The Relationship Between Urine Uromodulin and Blood Pressure Changes: The DASH-Sodium Trial

Abstract BACKGROUND Uromodulin modulates the sodium-potassium-two-chloride transporter in the thick ascending limb of the loop of Henle, and its overexpression in murine models leads to salt-induced hypertension. We hypothesized that individuals with higher baseline levels of urine uromodulin would have a greater increase in systolic blood pressure (SBP) for the same increase in sodium compared with those with lower uromodulin levels. METHODS We used data from 157 subjects randomized to the control diet of the Dietary Approaches to Stop Hypertension (DASH)-Sodium trial who were assigned to 30 days of low (1,500 mg/d), medium (2,400 mg/d), and high salt (3,300 mg/d) diets in random order. Blood pressure was measured prerandomization and then weekly during each feeding period. We evaluated the association of prerandomization urine uromodulin with change in SBP between diets, as measured at the end of each feeding period, using multivariable linear regression. RESULTS Baseline urine uromodulin stratified by tertiles was ≤17.64, 17.65–31.97, and ≥31.98 µg/ml. Across the tertiles, there were no significant differences in SBP at baseline, nor was there a differential effect of sodium diet on SBP across tertiles (low to high, P = 0.81). After adjusting for age, sex, body mass index, and race, uromodulin levels were not significantly associated with SBP change from low to high sodium diet (P = 0.42). CONCLUSIONS In a randomized trial of different levels of salt intake, higher urine uromodulin levels were not associated with a greater increase in blood pressure in response to high salt intake.

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Abstract P332: Urine Uromodulin Does Not Alter the Relationship Between Salt Intake and Blood Pressure: The DASH-Sodium Trial

Circulation ◽

10.1161/circ.141.suppl_1.p332 ◽

2020 ◽

Vol 141 (Suppl_1) ◽

Author(s):

Christine Bakhoum ◽

Cheryl A Anderson ◽

Stephen Juraschek ◽

Casey M Rebholz ◽

Lawrence J Appel ◽

...

Keyword(s):

Blood Pressure ◽

Systolic Blood Pressure ◽

Salt Intake ◽

Association Studies ◽

High Salt ◽

Thick Ascending Limb ◽

Genome Wide Association Studies ◽

Feeding Period ◽

Sodium Diet ◽

High Salt Intake

Introduction: Genome-wide association studies have revealed susceptibility variants for hypertension in the UMOD gene. The encoded protein, uromodulin, modulates NKCC2 transporter in the thick ascending limb of the loop of Henle, and its overexpression in murine models leads to salt-induced hypertension. Hypothesis: Individuals with higher levels of urine uromodulin will have a greater increase in systolic blood pressure compared to those with lower uromodulin levels. Methods: We used data from 157 subjects in the control diet of the DASH-Sodium trial assigned to 30 days of low (1500 mg/d), medium (2400 mg/d), and high salt (3300 mg/d) diets in random order. Blood pressure was measured at baseline and at 5 visits during the last 9 days of each feeding period. We evaluated the association of urine uromodulin with change in systolic blood pressure between diets, as measured by the average at the end of each feeding period, using multivariable linear regression. Results: Baseline urine uromodulin stratified by tertiles was less than or equal to 17.64, 17.65 - 31.97, and greater than or equal to 31.98 μg/mL (overall mean 30.0 μg/mL, SEM 1.85 μg/mL). Across the tertiles, there were no significant differences in systolic blood pressure (SBP) at baseline, nor was there a differential effect of sodium diet on SBP across tertiles (low to high p = 0.81, Figure). After adjusting for age, sex, BMI, and race, uromodulin levels were not significantly associated with SBP change from low to high sodium diet (β = -0.68 per 10 μg/mL increase in urine uromodulin, p = 0.28). Conclusion: In a randomized trial of different levels of salt intake, higher urine uromodulin levels were not associated with a greater increase in blood pressure in response to high salt intake. Further human studies are needed to evaluate the findings seen in animal models, where the expression of higher levels of urine uromodulin has been associated with salt sensitive hypertension.

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Abstract 142: A Fructose-but Not a Glucose-enriched Diet, Induces a Salt-dependent Increase in Blood Pressure and Enhances NKCC2 Phosphorylation in Normal Rats

Hypertension ◽

10.1161/hyp.66.suppl_1.142 ◽

2015 ◽

Vol 66 (suppl_1) ◽

Author(s):

Keyona N King-Medina ◽

Emily Henson ◽

Pablo Ortiz

Keyword(s):

Blood Pressure ◽

Drinking Water ◽

Salt Intake ◽

Caloric Intake ◽

High Salt ◽

Human Consumption ◽

Thick Ascending Limb ◽

Sprague Dawley ◽

High Fructose ◽

High Salt Intake

Human consumption of fructose as a sweetener has increased in the past 30 years. High fructose intake has been implicated in the development of hypertension, diabetes, and obesity. In the US, the upper 10th percentile of the population consumes up to 40% of their caloric intake from added sugars, in which fructose represents half of these. Fructose metabolism is strikingly different from that of glucose. Yet, the effect of a fructose or glucose-enriched diet in salt handling by the kidney, affecting blood pressure, and its interaction with high salt intake has been poorly studied. In genetic models of salt-sensitive hypertension, the activity of the Na + /K + /2Cl - cotransporter (NKCC2) in the thick ascending limb (TAL) is abnormally enhanced. We hypothesized that chronic fructose in drinking water induces a salt-dependent increase in blood pressure and stimulates NKCC2 during high salt intake in normal rats. Sprague-Dawley rats were given 20% fructose or 20% glucose in drinking water for 1 week after which a high salt (HS) diet (4% Na + in chow) was started for 3 weeks. When we measured systolic blood pressure (SBP) by tail cuff plethysmography in fructose-fed and glucose-fed rats on a HS diet, only the fructose-fed rats had an increased SBP from 120±10 to 132±6 mmHg on day 7 of HS (p<0.01). SBP continued to increase up to 144±18 mmHg after 3 weeks (p<0.01 vs glucose). Fructose or glucose alone did not increase SBP after 4 weeks. We then repeated the protocol using radiotelemetry to monitor the blood pressure (BP). In rats fed fructose, by day 5 of HS the SBP increased by 12±3 mmHg (p<0.02) and SBP remained elevated for 3 weeks (delta: 10±2.5 mmHg, n=3). In rats fed glucose, a HS diet did not significantly change SBP for 3 weeks (n=5). Moreover, NKCC2 activity in the TAL is enhanced by phosphorylation at Thr96, 101. We found that NKCC2 phosphorylation was higher in rats fed fructose plus HS (p<0.02) but not in rats fed glucose plus HS for 3 weeks (HS: 100, fructose+HS: 250±40%, glucose+HS: 95±10%). Therefore, we conclude that a high fructose (but not a glucose) diet in normal rats induces a salt-dependent increase in BP independently from caloric intake. Thus, the increase in BP may in part be due to the stimulation of NKCC2 phosphorylation in the TAL by fructose.

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Blunted hypertensive effect of combined fructose and high-salt diet in gene-targeted mice lacking functional serum- and glucocorticoid-inducible kinase SGK1

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00382.2005 ◽

2006 ◽

Vol 290 (4) ◽

pp. R935-R944 ◽

Cited By ~ 51

Author(s):

Dan Yang Huang ◽

Krishna M. Boini ◽

Björn Friedrich ◽

Marco Metzger ◽

Lothar Just ◽

...

Keyword(s):

Blood Pressure ◽

Flow Rate ◽

Fluid Intake ◽

Salt Intake ◽

Control Diet ◽

High Salt ◽

Urinary Flow Rate ◽

Urinary Flow ◽

High Salt Intake

Serum- and glucocorticoid-inducible kinase (SGK1) is transcriptionally upregulated by mineralocorticoids and activated by insulin. The kinase stimulates the renal epithelial Na+ channel and may thus participate in blood pressure regulation. Hyperinsulinemia is triggered by dietary fructose, which sensitizes blood pressure for salt intake. The role of SGK1 in hypertensive effects of combined fructose and high-salt intake was thus explored in SGK1 knockout mice ( sgk1−/−) and their wild-type littermates ( sgk1+/+). Renal SGK1 transcript levels of sgk1+/+ mice were significantly elevated after fructose diet. Under control diet, fluid intake, urinary flow rate, urinary Na+, K+, and Cl− excretion, and blood pressure were similar in sgk1−/− and sgk1+/+ mice. Addition of 10% fructose to drinking water increased fluid intake and urinary flow rate in both genotypes, and did not significantly alter urinary Na+, K+, and Cl− output in either genotype. Additional high NaCl diet (4% NaCl) did not significantly alter fluid intake and urine volume but markedly increased urinary output of Na+ and Cl−, approaching values significantly ( P < 0.05) larger in sgk1−/− than in sgk1+/+ mice (Na+: 2,572 ± 462 vs. 1,428 ± 236; Cl−: 2,364 ± 388 vs. 1,379 ± 225 μmol/24 h). Blood pressure was similar in sgk1+/+ and sgk1−/− mice at control diet or fructose alone but increased only in sgk1+/+ mice (115 ± 1 vs. 103 ± 0.7 mmHg, P < 0.05) after combined fructose and high-salt intake. Acute intravenous insulin infusion (during glucose clamp) caused antinatriuresis in sgk1+/+ mice, an effect significantly blunted in sgk1−/− mice. The observations reveal a pivotal role of SGK1 in insulin-mediated sodium retention and the salt-sensitizing hypertensive effect of high fructose intake.

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Soybean proteins counteract heart remodeling in wistar rats fed a high sodium chloride diet

Nephrology (Saint-Petersburg) ◽

10.36485/1561-6274-2019-236-92-99 ◽

2019 ◽

Vol 23 (6) ◽

pp. 92-99

Author(s):

I. G. Kayukov ◽

O. N. Beresneva ◽

M. M. Parastaeva ◽

G. T. Ivanova ◽

A. N. Kulikov ◽

...

Keyword(s):

Blood Pressure ◽

Sodium Chloride ◽

Cardiac Remodeling ◽

Wistar Rats ◽

Salt Intake ◽

Left Ventricular ◽

High Salt ◽

Soy Proteins ◽

High Sodium ◽

Heart Remodeling

BACKGROUND. Increased salt intake is associated with a number of cardiovascular events, including increased blood pressure (BP) and the development of left ventricular hypertrophy (LVH). However, there is much evidence that a high content of sodium chloride in the diet does not always lead to an increase in BP, but almost inevitably causes cardiac remodeling, in particular, LVH. Many aspects of myocardial remodeling induced by high sodium content in the food have not been studied enough. THE AIM of the study was to trace the echocardiographic changes in Wistar rats fed the high salt ration and the high salt ration supplemented with soy proteins.MATERIAL AND METHODS. Echocardiography and BP measurements were performed on male Wistar rats, divided into three groups. The first (control; n = 8) included rats that received standard laboratory feed (20.16 % animal protein and 0.34 % NaCl); the second (n = 10) – animals that received standard feed and 8 % NaCl (high salt ration). The third group (n = 10) consisted of rats who consumed a low-protein diet containing 10 % soy protein isolate (SUPRO 760) and 8 % NaCl. The follow-up period was 2 and 4 months.THE RESULTS of the study showed that: (1) the intake of a large amount of salt with a diet does not necessarily lead to the formation of arterial hypertension; (2) despite the absence of a distinct increase in BP, under these conditions signs of cardiac remodeling, in particular, LVH, appear rather quickly; (3) supplementing a high-salt diet with soy isolates counteracts the development of LVH.CONCLUSION. High salt intake with food can cause heart remodeling, regardless of blood pressure, while soy proteins can counteract this process.

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High salt intake: detrimental not only for blood pressure, but also for bone health?

Endocrine ◽

10.1007/s12020-015-0626-6 ◽

2015 ◽

Vol 49 (3) ◽

pp. 580-582 ◽

Cited By ~ 2

Author(s):

Thomas Remer

Keyword(s):

Blood Pressure ◽

Bone Health ◽

Salt Intake ◽

High Salt ◽

High Salt Intake

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Abstract 040: Upregulation Of Cyp Epoxygenase In The Connecting Tubule(cnt)/cortical Collecting Duct (ccd) Is Essential For High Potassium (k) Intake-induced Antihypertensive Effect

Circulation Research ◽

10.1161/res.113.suppl_1.a040 ◽

2013 ◽

Vol 113 (suppl_1) ◽

Author(s):

Daohong Lin ◽

Chengbiao Zhang ◽

Lijun Wang ◽

Wenhui Wang

Keyword(s):

Antihypertensive Effect ◽

Salt Intake ◽

Collecting Duct ◽

Smooth Muscles ◽

High Salt ◽

Conditional Knockout ◽

Na Channel ◽

Thick Ascending Limb ◽

High K ◽

High Salt Intake

Cyp epoxygenase is responsible for metabolizing arachidonic acid to epoxyeicosatrienoic acid (EET) in the kidney and vascular tissues. EET has been shown to cause vasodilation by stimulating Ca 2+ -activated K channels in vascular smooth muscles and to have natriuretic effect by inhibiting the epithelial Na channel (ENaC) in the kidney. In the present study we used real time PCR technique to examine the effect of high salt intake or high K intake on Cyp2c44 (a major type of Cyp epoxygenase in the mouse kidney) in the proximal tubule (PxT), thick ascending limb (TAL), distal convoluted tubule (DCT) and the CNT/CCD. An increase in dietary Na content stimulates the expression of Cyp2c4 in TAL, DCT and CNT/CCD but not in PxT while an increase in dietary K intake augments the expression of Cyp2c44 only in DCT and CNT/CCD. Neither high salt intake nor high K intake has a significant effect on the blood pressure (BP) in wt mice. However, high K intake increased BP in CNT/CCD specific conditional knockout (KO) mice. In contrast, the high Na intake did not significantly increase the BP in those KO mice. This suggests that Cyp2c44 in the CNT/CCD plays a key role in preventing hypertension induced by increasing dietary K intake. Administration of amiloride (a ENaC inhibitor) restored the normal BP in KO mice fed high K diet, suggesting that down-regulation of Cyp2c44 may enhance the Na absorption in the CNT/CCD. This notion was also supported by metabolic cage study demonstrating that renal Na excretion was compromised in KO mice. We conclude that Cyp2c44 plays a key role in stimulating renal Na excretion during increasing dietary K intake and that Cyp-epoxygenase is required for antihypertensive effect induced by high K intake.

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Relationship Between Salt Intake and Blood Pressure in Hypertensive Patients in Beijing

American Journal of Hypertension ◽

10.1093/ajh/hpaa009 ◽

2020 ◽

Vol 33 (4) ◽

pp. 371-371

Author(s):

Hong-yi Wang ◽

Yong-jie He ◽

Wei Li ◽

Fan Yang ◽

Ning-ling Sun

Keyword(s):

Blood Pressure ◽

Ambulatory Blood Pressure ◽

Salt Intake ◽

Blood Pressure Monitoring ◽

Urinary Sodium Excretion ◽

High Salt ◽

Pressure Monitoring ◽

Hypertensive Patients ◽

High Salt Intake ◽

Tertiary Hospitals

Abstract Background To survey the relationship between salt intake and blood pressure in hypertensive patients in Beijing. Methods A cross-sectional survey was used. Essential hypertensive patients were enrolled and divided into three groups (low, medium, and high salt intake) according to their 24 h urinary sodium excretion, which was used to access the salt intake. Blood pressure was measured through office measurement and ambulatory blood pressure monitoring. Results A total of 2,241 patients were enrolled with a mean age of 59.5 ± 13.8 years, mean blood pressure of 141.1 ± 18.5/84.6 ± 12.7 mm Hg, and urinary sodium excretion of 163.9 (95% CI 160.3–167.4) mmol [equal to salt intake 9.59 (9.38–9.79) g/d]. There were 1,544 cases from tertiary hospitals and the other 697 cases from community hospitals. Patients from community hospitals took more salt than patients from tertiary hospitals. Patients with high salt intake were younger than patients with low and medium salt intake. There were more males in high salt intake group than in the other two groups. Ambulatory blood pressure monitoring showed that patients with high salt intake had higher mean blood pressure not only in daytime, but also at night. The diastolic blood pressure in patients with medium salt intake was higher than that in patients with low salt intake. Conclusions Higher salt intake was associated with higher ambulatory blood pressure in hypertensive patients. More effort should be made to lower salt intake to improve blood pressure control rate.

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High Salt Intake Augments Blood Pressure Responses During Submaximal Aerobic Exercise

Journal of the American Heart Association ◽

10.1161/jaha.120.015633 ◽

2020 ◽

Vol 9 (10) ◽

Cited By ~ 1

Author(s):

Matthew C. Babcock ◽

Austin T. Robinson ◽

Kamila U. Migdal ◽

Joseph C. Watso ◽

Christopher R. Martens ◽

...

Keyword(s):

Blood Pressure ◽

Aerobic Exercise ◽

Salt Intake ◽

High Salt ◽

High Salt Intake ◽

Submaximal Aerobic Exercise ◽

Blood Pressure Responses

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Salt-sensitive splice variant of nNOS expressed in the macula densa cells

AJP Renal Physiology ◽

10.1152/ajprenal.00650.2009 ◽

2010 ◽

Vol 298 (6) ◽

pp. F1465-F1471 ◽

Cited By ~ 38

Author(s):

Deyin Lu ◽

Yiling Fu ◽

Arnaldo Lopez-Ruiz ◽

Rui Zhang ◽

Ramiro Juncos ◽

...

Keyword(s):

Salt Intake ◽

Splice Variants ◽

Macula Densa ◽

High Salt ◽

Tubuloglomerular Feedback ◽

No Production ◽

Thick Ascending Limb ◽

High Salt Diet ◽

Salt Diet ◽

High Salt Intake

Neuronal nitric oxide synthase (nNOS), which is abundantly expressed in the macula densa cells, attenuates tubuloglomerular feedback (TGF). We hypothesize that splice variants of nNOS are expressed in the macula densa, and nNOS-β is a salt-sensitive isoform that modulates TGF. Sprague-Dawley rats received a low-, normal-, or high-salt diet for 10 days and levels of the nNOS-α, nNOS-β, and nNOS-γ were measured in the macula densa cells isolated with laser capture microdissection. Three splice variants of nNOS, α-, β-, and γ-mRNAs, were detected in the macula densa cells. After 10 days of high-salt intake, nNOS-α decreased markedly, whereas nNOS-β increased two- to threefold in the macula densa measured with real-time PCR and in the renal cortex measured with Western blot. NO production in the macula densa was measured in the perfused thick ascending limb with an intact macula densa plaque with a fluorescent dye DAF-FM. When the tubular perfusate was switched from 10 to 80 mM NaCl, a maneuver to induce TGF, NO production by the macula densa was increased by 38 ± 3% in normal-salt rats and 52 ± 6% ( P < 0.05) in the high-salt group. We found 1) macula densa cells express nNOS-α, nNOS-β, and nNOS-γ, 2) a high-salt diet enhances nNOS-β, and 3) TGF-induced NO generation from macula densa is enhanced in high-salt diet possibly from nNOS-β. In conclusion, we found that the splice variants of nNOS expressed in macula densa cells were α-, β-, and γ-isoforms and propose that enhanced level of nNOS-β during high-salt intake may contribute to macula densa NO production and help attenuate TGF.

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