scholarly journals Association of Genetic Variants of Klotho with BP Responses to Dietary Sodium or Potassium Intervention and Long-Term BP Progression

2021 ◽  
pp. 1-9
Author(s):  
Jia-Wen Hu ◽  
Tao Shi ◽  
Jian-Jun Mu
Keyword(s):  
Genetic Variants ◽  
Dietary Intervention ◽  
High Salt ◽  
Dietary Sodium ◽  
Nucleotide Polymorphisms ◽  
High Salt Diet ◽  
Salt Diet ◽  
Common Genetic Variants ◽  
Salt Sensitive Hypertension

<b><i>Objectives:</i></b> Klotho (<i>KL</i>) plays pivotal roles in the progression of salt-sensitive hypertension. Salt-sensitive hypertension was associated with <i>KL</i> genotypes. We aimed to explore the association of common genetic variants of <i>KL</i> with individual blood pressure (BP) responses to sodium and potassium through a dietary intervention study as well as long-term BP progression. <b><i>Methods:</i></b> We conducted family-based dietary interventions among 344 participants from 126 families in rural villages of northern China in 2004. Subjects sequentially underwent a baseline diet, a low-salt diet (51.3 mmol/day Na), a high-salt diet (307.8 mmol/day Na), and a high-salt + potassium supplementation diet (307.8 mmol/day Na + 60 mmol/day K). After dietary intervention, we followed up with these participants in 2009 and 2012. The associations between 6 single-nucleotide polymorphisms (SNPs) of <i>KL</i> and phenotypes were analyzed through a linear mixed-effects model. <b><i>Results:</i></b> SNPs rs211247 and rs1207568 were positively correlated with the BP response to high-salt diet in the dominant model after adjusting for confounders (β = 1.670 and 2.163, <i>p</i> = 0.032 and 0.005, respectively). BPs rs526906 and rs525014 were in a haplotype block. Block rs526906-rs525014 was positively correlated with diastolic BP response to potassium and potassium sensitivity in the additive model (β = 0.845, <i>p</i> = 0.032). In addition, regression analysis indicated that rs211247 was associated with long-term systolic BP alterations after 8 years of follow-up in the recessive model (β = 20.47, <i>p</i> = 0.032). <b><i>Conclusions:</i></b> Common variants of the <i>KL</i> gene might modify individual BP sensitivity to sodium or potassium and influence the long-term progression of BP, suggesting a potential role in the development of salt-sensitive hypertension. Thus, <i>KL</i> may be a new early intervention target for salt-sensitive hypertension.

Short-Term NOS II Inhibition Leads to Long-Term Salt-Sensitivity in Dahl Salt-Resistant Rats

Hypertension ◽  
2000 ◽  
Vol 36 (suppl_1) ◽  
pp. 713-713
Author(s):  
M. Audrey Rudd ◽  
George Toolan ◽  
Maria R Trolliet ◽  
Timothy Cloutier ◽  
Karlene Maitland ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Systolic Blood Pressure ◽  
High Salt ◽  
Salt Treatment ◽  
High Salt Diet ◽  
Salt Diet ◽  
Oxide Synthase ◽  
Salt Sensitive Hypertension ◽  
Inducible Nitric Oxide

P111 We have previously shown that inhibition of inducible nitric oxide synthase (NOS II) evokes a salt-sensitive increase in blood pressure in Dahl salt-resistant rats when given a high salt (8% NaCl) diet for 7 days. To determine whether or not the effect of NOS II inhibition is short-lived, we continued the high salt diet for an additional 3 weeks following the discontinuation of the NOS II inhibitor. DR rats were given one of two NOS II selective inhibitors, AMT (300 nmoles/hr) and 1400W (35 nmoles/hr) for 2 weeks. A high salt diet was initiated after the first week of NOS II inhibition and continued for an additional 3 weeks for a total of 4 weeks of high salt treatment. Control DR rats received high salt alone for 4 weeks. Systolic blood pressure was taken at baseline and once weekly for the treatment period. Blood pressure significantly increased in DR rats after 1 week of high salt following NOS II inhibition. The blood pressure remained elevated throughout the 4-week period of high salt treatment despite the discontinuation of NOS II inhibitors 1 week following the initiation of the high salt diet. There was no significant change in blood pressure in DR rats on high salt diet alone. These data suggest that salt-sensitive hypertension can be evoked by transient NOS II inhibitor exposure. We conclude that tranisent NOS II inhibition may initiate events or processes that high salt maintains leading to sustained elevation in systolic blood pressure.

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.

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.

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.

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.

Sign in / Sign up

Export Citation Format

Share Document