Abstract P010: D 1 R And D 5 R And Their Role In The Etiology Of Inverse Salt Sensitivity Of Blood Pressure

Hypertension ◽  
2020 ◽  
Vol 76 (Suppl_1) ◽  
Author(s):  
John J Gildea ◽  
Michael G Daley ◽  
Peng Xu ◽  
Katherine A Schiermeyer ◽  
Wei Yue ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Salt Sensitivity ◽  
T Test ◽  
Morbidity And Mortality ◽  
The Novel ◽  
Proximal Tubule Cells ◽  
Mortality And Morbidity ◽  
R And D ◽  
Low Sodium ◽  
Renal Proximal Tubule Cells

Cardiovascular studies show increased morbidity and mortality in individuals consuming low sodium diets as well as high salt diets. The incidence of salt sensitivity of blood pressure (SS) in normotensives is approximately 18%, causing similar mortality and morbidity as hypertensives. Paradoxically, approximately 15% of normotensives demonstrate an increase in blood pressure on low sodium diets, known as inverse salt sensitivity (ISS). However, little is known about the morbidity and mortality associated with ISS, let alone the mechanisms behind this condition. Since dopamine regulates up to 75% of renal sodium handling, we hypothesized that the dopamine 1 and 5 receptors (D1R, D5R) were involved with the etiology of ISS. Using renal proximal tubule cells (RPTC) isolated from salt diet participant’s urine exposed to 90 mM salt (NaCl) (2 hr), we demonstrated reduced binding of the non-cell permeable D1-like antagonist (D1R and D5R) bodipy-530 SKF83566 (Fl-SKF) in the ISS RPTC when compared to salt resistant (SR) RPTC (ISS -13.9 ± 3.8% vs SR -1.1 ± 3.2%, n=12, p<0.05, t-test). Incubation in 190 mM NaCl for 2 hours and overnight (ON) increased Fl-SKF binding only in the ISS RPTCs but not the SR RPTC when compared to 140 mM NaCl (NS) (ISS 2 Hours +16.6 ± 6.2% and ISS ON +12.0 ± 2.8%, n=12, p<0.05 vs NS, t-test). ON incubation in 90 mM NaCl reduced Fl-SKF binding in both ISS and SR RPTC (ISS -15.2 ± 2.9% and SR -16.3 ± 2.3%, n=12, p<0.01, vs NS, t-test), and this effect was completely blocked by co-incubation with the angiotensin type 1 receptor (AT1R) antagonist losartan (LOS, 1 uM). The decrease in Fl-SKF binding in 90 mM NaCl was attributed to the D5R, and an increase in FL-SKF binding in 190 mM NaCl was verified to be due to an increase in plasma membrane D1R expression using antibodies directed to extracellular epitopes. A D5R specific monoclonal antibody developed in-house binds to the third extracellular loop of this receptor in order to measure these receptors selectively. Continued studies will be conducted with these cell lines with D1R and D5R knocked down to determine specific roles these receptors have in the novel ISS phenotype.

Abstract P009: Differential Redox Signaling In Urine Derived Renal Proximal Tubule Cells Isolated From Inverse Salt Sensitive Vs Salt Resistant Clinical Study Participants

Hypertension ◽  
2020 ◽  
Vol 76 (Suppl_1) ◽  
Author(s):  
John J Gildea ◽  
Michael G Daley ◽  
Peng Xu ◽  
Katherine Schiermeyer ◽  
Wei Yue ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Proximal Tubule ◽  
Redox Signaling ◽  
T Test ◽  
Wild Type ◽  
Proximal Tubule Cells ◽  
Low Sodium ◽  
Insulator Function ◽  
Tubule Cells ◽  
Renal Proximal Tubule Cells

Increased morbidity and mortality occurs in some individuals consuming low sodium diets. We demonstrated that single nucleotide polymorphisms (SNPs) in the dopamine type 2 receptor (D2R) as well as lower expression of cellular and plasma membrane D2R are associated with inverse salt sensitivity (ISS, a paradoxical increase in blood pressure while on the low sodium diet). Urine derived human renal proximal tubule cells (RPTC) were cultured from 3 separate ISS and 3 salt resistant (SR, resists blood pressure change on both low and high sodium diets) participants. D2R reduces cellular redox signaling so we hypothesized that an aberrant redox state occurs in ISS and SR RPTC exposed to different NaCl concentrations. RPTC incubated in 90 mM NaCl (low salt - LS) for 2 hours in both ISS and SR RPTCs had a significant reduction of monochlorobimane (mBCl - reduced glutathione indicator) compared to 140 mM NaCl (normal salt -NS) (SR -7.1± 2.1% and ISS -9.7 ± 1.6% vs NS, n=12, p<0.05, t-test). Only ISS RPTC had a significant increase in mBCl fluorescence in 190 mM NaCl (ISS +7.0 ± 2.5% vs NS, n=12, p<0.05, t-test) and mBCl fluorescence was not affected by incubation with losartan (angiotensin type 1 receptor inhibitor). 3-Aminobenzamide (3AB, 1 mM) inhibits Parp1 (poly[ADP-ribose] synthase), a protein necessary for the transcriptional repressor CTCF insulator function. 3AB reversed the lower mBCl fluorescence only in the SR RPTC, suggesting that reducing CTCF insulator function only affects D2R wild type cells. mBCl fluorescence in ISS RPTC showed a greater reduction by LOS vs SR RPTC (ISS -49.3 ± 1.5% vs SR -37.3 ± 4.8%, n=12, p<0.05, t-test), which was blocked by nemonapride (NEM, 1 uM, D2R antagonist) and further reduced the mBCl fluorescence only in the SR RPTC. Whether these differences in salt sensitivities are due to differential effects of CTCF insulator function at the homozygous variant or wild type D2R warrants further studies.

Abstract MP11: Decreased Expression Of Ace2 Is Associated Urine Derived Human Renal Proximal Tubule Cells From Inverse Salt Sensitivity Participants Cultured In Low Salt Conditions

Hypertension ◽  
2021 ◽  
Vol 78 (Suppl_1) ◽  
Author(s):  
John J Gildea ◽  
Peng Xu ◽  
Katie Schiermeyer ◽  
Wei Yue ◽  
Robin A Felder
Keyword(s):  
Proximal Tubule ◽  
Salt Sensitivity ◽  
Renal Proximal Tubule ◽  
Ang Ii ◽  
Proximal Tubule Cells ◽  
Low Sodium Diet ◽  
Low Sodium ◽  
Low Salt ◽  
Tubule Cells ◽  
Renal Proximal Tubule Cells

Increased morbidity and mortality occurs in some individuals consuming low sodium diets. Inverse salt sensitivity (ISS) is the paradoxical increase in blood pressure of individuals to a low sodium diet. Our group previously reported decreased expression of dopamine type 2 receptor (D 2 R), increased expression Aminopeptidase N, and increased Ang II dependent sodium transport in human urine derived renal proximal tubule cells isolated from ISS participants. In an attempt to understand the increased Ang II sensitivity demonstrated in ISS cells, we examined angiotensin converting enzyme 2 (ACE2), a membrane associated enzyme involved in the metabolism of Ang II. Urine derived renal proximal tubule cells grown and immortalized from ISS participants were compared to cells from salt resistant (SR) participants cultured in iso-osmotic media with low salt (LS, 90 mM NaCl) normal salt (NS, 140 mM NaCl) and high salt (HS, 190 mM NaCl). Cells were incubated in LS, NS, and HS media with and without losartan (LOS,1 μM) overnight (18 hours) and ACE2 expression levels determined by in-cell western blot. A monoclonal antibody specific to an extracellular epitope of ACE2 was used as the primary antibody and an Alexa-647 anti-mouse secondary antibody. ACE2 expression was only reduced in ISS cells in LS condition (28.7±2.1 % reduction, ISS LS vs SR LS, N=4 per group, p<0.05). Addition of losartan completely blocked the decrease in ACE2 expression in low salt conditions in ISS in urine derived human renal proximal tubule cells. No other changes in ACE2 expression were found between ISS and SR in either NS or HS conditions and with or without losartan. In conclusion, a decreased expression of ACE2 in ISS urine proximal tubule cells could explain the previously reported increased sensitivity of ISS cells to Ang II by increasing the half-life of Ang II under low salt conditions.

Abstract 79: Caveolin-1 Knockout Mice Have Salt-Sensitive Hypertension and Dopamine-1 Receptor Defects in Renal Cortex and Isolated Renal Proximal Tubule Cells

Hypertension ◽  
2013 ◽  
Vol 62 (suppl_1) ◽  
Author(s):  
John J Gildea ◽  
Nancy L Howell ◽  
Robert E Van Sciver ◽  
Brandon A Kemp ◽  
Robert M Carey ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Proximal Tubule ◽  
Kinase Activity ◽  
Renal Cortex ◽  
Renal Proximal Tubule ◽  
Normal Blood Pressure ◽  
Proximal Tubule Cells ◽  
Caveolin 1 ◽  
Tubule Cells ◽  
Renal Proximal Tubule Cells

Dopamine-1 receptors (D1R) are necessary for kidney proximal tubule-dependent natriuresis and maintenance of normal blood pressure, especially under high salt conditions. G-protein coupled receptor kinase 4 (GRK4) is a negative regulator of D1R function and single nucleotide polymorphisms in GRK4 have been associated with both hypertension and salt sensitivity in humans. Caveolin-1 (CAV1) directly binds to GRK4 and decreases kinase activity. We hypothesized that CAV1 knockout mice (CAV1KO) would have increased GRK4 kinase activity due to lack of physical interaction and inhibition of GRK4; thus overactive GRK4 would inactivate the D1R. Mean arterial blood pressure (MAP, in mmHg ±SEM) measured over 5 days was not significantly different for Wild-type mice (WT, 128.9±4.2 mmHg, n=4) vs CAV1KO (129.5±3.5 mmHg, n=4) on normal chow (0.3% sodium). However, on a 4% high sodium diet, the MAP of CAV1KO mice increased in just 2 days by 20.1±4.2 mmHg (p<0.05 vs either Day 0 CAV1KO or Day 2 WT, n=4). The CAV1KO MAP increased by 25.9±6.6 mmHg by day 7 (p<0.05 vs either Day 0 CAV1KO or Day 7 WT, n=4). Hyperphosphorylation and inactivation of the D1R in renal cortex was examined by looking at phospho-serine D1R by immuno-precipitation and Western dot blotting. A 92.5% ± 18.8 SEM increase in phospho-D1R was found in the CAV1KO renal cortex (n=4, p<0.01 vs WT; 14,574/7570 RFU). Cortical slices were made and incubated for 30 minutes with fenoldopam (FEN, 10 μM) with or without LE300 (D1R-like antagonist, 10 μM) or vehicle (VEH). Cyclic AMP was measured by TR-FRET (Lance, Perkin Elmer). FEN significantly increased cAMP 5.6 fold ± 1.2 SEM (n=4, p<0.01 vs VEH; 7.84/1.4 pmole/mg protein) in WT but not in CAV1KO slices, and this effect was completely blocked by LE300. Primary mouse CAV1KO and WT renal proximal tubule cell lines were established and monensin (sodium ionophore, 5 μM, 30 minutes)-induced plasma membrane D1R recruitment increased as measured by confocal microscopy in WT (30.4% ± 7.4 SEM, n=11, p<0.01 vs VEH; 8990/6894 RFU) but not in CAV1KO proximal tubule cells. In summary, CAV1 is necessary in high salt conditions for maintaining normal blood pressure in mice and for preserving normal D1R function in kidney cortex and in mouse renal proximal tubule cells.

scholarly journals Tandem Requirement for Full Renal D1R and D5R Activity

2019 ◽  
Author(s):  
Selim Rozyyev ◽  
Annabelle P. Crusan ◽  
Andrew C. Tiu ◽  
Julie A. Jurgens ◽  
Justin Michael B. Quion ◽  
...  
Keyword(s):  
Proximal Tubule ◽  
Structural Features ◽  
Renal Proximal Tubule ◽  
Proximal Tubules ◽  
Proximal Tubule Cells ◽  
Renal Proximal Tubules ◽  
Genetic Ablation ◽  
R And D ◽  
Tubule Cells ◽  
Renal Proximal Tubule Cells

ABSTRACTThe peripheral dopaminergic system promotes the maintenance of blood pressure homeostasis by engendering natriuresis, mainly through the renal D1R and D5R receptors. This effect is most apparent under conditions of moderate body sodium excess. Human and rodent renal proximal tubules express both receptors, which share common structural features and pharmacological profiles. Genetic ablation of either receptor in the kidney results in hypertension in mice. In this study, we demonstrated that in renal proximal tubules, these two receptors colocalized, co-immunoprecipitated, co-segregated in lipid rafts, and heterodimerized with one another, which was enhanced by treatment with the D1R/D5R agonist fenoldopam (1 μM, 30 min). Gene silencing via antisense oligonucleotides in renal proximal tubule cells abrogated cAMP production and sodium transport in response to fenoldopam. Our results highlight the cooperation and co-dependence of these two receptors through heterodimerization in renal proximal tubule cells.

Abstract MP61: Sex Difference In The Response Of Human Renal Proximal Tubule Cells To A Nephrotoxic Agent.

Hypertension ◽  
2021 ◽  
Vol 78 (Suppl_1) ◽  
Author(s):  
Shaun Moore ◽  
Megha Kumar ◽  
Daniel Yaqub ◽  
John J Gildea ◽  
Robin Felder ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Proximal Tubule ◽  
Dopamine D2 Receptor ◽  
Renal Proximal Tubule ◽  
Ki 67 ◽  
Proximal Tubule Cells ◽  
Renal Inflammation ◽  
Males And Females ◽  
Tubule Cells ◽  
Renal Proximal Tubule Cells

Our previous work indicated that the renal dopamine D2 receptor (D2R) has a significant role in regulating renal inflammation and injury, as well as in blood pressure control. In mice, D2R has protective effects in the kidney by limiting the inflammatory and fibrotic reaction; impaired D2R function results in renal inflammation and damage. Some common single nucleotide polymorphisms (SNPs; rs 6276 and 6277) in the human DRD2 gene are associated with decreased D 2 R expression and function and high blood pressure. To determine the effects of the presence of SNPs in the response to the nephrotoxic aristolochic acid (AA, 5μg/ml, 24 h), we studied immortalized human renal proximal tubule cells isolated from normal tissue of nephrectomies and genotyped for DRD2 SNPs and DRD2 wild-type (WT). We also determined whether this response is sex dependent. D2R protein was higher in male than in female WT (135±5 vs 100±4%; n=3/group; P<0.04) and lower in males with SNPs (43±2%, P<0.05) and females with SNPs (23±2%,P<0.05), compared with their respective WT counterparts. In both male groups (WT and SNPs), AA increased D2R protein by 80-100% but had no effect in WT females and increased ~50% in females with SNPs. The TNFα mRNA was higher in males with WT and SNPs which was increased by AA 9-10-fold in WT males and females but only 2-3-fold in those with SNPs. The TGFβ mRNA was similar in WT males and females and increased to the same extent in both groups with SNPs and was not affected by AA in all groups. Col1a1 mRNA was higher (30%) in WT males and females than those with SNPs; AA decreased Col1a1 mRNA in all groups. FN1 mRNA was higher (30-40%) in males and females with SNPs than WT; AA increased FN1 mRNA only in males and females with SNPs. The mRNA expression of the cell proliferation marker Ki-67 was higher in WT females than WT males (1.5-2-fold) and higher with SNPs than WT in both groups; AA increased Ki-67 mRNA in both groups and to a greater extent in males than in females. Taken together our data indicate that the presence of DRD2 SNPs affects the baseline expression of inflammatory and fibrotic factors and the response to AA is dependent on both sex and the presence of DRD2 SNPs. These data may have potential clinical translation since rs6276/6277 is commonly expressed (42%/23%) in the human population.

Abstract P205: Finger Ring Provides Nocturnal Blood Pressure Dipping Status Based On Analysis Of Oscillatory Photoplethysmography

Hypertension ◽  
2020 ◽  
Vol 76 (Suppl_1) ◽  
Author(s):  
Robin A Felder ◽  
Katherine Schiermeyer ◽  
Mahabuba Akhter ◽  
Peng Xu ◽  
Wei Yue ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Ambulatory Blood Pressure Monitoring ◽  
Ambulatory Blood Pressure ◽  
Blood Pressure Monitoring ◽  
Study Participant ◽  
Salt Sensitivity ◽  
Morbidity And Mortality ◽  
Pressure Monitoring ◽  
Salt Diet ◽  
Nocturnal Blood Pressure

Ambulatory blood pressure monitoring is more useful for the diagnosis of various forms of hypertension including white coat and morning surge as well as other conditions that are associated with increased morbidity and mortality such as sleep apnea. Nocturnal changes in blood pressure (BP) can also aid in the diagnosis of various manifestations of blood pressure independent of hypertension known as salt sensitivity (SS) and inverse salt sensitivity (ISS) of blood pressure. SS individuals experience an increase in BP on a high salt diet while ISS individuals experience a paradoxical increase in BP on a low salt diet. SS and ISS phenotypes affect approximately 18% and 15% of normotensives, respectively, which may result in significant morbidity and mortality similar to untreated hypertension. Consuming a personally appropriate salt diet can result in a circadian drop in BP during sleep, and failure to “dip” can lead to significant cardiovascular diseases. Nocturnal dipping is usually recorded using an ambulatory blood pressure monitoring (ABPM) device. Arterial pulse wave measurements using oscillatory photoplethysmography (OP) are minimally invasive when compared to an inflatable cuff, which can disturb sleep and raise blood pressure. We measured nocturnal blood pressure using a ring based photoplethysmograph (SensoGram Technologies, Plano Texas). A UVA Salt Study participant wore their device upon going to bed and then uploaded nocturnal data to the internet each morning. Systolic and diastolic BP is capable of being measured 30 times a minute for approximately 9 hours and providing over 5000 data points each night. Three representative dipping profiles for an individual yielded a dipping reduction of 24% ± 3% for systolic and 40% ± 10% for diastolic (1 - mid-sleeping lowest value/start of evening highest value). This additional data afforded by nocturnal BP measurement is anticipated to improve diagnostic opportunities in the measurement of SS and ISS phenotypes and provide the user with reassurance that nocturnal BP dipping is occurring.

Abstract P032: Dopamine Type 2 Receptor (D 2 R) Expression Modulates The Salt (NaCl) Induced Plasma Membrane Receptor Recruitment Of The Natriuretic Angiotensin Type 2 Receptor (AT 2 R) In Renal Proximal Tubule Cells Obtained From The Urine Of Salt Study Participants

Hypertension ◽  
2020 ◽  
Vol 76 (Suppl_1) ◽  
Author(s):  
John J Gildea ◽  
Peng Xu ◽  
Katherine Schiermeyer ◽  
Wei Yue ◽  
Robert M Carey ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
Cell Surface ◽  
Proximal Tubule ◽  
Cell Line ◽  
T Test ◽  
Proximal Tubule Cells ◽  
Membrane Recruitment ◽  
Tubule Cells ◽  
Renal Proximal Tubule Cells

The effect of D2R expression on the natriuretic AT2R plasma membrane recruitment in high (190 mM NaCl) and normal (140 mM NaCl) salt conditions was measured in human renal proximal tubule cells (RPTC) obtained from urine provided by salt study diet volunteers that were either salt resistant (SR) or inverse salt sensitive (ISS) (increased blood pressure on a low salt diet). Basal D2R expression was 36.9% ± 2.6% lower in ISS vs SR control n=5, p<0.01). D2R expression in the SR was reduced by siRNA (37.1% ± 2.0% reduction in ISS vs SR control, n=5, p<0.01, t-test). The ISS D2R expression was returned to normal levels by D2R overexpression using BacMam technology (22.5% ± 0.9% increase for ISS vs SR control siRNA, n=5, p<0.01, t-test). Culturing SR and ISS cell lines in normal salt (NS, 140 mM NaCl) and high salt (HS, 190 mM NaCl) leads to the recruitment of AT2R to the cell surface in the ISS cell line (ISS Control: NS 47978 ± 2728 RFU vs HS 74056 ± 3002 RFU, n=5, p<0.001, t-test), but not in the SR cell line. Knockdown of D2R using siRNA in the SR cell line altered the HS response in the SR cell line to that measured in the ISS cell line (SR D2R siRNA: NS 48514 ± 2560 RFU vs HS 82599 ± 1492 RFU, n=5, p<0.001, t-test), and the difference between SR HS control siRNA and SR HS D2R siRNA is also highly significant (SR HS: control siRNA 60154 ± 3347 RFU vs SR HS D2R siRNA 82599 ± 1492 RFU, n=5, p<0.001, t-test). Further lowering of D2R in ISS with D2R siRNA still showed a significant translocation of AT2R to the cell surface under HS (ISS D2R siRNA: NS 47953 ± 3058 RFU vs HS 80284 ± 2173 RFU, n-5, p<0.001, t-test) but not a further enhancement over SR siRNA. Overexpression of D2R in the ISS cell line completely blocked the HS AT2R cell surface recruitment, thus converting the ISS HS phenotype of ISS to a cell line that resembled a SR cell line. In conclusion, we have shown that a clear ISS phenotype of HS AT2R plasma membrane recruitment can be replicated in an SR cell line by reducing D2R expression using siRNA to levels seen in an ISS cell line. Similarly, overexpressing D2R in an ISS cell line to a level seen in SR cells reverts the ISS cells back to a SR associated sodium induced AT2R cell surface recruitment.

Abstract 12: The Etiology Of Inverse Salt Sensitivity Of Blood Pressure: Mirna-485-5p Binds To The Dopamine Type 2 Receptor (d 2 R) Snp Rs6276 And Decreases D 2 R Expression

Hypertension ◽  
2020 ◽  
Vol 76 (Suppl_1) ◽  
Author(s):  
John J Gildea ◽  
Peng Xu ◽  
Katherine Schiermeyer ◽  
Wei Yue ◽  
Robert M Carey ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Cell Lines ◽  
Salt Sensitivity ◽  
Wild Type ◽  
Binding Studies ◽  
Mirna Mimic ◽  
Low Sodium Diet ◽  
Renal Proximal Tubule Cells ◽  
20 Nm ◽  
Cell Phenotypes

Inverse salt sensitivity is the paradoxical increase in blood pressure of individuals to a low sodium diet. rs6276, a single nucleotide polymorphism found in the 3’ untranslated region of the D2R gene (DRD2), which is associated with decreased expression and is also associated with the inverse salt sensitive phenotype (ISS). Urine derived renal proximal tubule cells grown from ISS participants with homozygous rs6276 SNPs vs salt resistant (SR) wild type for rs6276 SNPs have decreased expression of D2R as measured by receptor binding studies using BodipyFL-Spiperone (100 nM for 2 hrs, -36.9% ± 2.6% reduction in ISS-10 vs SR-6, n=5, p<0.01). miRNA-485-5p potentially binds to the rs6276 SNP in the 3’ UTR site and therefore could be a member of a newly identified classification of SNPs called miRSNPs. We transfected a miRNA-485-5p miRNA mimic and a miRNA blocker (20 nM for 72 hrs) to determine the effect on D2R expression on both wild type and homozygous variant SNP participant cell lines. Transfection of mir-485-5p only alters the expression of D2R in the ISS cell lines with SNPs (52619 ± 2001 RFU ISS control miRNA vs 69496 ± 2108 RFU ISS-10 miRNA blocker and vs 30434 ± 1824 RFU ISS-10 miRNA mimic, n=9, p<0.01, one-way ANOVA). The miRNA-485-5p blocker was able to return the D2R expression levels back to levels found in SR cells. Further studies are necessary to determine if the miRNA-485-5p mimic enhances and miRNA-485-5p blocker reverses any of the ISS cell phenotypes identified.

Abstract 025: Urine Angiotensinogen and Salt-Sensitivity of Blood Pressure: The GenSalt Study

Circulation ◽  
2013 ◽  
Vol 127 (suppl_12) ◽  
Author(s):  
Casey M Rebholz ◽  
Jing Chen ◽  
Qi Zhao ◽  
Dongfeng Gu ◽  
Jichun Chen ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Standard Deviation ◽  
Confidence Interval ◽  
Systolic Blood Pressure ◽  
Salt Sensitivity ◽  
Angiotensin System ◽  
High Sodium ◽  
Low Sodium ◽  
Study Participants ◽  
Urine Levels

Urine excretion of angiotensinogen (AGT) has been proposed as a biomarker of intrarenal renin-angiotensin system activity, and therefore as a proxy for blood pressure regulation and sodium homeostasis. The association between urine levels of AGT and blood pressure response to dietary sodium intake has not been previously examined in the general population. We assessed the hypothesis that there is a direct relationship between urine levels of AGT and salt-sensitivity of blood pressure among participants of the Genetic Epidemiology Network of Salt Sensitivity (GenSalt) replication study. A 7-day low-sodium intervention, followed by a 7-day high-sodium intervention was carried out among 698 GenSalt-replication study participants from rural areas of north China. Absolute urine AGT excretion (μg/24 hours) and AGT-to-creatinine ratio (AGT/Cr, μg/g) were estimated at baseline for a random sample of 100 study participants. Nine blood pressure measurements were obtained at baseline and on the last three days of each intervention period. The absolute and percent changes in mean blood pressure from low-sodium to high-sodium intervention were used to assess salt-sensitivity. Median AGT and AGT/Cr were significantly (both p=0.01) reduced during the low-sodium intervention (AGT: 7.16 μg/24 hours, AGT/Cr: 8.36 μg/g) and increased during the high-sodium intervention (AGT: 8.84 μg/24 hours, AGT/Cr: 10.92 μg/g) compared to baseline (AGT: 8.28 μg/24 hours, AGT/Cr: 9.40 μg/g). Log-transformed AGT and AGT/Cr ratio at baseline was significantly and positively associated with blood pressure at baseline and at the end of each intervention. For example, one standard deviation higher log-transformed AGT/Cr ratio (1.2 μg/g) was associated with a 4.0 mm Hg (95% confidence interval: 1.3, 6.7) higher systolic blood pressure level at the end of the high-sodium intervention (p=0.004). One standard deviation higher log-transformed AGT/Cr ratio was associated with 1.58-times increased odds of high salt-sensitivity (≥5% change) of blood pressure (95% confidence interval: 1.00, 2.50; p=0.049). Log-transformed AGT/Cr ratio at baseline was positively associated with absolute and percent systolic blood pressure change from low- to high-sodium interventions (absolute: r=0.23, p=0.02; percent: r=0.20, p=0.047). In conclusion, elevated levels of urine AGT are associated with sodium-sensitivity of blood pressure. Augmentation of renal-angiotensin system activity may play an important role in the development of salt-sensitive hypertension.

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