Possible Involvement of Up-regulated Salt Dependent Glucose Transporter-5 (SGLT5) in High-fructose Diet-induced Hypertension

Abstract Excessive fructose intake causes a variety of adverse conditions (e.g., obesity, hepatic steatosis, insulin resistance and uric acid overproduction). Particularly, high fructose-induced hypertension is the most common and significant pathological setting, however, its underlying mechanisms are not established. We investigated these mechanisms in 7-week-old male SD rats fed a diet containing 60% glucose (GLU) or 60% fructose (FRU) for 3, 6, or 12 weeks. Daily food consumption was measured to avoid between-group discrepancies in caloric/salt intake, adjusting for feeding amounts. The FRU rats' mean blood pressure was significantly higher and fractional sodium excretion (FENa) was significantly lower, indicating that the high-fructose diet caused salt retention. The FRU rats' kidney weight and glomerular surface area were greater, suggesting that the high-fructose diet induced an increase in extracellular fluid volume. The GLUT5 and ketohexokinase expressions, an enzyme required for fructose metabolism, were up-regulated in FRU. Cortical ATP levels were significantly lower in FRU, which might indicate ATP consumption due to fructose metabolism. Unlike previous reports, the high-fructose diet did not affect NHE3 expression. A gene chip analysis conducted to identify susceptible molecules revealed that only Slc5a10 (corresponding to SGLT5) in FRU showed >2-fold up-regulation versus GLU. RT-PCR and in situ hybridization confirmed the SGLT5 up-regulation. Our findings may indicate that the high-fructose diet increased sodium reabsorption principally through up-regulated SGLT5, finally causing salt-sensitive hypertension.

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Epithelial Sodium Channel and Salt-Sensitive Hypertension

Hypertension ◽

10.1161/hypertensionaha.120.14481 ◽

2021 ◽

Vol 77 (3) ◽

pp. 759-767

Author(s):

Stephanie M. Mutchler ◽

Annet Kirabo ◽

Thomas R. Kleyman

Keyword(s):

Blood Pressure ◽

Sodium Channel ◽

Salt Intake ◽

Extracellular Fluid ◽

Pressure Rise ◽

Epithelial Sodium Channel ◽

Sodium Reabsorption ◽

High Salt Intake ◽

Salt Sensitive Hypertension

The development of high blood pressure is influenced by genetic and environmental factors, with high salt intake being a known environmental contributor. Humans display a spectrum of sodium-sensitivity, with some individuals displaying a significant blood pressure rise in response to increased sodium intake while others experience almost no change. These differences are, in part, attributable to genetic variation in pathways involved in sodium handling and excretion. ENaC (epithelial sodium channel) is one of the key transporters responsible for the reabsorption of sodium in the distal nephron. This channel has an important role in the regulation of extracellular fluid volume and consequently blood pressure. Herein, we review the role of ENaC in the development of salt-sensitive hypertension, and present mechanistic insights into the regulation of ENaC activity and how it may accelerate sodium-induced damage and dysfunction. We discuss the traditional role of ENaC in renal sodium reabsorption and review work addressing ENaC expression and function in the brain, vasculature, and immune cells, and how this has expanded the implications for its role in the initiation and progression of salt-sensitive hypertension.

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Abstract 328: High Fructose but not High Glucose Intake Induces Salt-sensitive Hypertension and Enhances NKCC2 Phosphorylation in Normal Rats.

Hypertension ◽

10.1161/hyp.64.suppl_1.328 ◽

2014 ◽

Vol 64 (suppl_1) ◽

Author(s):

Emily Henson ◽

Gustavo Ares ◽

Mohammed Haque ◽

Pablo Ortiz

Keyword(s):

Blood Pressure ◽

Drinking Water ◽

Salt Intake ◽

High Salt ◽

Sprague Dawley ◽

High Fructose Diet ◽

Fructose Intake ◽

Sprague Dawley Rats ◽

High Fructose ◽

Salt Sensitive Hypertension

Consumption of fructose as a sweetener has increased in the past three decades. A high-fructose diet has been implicated in the epidemic of diabetes, obesity, and hypertension. A third of the US population consumes 20-40% of their caloric intake from added sugars, with half of those calories from fructose. Little is known about the role of high fructose intake in renal salt handling and blood pressure regulation during high salt intake. In genetic models of salt-sensitive hypertension, the Na/K/2Cl cotransporter NKCC2 plays an important role by reabsorbing NaCl in the thick ascending limb (TAL). We hypothesized that 20% fructose in drinking water stimulates NKCC2 and sensitizes normal rats to high salt induced hypertension. Adult Sprague-Dawley rats were given 20% fructose or 20% glucose in drinking water for 1 week after which a high salt diet (4% Na in chow) was started. Systolic blood pressure (SBP) was measured every other day by tail cuff after 2 weeks of training. After one week of fructose or glucose alone, SBP did not change. In rats fed fructose, adding a 4% NaCl diet increased SBP to 128±6 mmHg by day 2 (p<0.01 vs glucose) and continued to increase up to 144±18 mmHg after 2 weeks on high salt (p<0.01 vs baseline; p<0.01 vs glucose). In glucose-fed rats high salt did not increase SBP (from 122±6 to 116±9 mmHg). 20% fructose alone for 3 weeks, or high salt alone did not change SBP. NKCC2 phosphorylation at Thr96,101 is associated with enhanced TAL NaCl reabsorption. We found that NKCC2 phosphorylation at Thr96,101 (normalized to total NKCC2) was higher in TALs isolated from rats fed fructose plus salt for 2 weeks compared to high salt alone (high-salt: 100%; fructose + high-salt: 250±40%, p<0.05). We concluded that a high fructose but not high glucose diet induces salt-sensitive hypertension in Sprague Dawley rats. This effect occurs within 1 week of a high fructose diet. In addition, a high fructose diet may stimulate NKCC2 activity by enhancing its phosphorylation. These data suggest that high fructose intake may increase blood pressure by preventing appropriate renal NaCl excretion during high dietary salt intake.

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Sex differences in renal and metabolic responses to a high-fructose diet in mice

AJP Renal Physiology ◽

10.1152/ajprenal.00403.2014 ◽

2015 ◽

Vol 308 (5) ◽

pp. F400-F410 ◽

Cited By ~ 17

Author(s):

Nikhil Sharma ◽

Lijun Li ◽

C. M. Ecelbarger

Keyword(s):

Sex Differences ◽

Glucose Transporter ◽

Collecting Duct ◽

Urine Volume ◽

Thick Ascending Limb ◽

Male Mice ◽

Male And Female ◽

Female Mice ◽

High Fructose Diet ◽

High Fructose

High fructose intake has been associated with increased incidences of renal disease and hypertension, among other pathologies. Most fructose is cleared by the portal system and metabolized in the liver; however, systemic levels of fructose can rise with increased consumption. We tested whether there were sex differences in the renal responses to a high-fructose diet in mice. Two-month-old male and female C57BL6/129/SV mice ( n = 6 mice per sex per treatment) were randomized to receive control or high-fructose (65% by weight) diets as pelleted chow ad libitum for 3 mo. Fructose feeding did not significantly affect body weight but led to a 19% and 10% increase in kidney weight in male and female mice, respectively. In male mice, fructose increased the expression (∼50%) of renal cortical proteins involved in metabolism, including glucose transporter 5 (facilitative fructose transporter), ketohexokinase, and the insulin receptor (β-subunit). Female mice had lower basal levels of glucose transporter 5, which were unresponsive to fructose. However, female mice had increased urine volume and plasma K+ and decreased plasma Na+ with fructose, whereas male mice were less affected. Likewise, female mice showed a two- to threefold reduction in the expression Na+-K+-2Cl− cotransporter 2 in the thick ascending limb and aquaporin-2 in the collecting duct with fructose relative to female control mice, whereas male mice had no change. Overall, our results support greater proximal metabolism of fructose in male animals and greater distal tubule/collecting duct (electrolyte homeostasis) alterations in female animals. These sex differences may be important determinants of the specific nature of pathologies that develop in association with high fructose consumption.

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A Mouse Model for Liddle's Syndrome

Journal of the American Society of Nephrology ◽

10.1681/asn.v10122527 ◽

1999 ◽

Vol 10 (12) ◽

pp. 2527-2533 ◽

Cited By ~ 2

Author(s):

SYLVAIN PRADERVAND ◽

QING WANG ◽

MICHEL BURNIER ◽

FRIEDRICH BEERMANN ◽

JEAN DANIEL HORISBERGER ◽

...

Keyword(s):

Mouse Model ◽

Salt Intake ◽

Sodium Reabsorption ◽

Dietary Salt ◽

Human Form ◽

Dominant Form ◽

Liddle’S Syndrome ◽

High Salt Intake ◽

Liddle's Syndrome ◽

Salt Sensitive Hypertension

Abstract. Liddle's syndrome (or pseudoaldosteronism) is an autosomal dominant form of salt-sensitive hypertension, due to abnormal sodium transport by the renal tubule. To study the pathophysiology of salt sensitivity, a mouse model for Liddle's syndrome has been generated by Cre/loxP-mediated recombination. Under normal salt diet, mice heterozygous (L/+) and homozygous (L/L) for Liddle mutation (L) develop normally during the first 3 mo of life. In these mice, BP is not different from wild type despite evidence for increased sodium reabsorption in distal colon and low plasma aldosterone, suggesting chronic hypervolemia. Under high salt intake, the Liddle mice develop high BP, metabolic alkalosis, and hypokalemia accompanied by cardiac and renal hypertrophy. This animal model reproduces to a large extent a human form of salt-sensitive hypertension and establishes a causal relationship between dietary salt, a gene expressed in kidney and hypertension.

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Abstract 296: Norepinephrine Evoked Salt-Sensitive Hypertension Results in Impaired NCC Function, but Not Expression

Hypertension ◽

10.1161/hyp.62.suppl_1.a296 ◽

2013 ◽

Vol 62 (suppl_1) ◽

Author(s):

Kathryn Walsh ◽

Sarah Mahne ◽

Jill T Kuwabara ◽

Richard D Wainford

Keyword(s):

Salt Intake ◽

Pcr Analysis ◽

Kidney Cortex ◽

Sprague Dawley ◽

Sodium Homeostasis ◽

Sd Rats ◽

High Salt Intake ◽

Induced Hypertension ◽

Salt Sensitive Hypertension ◽

The Impact

Aim: Recent controversial studies have proposed that excess norepinephrine (NE) evokes impaired NCC regulation to drive salt-sensitive hypertension. The following studies examine the impact of excess NE on salt-sensitivity and sodium homeostasis in conscious Sprague-Dawley (SD) rats. Methods: Naïve male SD rats, rats receiving a s.c. vehicle infusion (DMSO/Saline, 50:50), or rats receiving a s.c. NE infusion (600ng/min) were fed a 0.4% (NS) or 8% NaCl (HS) diet for 14 days. Additional rats received s.c. hydrochlorothiazide (HCTZ, 4mg/kg/d) in combination with NE (600ng/min) for 14 days on HS. On day 14, MAP, FENa, MAP response to i.v. hexamethonium (30mg/kg), and peak natriuresis to i.v. HCTZ (2mg/kg) infusion were assessed (N=4/gp). A PCR array examining NCC associated genes was performed on kidney cortex samples from each group. Results: NE increased MAP, FENa and vascular sympathetic tone (MAP [mmHg] NS 127±2, NE+NS 151±3, p<0.05). We observed no difference between the naïve and vehicle rats. A HS diet exacerbated NE induced hypertension (MAP [mmHg] HS 129±2, NE+HS 172±4, p<0.05), reduced FENa and prevented a salt stimulated reduction in HCTZ evoked natriuresis. Co-infusion of HCTZ with NE abolished the salt-sensitive component of NE-induced hypertension (MAP [mmHg] NE+HCTZ+HS: 152±3, p<0.05). PCR analysis revealed a significant increase in serine/threonine kinase 39 (0.83-fold increase vs. Naïve SD on NS) mRNA in NE+HS rats. We did not see NE or HS evoked changes in OSR-1, WNK4 or NCC mRNA in any group. Conclusion: The results support previous studies in mice and highlight an opposing interaction between excess NE and high salt intake on sodium homeostasis which exacerbated NE-induced hypertension via a mechanism independent of NE-mediated vascular constriction. Physiologically, our results show impaired NCC function, supporting previous data. In contrast, we failed to detect elevated NCC or WNK4 mRNA in response to NE infusion contradicting data generated in mice and suggesting a key role of altered NCC phosphorylation versus expression in NE treated rats.

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Role of the Kidneys in Resistant Hypertension

International Journal of Hypertension ◽

10.4061/2011/143471 ◽

2011 ◽

Vol 2011 ◽

pp. 1-8 ◽

Cited By ~ 23

Author(s):

Z. Khawaja ◽

C. S. Wilcox

Keyword(s):

Resistant Hypertension ◽

Salt Intake ◽

Antihypertensive Drugs ◽

Critical Role ◽

Diuretic Therapy ◽

Extracellular Fluid ◽

Treatment Resistance ◽

Sodium Reabsorption ◽

Dietary Salt ◽

Dietary Salt Intake

Resistant hypertension is a failure to achieve goal BP (<140/90 mm Hg for the overall population and <130/80 mm Hg for those with diabetes mellitus or chronic kidney disease) in a patient who adheres to maximum tolerated doses of 3 antihypertensive drugs including a diuretic. The kidneys play a critical role in long-term regulation of blood pressure. Blunted pressure natriuresis, with resultant increase in extracellular fluid volume, is an important cause of resistant hypertension. Activation of the renin-angiotensin-aldosterone system, increased renal sympathetic nervous system activity and increased sodium reabsorption are important renal mechanisms. Successful treatment requires identification and reversal of lifestyle factors or drugs contributing to treatment resistance, diagnosis and appropriate treatment of secondary causes of hypertension, use of effective multidrug regimens and optimization of diuretic therapy. Since inappropriate renal salt retention underlies most cases of drug-resistant hypertension, the therapeutic focus should be on improving salt depleting therapy by assessing and, if necessary, reducing dietary salt intake, optimizing diuretic therapy, and adding a mineralocorticoid antagonist if there are no contraindications.

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Inulin supplementation prevents high fructose diet-induced hypertension in rats

Clinical Nutrition ◽

10.1016/j.clnu.2008.01.015 ◽

2008 ◽

Vol 27 (2) ◽

pp. 276-282 ◽

Cited By ~ 29

Author(s):

Marie-Hélène Rault-Nania ◽

Céline Demougeot ◽

Elyett Gueux ◽

Alain Berthelot ◽

Stanislaw Dzimira ◽

...

Keyword(s):

High Fructose Diet ◽

High Fructose ◽

Induced Hypertension

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Mechanisms of blood pressure salt sensitivity: new insights from mathematical modeling

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00353.2016 ◽

2017 ◽

Vol 312 (4) ◽

pp. R451-R466 ◽

Cited By ~ 18

Author(s):

John S. Clemmer ◽

W. Andrew Pruett ◽

Thomas G. Coleman ◽

John E. Hall ◽

Robert L. Hester

Keyword(s):

Mathematical Modeling ◽

Blood Pressure ◽

Salt Intake ◽

Peripheral Resistance ◽

Extracellular Fluid ◽

Physiological Model ◽

Salt Sensitivity ◽

Sodium Reabsorption ◽

Ang Ii ◽

Bilateral Renal Artery Stenosis

Mathematical modeling is an important tool for understanding quantitative relationships among components of complex physiological systems and for testing competing hypotheses. We used HumMod, a large physiological model, to test hypotheses of blood pressure (BP) salt sensitivity. Systemic hemodynamics, renal, and neurohormonal responses to chronic changes in salt intake were examined during normal renal function, fixed low or high plasma angiotensin II (ANG II) levels, bilateral renal artery stenosis, increased renal sympathetic nerve activity (RSNA), and decreased nephron numbers. Simulations were run for 4 wk at salt intakes ranging from 30 to 1,000 mmol/day. Reducing functional kidney mass or fixing ANG II increased salt sensitivity. Salt sensitivity, associated with inability of ANG II to respond to changes in salt intake, occurred with smaller changes in renal blood flow but greater changes in glomerular filtration rate, renal sodium reabsorption, and total peripheral resistance (TPR). However, clamping TPR at normal or high levels had no major effect on salt sensitivity. There were no clear relationships between BP salt sensitivity and renal vascular resistance or extracellular fluid volume. Our robust mathematical model of cardiovascular, renal, endocrine, and sympathetic nervous system physiology supports the hypothesis that specific types of kidney dysfunction, associated with impaired regulation of ANG II or increased tubular sodium reabsorption, contribute to BP salt sensitivity. However, increased preglomerular resistance, increased RSNA, or inability to decrease TPR does not appear to influence salt sensitivity. This model provides a platform for testing competing concepts of long-term BP control during changes in salt intake.

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Sympathetic Regulation of the NCC (Sodium Chloride Cotransporter) in Dahl Salt–Sensitive Hypertension

Hypertension ◽

10.1161/hypertensionaha.120.15928 ◽

2020 ◽

Vol 76 (5) ◽

pp. 1461-1469

Author(s):

Franco Puleo ◽

Kiyoung Kim ◽

Alissa A. Frame ◽

Kathryn R. Walsh ◽

Mohammed Z. Ferdaus ◽

...

Keyword(s):

Blood Pressure ◽

Sodium Chloride ◽

Salt Intake ◽

High Salt ◽

Sodium Reabsorption ◽

Sprague Dawley ◽

Sodium Chloride Cotransporter ◽

High Salt Intake ◽

Sympathetic Regulation ◽

Salt Sensitive Hypertension

Increased sympathoexcitation and renal sodium retention during high salt intake are hallmarks of the salt sensitivity of blood pressure. The mechanism(s) by which excessive sympathetic nervous system release of norepinephrine influences renal sodium reabsorption is unclear. However, studies demonstrate that norepinephrine can stimulate the activity of the NCC (sodium chloride cotransporter) and promote the development of SSH (salt-sensitive hypertension). The adrenergic signaling pathways governing NCC activity remain a significant source of controversy with opposing studies suggesting a central role of upstream α 1 - and β-adrenoceptors in the canonical regulatory pathway involving WNKs (with-no-lysine kinases), SPAK (STE20/SPS1-related proline alanine-rich kinase), and OxSR1 (oxidative stress response 1). In our previous study, α 1 -adrenoceptor antagonism in norepinephrine-infused male Sprague-Dawley rats prevented the development of norepinephrine-evoked SSH in part by suppressing NCC activity and expression. In these studies, we used selective adrenoceptor antagonism in male Dahl salt–sensitive rats to test the hypothesis that norepinephrine-mediated activation of the NCC in Dahl SSH occurs via an α 1 -adrenoceptor dependent pathway. A high-salt diet evoked significant increases in NCC activity, expression, and phosphorylation in Dahl salt–sensitive rats that developed SSH. Increases were associated with a dysfunctional WNK1/4 dynamic and a failure to suppress SPAK/OxSR1 activity. α 1 -adrenoceptor antagonism initiated before high-salt intake or following the establishment of SSH attenuated blood pressure in part by suppressing NCC activity, expression, and phosphorylation. Collectively, our findings support the existence of a norepinephrine-activated α 1 -adrenoceptor gated pathway that relies on WNK/SPAK/OxSR1 signaling to regulate NCC activity in SSH.

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