions of the COX-2 blocker NS-398 and the COX-1 blocker SC-560 into the renal medulla of Sprague-Dawley rats for 5 days induced ∼30- and 15-mmHg increases in mean arterial pressure, respectively. During similar high-salt intake, COX-1 knockout mice exhibited a gradual, but significant, increase in systolic blood pressure that was associated with a marked suppression of urinary PGE2 excretion. Therefore, we conclude that the two COX isoforms in the renal medulla play a similar role in the stabilization of arterial blood pressure during salt loading.

Download Full-text