Renal arteriolar Na+/Ca2+exchange in salt-sensitive hypertension

1999 ◽  
Vol 276 (4) ◽  
pp. F567-F573 ◽  
Author(s):  
Lawrence D. Nelson ◽  
M. Tino Unlap ◽  
James L. Lewis ◽  
P. Darwin Bell
Keyword(s):  
Cytosolic Calcium ◽  
Ringer Solution ◽  
High Salt ◽  
High Salt Diet ◽  
Salt Diet ◽  
Vascular Segment ◽  
Low Salt ◽  
Afferent Arterioles ◽  
Salt Sensitive Hypertension ◽  
Exchange Activity

The present studies were performed to assess Na+/Ca2+exchange activity in afferent and efferent arterioles from Dahl/Rapp salt-resistant (R) and salt-sensitive (S) rats. Renal arterioles were obtained by microdissection from S and R rats on either a low-salt (0.3% NaCl) or high-salt (8.0% NaCl) diet. On the high-salt diet, S rats become markedly hypertensive. Cytosolic calcium concentration ([Ca2+]i) was measured in fura 2-loaded arterioles bathed in a Ringer solution in which extracellular Na (Nae) was varied from 150 to 2 mM (Na was replaced with N-methyl-d-glucamine). Baseline [Ca2+]iwas similar in afferent arterioles of R and S rats fed low- and high-salt diet. The change in [Ca2+]i(Δ[Ca2+]i) during reduction in Nae from 150 to 2 mM was 80 ± 10 and 61 ± 3 nM (not significant) in afferent arterioles from R rats fed the low- and high-salt diet, respectively. In afferent arterioles from S rats on a high-salt diet, Δ[Ca2+]iduring reductions in Nae from 150 to 2 mM was attenuated (39 ± 4 nM) relative to the Δ[Ca2+]iof 79 ± 13 nM ( P < 0.05) obtained in afferent arterioles from S rats on a low-salt diet. In efferent arterioles, baseline [Ca2+]iwas similar in R and S rats fed low- and high-salt diets, and Δ[Ca2+]iin response to reduction in Naewas also not different in efferent arterioles from R and S rats fed low- or high-salt diets. Differences in regulation of the exchanger in afferent arterioles of S and R rats were assessed by determining the effects of protein kinase C (PKC) activation by phorbol 12-myristate 13-acetate (PMA, 100 nM) on Δ[Ca2+]iin response to reductions in Naefrom 150 to 2 mM. PMA increased Δ[Ca2+]iin afferent arterioles from R rats but not from S rats. These results suggest that Na+/Ca2+exchange activity is suppressed in afferent arterioles of S rats that are on a high-salt diet. In addition, there appears to be a defect in the PKC-Na+/Ca2+exchange pathway that might contribute to altered [Ca2+]iregulation in this important renal vascular segment in salt-sensitive hypertension.

Abstract 666: Monoclonal Anti-marinobufagenin Antibody Alters Profile Of Expression Of Profibrotic Genes In Aorta In Hypertensive Dahl-S Rats

Hypertension ◽  
2012 ◽  
Vol 60 (suppl_1) ◽  
Author(s):  
Olga V Fedorova ◽  
Victoria Shilova ◽  
Courtney A Marshall ◽  
Yongqing Zhang ◽  
Elin Lehrmann ◽  
...  
Keyword(s):  
Vascular Remodeling ◽  
Cardiac Fibrosis ◽  
High Salt ◽  
Tgfβ Signaling ◽  
High Salt Diet ◽  
Salt Diet ◽  
Uremic Cardiomyopathy ◽  
Low Salt ◽  
Salt Sensitive Hypertension ◽  
Paired Analysis

Elevated levels of cardiotonic steroid marinobufagenin (MBG) are implicated in pathogenesis of salt-sensitive hypertension in Dahl-S rats (DS), and induce cardiac fibrosis in rats with experimental uremic cardiomyopathy. We hypothesized that in hypertensive DS immunoneutralization of MBG with a monoclonal antibody (Mab) would affect expression of profibrotic genes and would exhibit anti-remodeling effects. We studied following groups (n=6 each): (1) DS on a low salt (0.3% NaCl) diet (LS); (2) DS on a high salt (8% NaCl) diet for 7 weeks (HS); (3) DS on a high salt diet for 7 weeks, following 3E9 anti-MBG Mab treatment for 5 days (HSAB). Levels of MBG, and levels of mRNA expression in aorta (microarray analysis, Illumina) were assessed. In HS vs. LS, BP increased by 78 mmHg (p<0.01), plasma MBG doubled (p<0.05), renal MBG excretion increased 6-fold (p<0.01), and relative weights of aortae increased (4.44±0.17 vs. 3.01±0.06 mg/mm x kg BW, p<0.01). In HSAB, BP decreased by 35 mmHg (p<0.01), and weights of aortae were markedly reduced (3.72±0.06 mg/mm x kg BW; p<0.01) vs. HS. In hypertensive DS, genes implicated in TGFβ-signaling (Table) were up-regulated, and were down-regulated following immunoneutralization of MBG. Thus, MBG participates in vascular remodeling in DS, and immunoneutralization of MBG produces an anti-remodeling effect associated with down-regulation of genes implicated in TGFβ-induced pro-fibrotic signaling. Table . Z-ratio of paired analysis of gene expression in aorta:

Abstract 160: Characterization of a Comt Knock-out Rat for Blood Pressure and Associated Phenotypes.

Hypertension ◽  
2012 ◽  
Vol 60 (suppl_1) ◽  
Author(s):  
Marc Casati ◽  
Mathew Hoffman ◽  
Rebecca Schilling ◽  
Michael Flister ◽  
Aron M Geurts ◽  
...  
Keyword(s):  
Blood Pressure ◽  
High Salt ◽  
Male Rats ◽  
Zinc Finger Nucleases ◽  
Dependent Manner ◽  
Electrolyte Excretion ◽  
High Salt Diet ◽  
Salt Diet ◽  
Low Salt ◽  
Salt Sensitive Hypertension

The catecholamine system plays an important role in the control of blood pressure and sodium excretion. One of the inactivation pathways of catecholamines is the enzymatic metabolism by catechol-O-methyltransferase (Comt). There are conflicting data regarding the role of Comt on the development of salt-sensitive hypertension, so the goal of our study was to evaluate the importance of Comt in the context of a susceptible background in vivo. Comt was mutated in the Dahl SS rat by zinc finger nucleases (ZFNs) injections targeting the sequence CTGTTCCAGGTCACCATCctcaatGGGGCATCCCAGGATCTT into SS/JrHsdMcwi (Dahl S) rat embryos. The resulting mutation was a 14-bp frameshift deletion in exon 4. Conscious blood pressure was measured by telemetry on male and female Comt knockout and wild type (WT) rats on low salt diet (0.4% NaCl) and during three weeks of high salt diet (8%NaCl). Disruption of Comt caused the protein not to express in the kidneys of the Dahl S rat. There were no differences in mean arterial pressure (MAP) between the Comt -/- and the Comt +/+ male rats at any time point during the day-night cycle at low or high salt diet. Body and organ weights, and protein and electrolyte excretion was also unchanged by the Comt mutation. On the other hand, female Comt -/- rats evidenced a higher MAP, which was only significantly higher at night during low salt diet (112±2 mmHg in Comt +/+ vs 125±2 mmHg in the Comt -/-, n>6) and both during day and night after 21 days of high-salt diet (∼ 30 mmHg difference between Comt +/+ and Comt -/- strains at both day and night). Systolic blood pressure differences were mostly responsible for the observed blood pressure diferences in females KO of the Comt gene, despite blood pressure effect, was not followed by a parallel difference in urine flow, electrolyte excretion or renal damage (protein and albumin excretion). In conclusion, we are the first ones to show that disruption of Comt enhances salt-sensitive hypertension in a gender-dependent manner.

scholarly journals Metabolic Syndrome and Salt-Sensitive Hypertension in Polygenic Obese TALLYHO/JngJ Mice: Role of Na/K-ATPase Signaling

2019 ◽  
Vol 20 (14) ◽  
pp. 3495 ◽  
Author(s):  
Yanling Yan ◽  
Jiayan Wang ◽  
Muhammad A. Chaudhry ◽  
Ying Nie ◽  
Shuyan Sun ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Renal Function ◽  
Significant Rise ◽  
Protein Carbonylation ◽  
High Salt ◽  
Kidney Cortex ◽  
High Salt Diet ◽  
Salt Diet ◽  
Salt Sensitive Hypertension

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.

Overload proteinuria is followed by salt-sensitive hypertension caused by renal infiltration of immune cells

2002 ◽  
Vol 283 (5) ◽  
pp. F1132-F1141 ◽  
Author(s):  
Violeta Alvarez ◽  
Yasmir Quiroz ◽  
Mayerly Nava ◽  
Héctor Pons ◽  
Bernardo Rodríguez-Iturbe
Keyword(s):  
Interstitial Nephritis ◽  
Renal Damage ◽  
High Salt ◽  
High Salt Diet ◽  
Salt Diet ◽  
Malondialdehyde Content ◽  
Induced Hypertension ◽  
Salt Sensitive Hypertension ◽  
And Control ◽  
And Oxidative Stress

Recent evidence suggests that salt-sensitive hypertension develops as a consequence of renal infiltration with immunocompetent cells. We investigated whether proteinuria, which is known to induce interstitial nephritis, causes salt-sensitive hypertension. Female Lewis rats received 2 g of BSA intraperitoneally daily for 2 wk. After protein overload (PO), 6 wk of a high-salt diet induced hypertension [systolic blood pressure (SBP) = 156 ± 11.8 mmHg], whereas rats that remained on a normal-salt diet and control rats (without PO) on a high-salt diet were normotensive. Administration of mycophenolate mofetil (20 mg · kg−1 · day−1) during PO resulted in prevention of proteinuria-related interstitial nephritis, reduction of renal angiotensin II-positive cells and oxidative stress (superoxide-positive cells and renal malondialdehyde content), and resistance to the hypertensive effect of the high-salt diet (SBP = 129 ± 12.2 mmHg). The present studies support the participation of renal inflammatory infiltrate in the pathogenesis of salt-sensitive hypertension and provide a direct link between two risk factors of progressive renal damage: proteinuria and hypertension.

scholarly journals Proximal tubule-targeted overexpression of the Cyp4a12-20-HETE synthase promotes salt-sensitive hypertension in male mice

2020 ◽  
Vol 319 (1) ◽  
pp. R87-R95
Author(s):  
Ankit Gilani ◽  
Kevin Agostinucci ◽  
Jonathan V. Pascale ◽  
Sakib Hossain ◽  
Sharath Kandhi ◽  
...  
Keyword(s):  
Proximal Tubule ◽  
Phosphoenolpyruvate Carboxykinase ◽  
Fold Increase ◽  
High Salt ◽  
Kidney Cortex ◽  
Male Mice ◽  
High Salt Diet ◽  
Salt Diet ◽  
Renal Microvasculature ◽  
Salt Sensitive Hypertension

20-Hydroxyeicosatetraenoic acid (20-HETE) has been linked to blood pressure (BP) regulation via actions on the renal microvasculature and tubules. We assessed the tubular 20-HETE contribution to hypertension by generating transgenic mice overexpressing the CYP4A12-20-HETE synthase (PT-4a12 mice) under the control of the proximal tubule (PT)-specific promoter phosphoenolpyruvate carboxykinase (PEPCK). 20-HETE levels in the kidney cortex of male (967 ± 210 vs. 249 ± 69 pg/mg protein) but not female (121 ± 15 vs. 92 ± 11 pg/mg protein) PT-4a12 mice showed a 2.5-fold increase compared with wild type (WT). Renal cortical Cyp4a12 mRNA and CYP4A12 protein in male but not female PT-4a12 mice increased by two- to threefold compared with WT. Male PT-4a12 mice displayed elevated BP (142 ± 1 vs. 111 ± 4 mmHg, P < 0.0001), whereas BP in female PT-4a12 mice was not significantly different from WT (118 ± 2 vs. 117 ± 2 mmHg; P = 0.98). In male PT-4a12 mice, BP decreased when mice were transitioned from a control-salt (0.4%) to a low-salt diet (0.075%) from 135 ± 4 to 120 ± 6 mmHg ( P < 0.01) and increased to 153 ± 5 mmHg ( P < 0.05) when mice were placed on a high-salt diet (4%). Female PT-4a12 mice did not show changes in BP on either low- or high-salt diet. In conclusion, the expression of Cyp4a12 driven by the PEPCK promoter is sex specific, probably because of its X-linkage. The salt-sensitive hypertension seen in PT-4a12 male mice suggests a potential antinatriuretic activity of 20-HETE that needs to be further explored.

scholarly journals Eplerenone inhibits aldosterone-induced renal expression of cyclooxygenase

2012 ◽  
Vol 13 (3) ◽  
pp. 353-359 ◽  
Author(s):  
MA Bayorh ◽  
A Rollins-Hairston ◽  
J Adiyiah ◽  
D Lyn ◽  
D Eatman
Keyword(s):  
Salt Intake ◽  
High Salt ◽  
Prostaglandin E ◽  
Renal Tubules ◽  
Protective Effects ◽  
High Salt Diet ◽  
Salt Diet ◽  
High Salt Intake ◽  
Low Salt ◽  
Cox 2

Introduction: The upregulation of cyclooxygenase (COX) expression by aldosterone (ALDO) or high salt diet intake is very interesting and complex in the light of what is known about the role of COX in renal function. Thus, in this study, we hypothesize that apocynin (APC) and/or eplerenone (EPL) inhibit ALDO/salt-induced kidney damage by preventing the production of prostaglandin E2 (PGE2). Methods: Dahl salt-sensitive rats on either a low-salt or high-salt diet were treated with ALDO (0.2 mg pellet) in the presence of EPL (100 mg/kg/day) or APC (1.5 mM). Indirect blood pressure, prostaglandins and ALDO levels and histological changes were measured. Results: Cyclooxygenase-2 (COX-2) levels were upregulated in the renal tubules and peritubular vessels after high-salt intake, and APC attenuated renal tubular COX-2 protein expression induced by ALDO. Plasma PGE2 levels were significantly reduced by ALDO in the rats fed a low-salt diet when compared to rats fed a high-salt diet. PGE2 was blocked by EPL but increased in the presence of APC. Conclusions: The beneficial effects of EPL may be associated with an inhibition of PGE2. The mechanism underlying the protective effects of EPL is clearly distinct from that of APC and suggests that these agents can have differential roles in cardiovascular disease.

Salt intake and insulin sensitivity in healthy human volunteers

2007 ◽  
Vol 113 (3) ◽  
pp. 141-148 ◽  
Author(s):  
Raymond R. Townsend ◽  
Shiv Kapoor ◽  
Christopher B. McFadden
Keyword(s):  
Insulin Sensitivity ◽  
Insulin Infusion ◽  
Salt Intake ◽  
Sodium Intake ◽  
High Salt ◽  
High Salt Diet ◽  
Salt Diet ◽  
Euglycaemic Clamp ◽  
Noradrenaline Concentration ◽  
Low Salt

The literature on salt intake and insulin sensitivity presents a mixed picture, as some studies have shown an increase, whereas others have shown a decrease, in insulin action as sodium intake is enhanced. In some cases, this may relate to the study of salt intake in patients with co-morbidities such as hypertension or diabetes. In the present study, we selected healthy normotensive lean volunteers who underwent a euglycaemic clamp following 6 days of a low-salt diet (20 mmol sodium daily) and, subsequently, 6 days of a high-salt diet (200 mmol sodium daily). Our results show an increase in insulin-mediated glucose disposal during euglycaemic clamp conditions that was significantly higher following the high-salt diet compared with the low-salt diet (7.41±0.41 compared with 6.11±0.40 mg·kg−1 of body weight·min−1 respectively; P=0.03). We measured calf blood flow before and during insulin infusion (no significant change after the two dietary salt interventions was detected) and plasma non-esterified fatty acids (also no significant differences were detected). We observed the expected increases in renin concentration and aldosterone activity in subjects on the low-salt diet, and also observed a significantly less increase in plasma noradrenaline concentration during euglycaemic insulin infusion following the high-salt compared with the low-salt diet. We propose that the 4–5-fold increase in serum aldosterone and the greater increase in plasma noradrenaline concentration following the low-salt intervention compared with the high-salt period may have contributed to the differences in insulin sensitivity following the adjustment in dietary sodium intake.

scholarly journals Salt-sensitive hypertension and cardiac hypertrophy in mice deficient in the ubiquitin ligase Nedd4-2

2008 ◽  
Vol 295 (2) ◽  
pp. F462-F470 ◽  
Author(s):  
Peijun P. Shi ◽  
Xiao R. Cao ◽  
Eileen M. Sweezer ◽  
Thomas S. Kinney ◽  
Nathan R. Williams ◽  
...  
Keyword(s):  
Cardiac Hypertrophy ◽  
Critical Role ◽  
Specific Inhibitor ◽  
Normal Diet ◽  
High Salt ◽  
High Salt Diet ◽  
Salt Diet ◽  
Ww Domains ◽  
Salt Sensitive Hypertension

Nedd4-2 has been proposed to play a critical role in regulating epithelial Na+ channel (ENaC) activity. Biochemical and overexpression experiments suggest that Nedd4-2 binds to the PY motifs of ENaC subunits via its WW domains, ubiquitinates them, and decreases their expression on the apical membrane. Phosphorylation of Nedd4-2 (for example by Sgk1) may regulate its binding to ENaC, and thus ENaC ubiquitination. These results suggest that the interaction between Nedd4-2 and ENaC may play a crucial role in Na+ homeostasis and blood pressure (BP) regulation. To test these predictions in vivo, we generated Nedd4-2 null mice. The knockout mice had higher BP on a normal diet and a further increase in BP when on a high-salt diet. The hypertension was probably mediated by ENaC overactivity because 1) Nedd4-2 null mice had higher expression levels of all three ENaC subunits in kidney, but not of other Na+ transporters; 2) the downregulation of ENaC function in colon was impaired; and 3) NaCl-sensitive hypertension was substantially reduced in the presence of amiloride, a specific inhibitor of ENaC. Nedd4-2 null mice on a chronic high-salt diet showed cardiac hypertrophy and markedly depressed cardiac function. Overall, our results demonstrate that in vivo Nedd4-2 is a critical regulator of ENaC activity and BP. The absence of this gene is sufficient to produce salt-sensitive hypertension. This model provides an opportunity to further investigate mechanisms and consequences of this common disorder.

Effect of Salt Intake and Potassium Supplementation on Urinary Renalase and Serum Dopamine Levels in Chinese Adults

Cardiology ◽  
2015 ◽  
Vol 130 (4) ◽  
pp. 242-248 ◽  
Author(s):  
Yang Wang ◽  
Dan Wang ◽  
Chao Chu ◽  
Jian-Jun Mu ◽  
Man Wang ◽  
...  
Keyword(s):  
Salt Intake ◽  
High Salt ◽  
Dietary Salt ◽  
High Potassium ◽  
High Salt Diet ◽  
Salt Diet ◽  
Dietary Salt Intake ◽  
Potassium Intake ◽  
Potassium Supplementation ◽  
Low Salt

Objective: The aim of our study was to assess the effects of altered salt and potassium intake on urinary renalase and serum dopamine levels in humans. Methods: Forty-two subjects (28-65 years of age) were selected from a rural community of northern China. All subjects were sequentially maintained on a low-salt diet for 7 days (3.0 g/day of NaCl), a high-salt diet for an additional 7 days (18.0 g/day of NaCl), and a high-salt diet with potassium supplementation for a final 7 days (18.0 g/day of NaCl + 4.5 g/day of KCl). Results: Urinary renalase excretions were significantly higher during the high-salt diet intervention than during the low-salt diet. During high-potassium intake, urinary renalase excretions were not significantly different from the high-salt diet, whereas they were significantly higher than the low-salt levels. Serum dopamine levels exhibited similar trends across the interventions. Additionally, a significant positive relationship was observed between the urine renalase and serum dopamine among the different dietary interventions. Also, 24-hour urinary sodium excretion positively correlated with urine renalase and serum dopamine in the whole population. Conclusions: The present study indicates that dietary salt intake and potassium supplementation increase urinary renalase and serum dopamine levels in Chinese subjects.

Salt-sensitive hypertension develops after transient induction of ANG II-dependent hypertension in Cyp1a1-Ren2 transgenic rats

2005 ◽  
Vol 288 (4) ◽  
pp. F810-F815 ◽  
Author(s):  
Laura L. Howard ◽  
Matthew E. Patterson ◽  
John J. Mullins ◽  
Kenneth D. Mitchell
Keyword(s):  
Blood Pressure ◽  
Renal Plasma Flow ◽  
Systolic Pressure ◽  
High Salt ◽  
Ang Ii ◽  
Transgenic Rats ◽  
High Salt Diet ◽  
Blood Pressure Elevation ◽  
Salt Diet ◽  
Salt Sensitive Hypertension

Transient exposure to ANG II results in the development of salt-sensitive hypertension in rats. This study was performed to determine whether a transient hypertensive episode can induce salt-sensitive hypertension in transgenic rats with inducible expression of the mouse Ren2 renin gene [strain name TGR(Cyp1a1-Ren2)]. Systolic blood pressures were measured in conscious male Cyp1a1-Ren2 rats ( n = 6) during control conditions and during dietary administration of indole-3-carbinol (I3C; 0.15%, wt/wt), for 14 days. Systolic pressure increased from 135 ± 5 to 233 ± 7 mmHg by day 14. I3C administration was terminated and blood pressure returned to normal levels (137 ± 5 mmHg) within 10 days. Subsequently, the rats were placed on a high-salt diet (8% NaCl) for 10 days. Systolic pressure increased by 34 ± 2 mmHg throughout 10 days of the high-salt diet. Neither glomerular filtration rate nor renal plasma flow was altered in Cyp1a1-Ren2 rats with salt-sensitive hypertension. In a separate group of male Cyp1a1-Ren2 rats ( n = 6) transiently induced with 0.15% I3C for 14 days, administration of the superoxide dismutase mimetic tempol (4-hydroxy-2,2,6,6-tetramethyl piperidinoxyl, 2 mM) attenuated the increase in systolic pressure induced by high salt. Systolic pressure increased by only 11 ± 1 mmHg throughout 8 days of a high-salt diet and tempol administration. Thus transient induction of ANG II-dependent hypertension via activation of the Cyp1a1-Ren2 transgene induces salt-sensitive hypertension in these transgenic rats. The attenuation by tempol of the high salt-induced blood pressure elevation indicates that ANG II-induced production of superoxide anion contributes to the development of salt-sensitive hypertension after transient induction of ANG II-dependent hypertension.

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