Are Local Renin–Angiotensin Systems the Focal Points for Understanding Salt Sensitivity in Hypertension?

2009 ◽  
pp. 1-6 ◽  
Author(s):  
Edward D. Frohlich
Keyword(s):  
Salt Sensitivity ◽  
Focal Points ◽  
Renin Angiotensin

Abstract 356: A Role for Renal Proximal Tubule Sodium Bicarbonate Cotransporter SLC4A5 in Salt-Sensitivity of Blood Pressure

Hypertension ◽  
2012 ◽  
Vol 60 (suppl_1) ◽  
Author(s):  
Julia M Carlson ◽  
John J Gildea ◽  
Helen E McGrath ◽  
Robin A Felder
Keyword(s):  
Sodium Bicarbonate ◽  
Proximal Tubule ◽  
Mrna Expression ◽  
Cell Lines ◽  
Renin Angiotensin System ◽  
Salt Sensitivity ◽  
Renal Proximal Tubule ◽  
Angiotensin System ◽  
Renin Angiotensin ◽  
Homozygous Variant

SLC4A5 is a sodium-bicarbonate co-transporter involved with sodium homeostasis. Based on unpublished data, two SLC4A5 single nucleotide polymorphisms (SNPs rs1017783 and rs7571842) have been highly associated with an individual’s salt-sensitivity status. Since the renal proximal tubule (RPT) regulates a large percentage of renal sodium transport, we investigated whether SLC4A5 was present in this nephron segment. Using confocal immunofluorescence microscopy, we found expression of SLC4A5 in human RPT cell plasma membrane and intracellular membrane vesicles. We then examined the physiologic implications of the SLC4A5 SNPs in human RPT cells. Using immunoblotting and RT-PCR, we found no significant differences in basal SLC4A5 expression in RPT cells between individuals that are homozygous variant at both SNPs and individuals that are wild-type (WT) for both alleles. Stimulation of the dopaminergic system with 1μM fenoldopam, or the renin-angiotensin system with 10 nM angiotensin II or 10 nM angiotensin III (n=18 per treatment) over 3 and 24 hours did not significantly alter SLC4A5 protein or 24 hour mRNA expression. These data indicate that SLC4A5 is not directly regulated by either the renal dopaminergic or renin-angiotensin system. However, 24 hour stimulation with the sodium ionophore monensin (MON, 1μM) significantly increased overall mRNA expression of SLC4A5 by 182±0.098% over vehicle (VEH) (ΔCq VEH=0.283±0.035; n=18, p<0.001). There was also a significant increase in SLC4A5 mRNA in three cell lines homozygous variant for both alleles compared to three WT cell lines following MON treatment at both 3 hours (138±0.10%; ΔCq WT MON = 0.5±0.052; n=9, p<0.05) and 24 hours (161±0.11%; ΔCq WT MON = 0.39±0.066; n=9, p<0.02). Three but not 24 hour stimulation with MON also significantly increased overall expression of SLC4A5 protein (137±0.00041%; RFU VEH=0.0030±0.00022; n=18, p<0.01). MON, by allowing salt to enter a cell, may be activating an enhancer that leads to increased transcription of SLC4A5 mRNA that is more effective in homozygous variant cell lines. These novel observations demonstrate that SNPs located in a non-promoter DNA intron are associated with enhanced promoter activity that is regulated by altered intracellular sodium.

Role of CYP2C9 genetic variants for salt sensitivity and the regulation of the renin–angiotensin–aldosterone system in normotensive men

2011 ◽  
Vol 29 (1) ◽  
pp. 56-61 ◽  
Author(s):  
Juliane Bolbrinker ◽  
Joachim Beige ◽  
Matthias Huber ◽  
Arya M Sharma ◽  
Alexander Thomas ◽  
...  
Keyword(s):  
Genetic Variants ◽  
Salt Sensitivity ◽  
Renin Angiotensin Aldosterone System ◽  
Renin Angiotensin

scholarly journals Renal interactions of renin-angiotensin system, nitric oxide and superoxide anion: implications in the pathophysiology of salt-sensitivity and hypertension

2009 ◽  
pp. S55-S68
Author(s):  
L Kopkan ◽  
L Červenka
Keyword(s):  
Nitric Oxide ◽  
Renal Function ◽  
Kidney Function ◽  
Superoxide Anion ◽  
Renin Angiotensin System ◽  
Salt Sensitivity ◽  
Regulatory Function ◽  
Angiotensin System ◽  
Renin Angiotensin ◽  
Enhanced Production

Renin-angiotensin system (RAS) plays a key role in the regulation of renal function, volume of extracellular fluid and blood pressure. The activation of RAS also induces oxidative stress, particularly superoxide anion (O(2)(-)) formation. Although the involvement of O(2)(-) production in the pathology of many diseases is known for long, recent studies also strongly suggest its physiological regulatory function of many organs including the kidney. However, a marked accumulation of O(2)(-) in the kidney alters normal regulation of renal function and thus may contribute to the development of salt-sensitivity and hypertension. In the kidney, O(2)(-) acts as vasoconstrictor and enhances tubular sodium reabsorption. Nitric oxide (NO), another important radical that exhibits opposite effects than O(2)(-), is also involved in the regulation of kidney function. O(2)(-) rapidly interacts with NO and thus, when O(2)(-) production increases, it diminishes the bioavailability of NO leading to the impairment of organ function. As the activation of RAS, particularly the enhanced production of angiotensin II, can induce both O(2)(-) and NO generation, it has been suggested that physiological interactions of RAS, NO and O(2)(-) provide a coordinated regulation of kidney function. The imbalance of these interactions is critically linked to the pathophysiology of salt-sensitivity and hypertension.

scholarly journals Variation in Renin-Angiotensin System and Salt-Sensitivity Genes and the Risk of Diabetes Mellitus Associated With the Use of Thiazide Diuretics

2009 ◽  
Vol 22 (5) ◽  
pp. 545-551 ◽  
Author(s):  
O. Bozkurt ◽  
A. de Boer ◽  
D. E. Grobbee ◽  
P. W. de Leeuw ◽  
A. A. Kroon ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Renin Angiotensin System ◽  
Salt Sensitivity ◽  
Thiazide Diuretics ◽  
Angiotensin System ◽  
Renin Angiotensin

scholarly journals Simulating a virtual population's sensitivity to salt and uninephrectomy

2017 ◽  
Vol 8 (1) ◽  
pp. 20160134 ◽  
Author(s):  
John S. Clemmer ◽  
Robert L. Hester ◽  
W. Andrew Pruett
Keyword(s):  
Human Physiology ◽  
Renal Mass ◽  
Clustering Algorithm ◽  
Renin Angiotensin System ◽  
Salt Sensitivity ◽  
Topological Data Analysis ◽  
Sodium Reabsorption ◽  
Virtual Patients ◽  
Angiotensin System ◽  
Renin Angiotensin

Salt sensitivity, with or without concomitant hypertension, is associated with increased mortality. Reduced functional renal mass plays an important role in causing salt-sensitive hypertension for many individuals. Factors that are important in the condition of decreased renal mass and how they affect blood pressure (BP) or salt sensitivity are unclear. We used HumMod, an integrative mathematical model of human physiology, to create a heterogeneous population of 1000 virtual patients by randomly varying physiological parameters. We examined potential physiological mechanisms responsible for the change in BP in response to high-salt diet (8× change in salt intake for three weeks) with full kidney mass and again after the removal of one kidney in the same group of virtual patients. We used topological data analysis (TDA), a clustering algorithm tool, to analyse the large dataset and separate patient subpopulations. TDA distinguished five unique clusters of salt-sensitive individuals (more than 15 mmHg change in BP with increased salt). While these clusters had similar BP responses to salt, different collections of variables were responsible for their salt sensitivity, e.g. greater reductions in glomerular filtration rate (GFR) or impairments in the renin–angiotensin system. After simulating uninephrectomy in these virtual patients, the three most salt-sensitive clusters were associated with a blunted increase in renal blood flow (RBF) and higher increase in loop and distal sodium reabsorption when compared with the salt-resistant population. These data suggest that the suppression of sodium reabsorption and renin–angiotensin system is key for salt resistance, and RBF in addition to GFR may be an important factor when considering criteria for kidney donors. Here, we show that in our model of human physiology, different derangements result in the same phenotype. While these concepts are known in the experimental community, they were derived here by considering only the data obtained from our virtual experiments. These methodologies could potentially be used to discover patterns in patient sensitivity to dietary change or interventions and could be a revolutionary tool in personalizing medicine.

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