Renin-Angiotensin System
Urinary Angiotensinogen Excretion Is Associated With Blood
Pressure Independent of the Circulating Renin–Angiotensin
System in a Group of African Ancestry
Frederic S. Michel,* Gavin R. Norton,* Muzi J. Maseko, Olebogeng H.I. Majane, Pinhas Sareli,
Angela J. Woodiwiss*
Downloaded from http://hyper.ahajournals.org/ by guest on June 14, 2017
Abstract—Although the circulating renin–angiotensin system (RAS) is suppressed in salt-sensitive populations, the role of
the intrarenal RAS in blood pressure (BP) control in these groups independent of the circulating RAS is uncertain. We
evaluated the relationship between 24-hour urinary angiotensinogen excretion and either office (mean of 5 measurements;
n=425) or 24-hour ambulatory (n=340) BP independent of the circulating RAS in a c­ ommunity-based sample of African
descent that had never received antihypertensive drug therapy. Circulating RAS activity was determined from plasma renin
and angiotensinogen and serum aldosterone concentrations. Urinary angiotensinogen to creatinine ratio (angiotensinogen/
creat) was correlated with plasma angiotensinogen concentrations (P<0.0005) but not with indexes of salt intake. However,
urinary angiotensinogen/creat was independently associated with office systolic BP (partial r=0.16; P<0.001), whereas
plasma angiotensinogen (partial r=0.07; P=0.14) was not independently associated with office systolic BP. Urinary
angiotensinogen/creat was also associated with 24-hour systolic BP (partial r=0.11; P<0.05). The relationships between
urinary angiotensinogen/creat and BP survived further adjustments for plasma angiotensinogen and serum aldosterone
concentrations, plasma renin concentrations, estimated glomerular filtration rate, urinary Na+/K+, or 24-hour urinary Na+
excretion rates (P<0.005 for all). Participants with the highest compared with the lowest quartile of urinary angiotensinogen/
creat showed an 8.2-mm Hg higher office (P<0.005) and 4.6-mm Hg higher 24-hour (P=0.01) systolic BP. In conclusion,
independent of the systemic RAS, including plasma angiotensinogen concentrations, urinary angiotensinogen excretion is
associated with BP in a salt-sensitive, low-renin group of African descent. These data lend further support for a role of the
RAS in BP control in salt-sensitive groups of African ancestry. (Hypertension. 2014;64:149-156.)
Key Words: African Continental Ancestry Group ◼ blood pressure monitoring, ambulatory ◼ renin–angiotensin
system ◼ urine angiotensinogen
I
n salt-sensitive populations, such as those of African ancestry, a high-sodium (Na+), low-potassium (K+) diet results in
renal Na+ retention and increases in blood pressure (BP).1,2 As a
consequence of an enhanced Na+ retention, renin release from
the juxtaglomerular apparatus decreases and the activity of the
systemic renin–angiotensin system (RAS) is suppressed.3–6
Thus, the effect of RAS blockers on BP in salt-sensitive populations such as those of African ancestry is limited,7,8 and RAS
blockers are not recommended as first-line therapy in these
populations.9,10 However, there is ongoing debate as to the
role of the RAS in salt-sensitive hypertension, particularly in
groups of African ancestry.
In addition to the systemic RAS, a complete local intrarenal RAS exists.11,12 In angiotensin II–induced hypertension, augmentation of intrarenal angiotensinogen mediates
intrarenal angiotensin II production.13–15 Because urinary
angiotensinogen is derived largely from proximal tubular
angiotensinogen, urinary angiotensinogen excretion is a biomarker of intrarenal RAS activity.16,17 Although associations
between urinary angiotensinogen excretion and BP have
previously been described,18–21 these relationships in typical
­salt-sensitive groups of African ancestry have been reported
on in only 12 black African men.20 Because intrarenal RAS
activation depends on the activity of the systemic RAS11,12 and
the systemic RAS is suppressed in groups of black African
descent,3–6,10 one would not predict an important role for the
intrarenal RAS in BP control in this ethnic group. However,
to what extent the effect of the intrarenal RAS on BP depends
on the systemic RAS is uncertain. Whether relationships
between urinary angiotensinogen excretion and BP are better
than the well-recognized relationships between plasma angiotensinogen concentrations22–24 or the circulating RAS25–29 and
BP has not been reported.18–21 Because the role of the intrarenal RAS in BP control in communities characterized by a
Received February 7, 2014; first decision February 27, 2014; revision accepted March 27, 2014.
From the Cardiovascular Pathophysiology and Genomics Research Unit, School of Physiology, Faculty of Health Sciences, University of the
Witwatersrand, Johannesburg, South Africa.
*These authors contributed equally to this work.
Correspondence to Angela J. Woodiwiss, Cardiovascular Pathophysiology and Genomics Research Unit, School of Physiology, University of the
Witwatersrand Medical School, 7 York Rd, Parktown 2193, Johannesburg, South Africa. E-mail [email protected]
© 2014 American Heart Association, Inc.
Hypertension is available at http://hyper.ahajournals.org
DOI: 10.1161/HYPERTENSIONAHA.114.03336
149
150 Hypertension July 2014
low circulating RAS, such as in groups of African ancestry, is
unknown, in the present study, we evaluated whether urinary
angiotensinogen excretion is associated with BP, independent
of the systemic RAS in a group of South Africans of African
ancestry.
Methods
Study Group
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The present study was conducted according to the principles outlined
in the Helsinki declaration. The Committee for Research on Human
Subjects of the University of the Witwatersrand approved the protocol (approval number: M02-04-72 and renewed as M07-04-69
and M12-04-108). Participants gave informed, written consent. The
study design has previously been described.24,29,30 Briefly, 425 participants of black African descent >16 years of age with 24-hour urine
samples who met with prespecified quality control criteria previously
described24,29 and who had never received antihypertensive drug
therapy were randomly recruited from the South West Township of
Johannesburg, South Africa. Of these participants, 340 had 24-hour
ambulatory BP monitoring that met with the European Society of
Hypertension guidelines (>14 and 7 readings for the computation of
day and night means, respectively).31
Clinical, Demographic, and Anthropometric
Measurements
A standardized questionnaire was administered to obtain demographic and clinical data.24,29,30 From height and weight measurements, body mass index (BMI) was calculated and participants
were identified as being overweight if their BMI was ≥25 kg/m2 and
obese if their BMI was ≥30 kg/m2. Standard laboratory blood and
urine tests were performed. Diabetes mellitus or abnormal blood glucose control was defined as the use of insulin or oral hypoglycemic
agents or an hemoglobin A1c >6.1%. Estimated glomerular filtration rate was determined using the abbreviated Modification of Diet
in Renal Disease study group equation: 186.3×(serum creatinine in
mg/dL−1.154)×(age in years−0.203)×1.212×0.742 (if woman).
Blood Pressure
Nurse-derived conventional BP was measured after 10 minutes of rest
in the seated position as previously described24,29,30 within a half hour
of obtaining blood samples in the opposite arm to that subjected to
venesection. Five consecutive BP readings were obtained using an
appropriately sized cuff, 30 to 60 seconds apart. The average of the
5 readings was taken as the BP. Only 0.23% of visits had fewer than
the planned BP recordings. The frequency of identical consecutive
recordings was 0.23% for systolic BP (SBP) and 0.94% for diastolic
BP. No BP values were recorded as an odd number. Of the SBP and
diastolic BP readings, 29.5% ended on a zero (expected=20%).
Ambulatory 24-hour, day, and night BP were determined using
SpaceLabs monitors (model 90207; Spacelabs, Redmond, WA) as
previously described.30 The size of the cuff was the same as that used
for conventional BP measurements. Monitors were programmed
to measure 24-hour BP at 15-minute intervals from 06:00 to 22:00
hours and at 30-minute intervals from 22:00 to 06:00 hours. Fixedclock time periods, identified as previously described,30 rather than
actual in bed and out of bed periods were statistically analyzed to
ensure that similar day and nighttime periods were selected for comparisons between individuals. Day and night periods ranged from
09:00 to 19:00 hours and from 23:00 to 05:00 hours, respectively.
No participants reported on daytime naps. Intraindividual means of
the ambulatory measurements were weighted by the time interval between successive readings.30 The average (±SD) number of BP readings obtained was 62.1±11.6 (range, 25–81) for the 24-hour period,
29.1±7.0 (range, 14–41) for the day, and 9.4±1.0 (range, 7–11) for
the night periods. Exclusion of readings obtained during the transition periods resulted in a lower number of readings for the day and
night periods combined compared with the total obtained for the 24hour period.
Circulating Renin, Aldosterone, and
Angiotensinogen Concentrations
Blood samples were obtained in the supine position after 10 minutes
of rest in the morning between 10:00 and 12:00 hours. After centrifugation, samples were stored at −70°C until the time of analysis.
Plasma renin concentrations were measured using an immunoradiometric technique (Renin III Generation, Cisbio International, Ceze,
France; intra-assay coefficients of variation ranging from 1.1%
for high concentrations to 4.5% for low concentrations and with a
mean interassay coefficient of variation of 5.3%). Serum aldosterone concentrations were measured using an 125I radioimmunoassay
(Coat-A-Count, Diagnostic Products Corporation, Los Angeles, CA;
intra-assay coefficients of variation ranging from 2.3% for high concentrations to 5.4% for low concentrations and with a mean interassay coefficient of variation of 5.4%). Plasma angiotensinogen
concentrations were determined using a human total angiotensinogen
solid phase sandwich ELISA (code No. 27412, Immuno-Biological
Laboratories, Co, Ltd, Gunma, Japan; intra-assay coefficients of
variation ranging from 4.4% for high concentrations to 5.5% for low
concentrations and with an interassay coefficient of variation ranging
from 4.3% for high concentrations to 7.0% for low concentrations).
Urine Measurements
Timed urine samples were obtained for a 24-hour period after discarding urine obtained immediately before the start of the collection period.
The mean (±SD) time period of urine collection was 24.5±1.5 hours
(range, 24.0–31.1 hours). The quality of urine sample collection was
determined as previously described.24,29 Urinary Na+, K+, and creatinine
concentrations were measured and 24-hour urine Na+ excretion rates
calculated from the product of 24-hour urine volumes and urine Na+
concentrations. Urinary angiotensinogen concentrations were determined using the same human total angiotensinogen solid phase sandwich ELISA (code No. 27412, Immuno-Biological Laboratories, Co,
Ltd, Gunma, Japan) as that used to determine plasma angiotensinogen
concentrations. Urine angiotensinogen excretion rates were expressed
as angiotensinogen to creatinine ratio (angiotensinogen/creat).
Data Analysis
For database management and statistical analysis, SAS software, version 9.3 (SAS Institute Inc, Cary, NC), was used. Data are shown as
mean±SD unless otherwise specified. Proportions were compared by
the χ2 statistic. Because circulating renin, aldosterone, and angiotensinogen concentrations were not normally distributed, in data analysis they were expressed as log renin, square root aldosterone, and
square root angiotensinogen values. Because urine angiotensinogen
excretion rates and urinary Na+/K+ were also not normally distributed, they were expressed as log urinary angiotensinogen/creat ratio
and log urinary Na+/K+. Relationships between urine angiotensinogen
excretion rates and BP were determined from multivariate regression
models with age, sex, BMI, the presence of diabetes mellitus/abnormal blood glucose control, regular alcohol consumption, and regular
tobacco use included in the regression models. The probability values derived from multivariate models were adjusted for nonindependence of family members using a mixed model of analysis as defined
by SAS software. Because estrogen influences angiotensinogen
expression and angiotensinogen is expressed in adipose tissue, we
also evaluated whether interactions between sex or BMI and urinary
angiotensinogen/creat ratios are associated with BP.
Results
Characteristics of the Participants
Table 1 shows the characteristics of the study sample and of
participants of the study sample who had 24-hour BP data that
met with prespecified quality control criteria. More women
than men participated. A high proportion of participants had
hypertension that had never been treated with antihypertensive drugs (24.2%).
Michel et al Urinary Angiotensinogen and BP 151
Table 1. Characteristics of Sample and Subgroup With
24-Hour BP Data
All (n=425)
With 24-h BP Data
(n=340)
62.6
61.8
Age, y
39.7±17.2
40.2±17.2
Body mass index, kg/m2
28.3±7.7
28.2±7.6
Characteristic
% Women
% Overweight/obese
23.1/36.7
22.9/36.2
% Regular tobacco
16.7
16.8
% Regular alcohol
23.5
24.1
% Females postmenopausal
31.9
32.4
% DM or HbA1c>6.1%
17.2
16.8
% Hypertension
24.2
25.0
Office SBP/DBP, mm Hg
126±21/83±12
126±21/83±12
24-h SBP/DBP, mm Hg
…
117±14/72±9
111±39
110±39
Estimated GFR, mL/min per 1.73 m2
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Urinary Na , mEq/24 h
108±71
107±72
Urinary Na+/K+
4.42±3.41
4.35±3.63
Plasma renin, pg/mL
31.9±61.7
30.4±50.8
Serum aldosterone, ng/dL
180±150
185±152
Plasma angiotensinogen, μg/mL
29.4±11.2
28.7±11.3
Urinary angiotensinogen/creatinine, μg/g
0.57±4.24
0.65±4.74
+
BP indicates blood pressure; DBP, diastolic BP; DM, diabetes mellitus; GFR,
glomerular filtration rate; HbA1c, hemoglobin A1c; K+, potassium; Na+, sodium;
and SBP, systolic BP.
Distribution of Circulating and Urinary RAS
Measurements
The distribution of plasma renin, serum aldosterone, and
plasma angiotensinogen concentrations, as well as the distribution of urine angiotensinogen/creat, departed from normality and were positively skewed (skewness: 5.44, 1.64, 1.49,
17.25; kurtosis: 45.4, 4.36, 6.47, 324.9; Shapiro–Wilk statistics: 0.47, 0.88, 0.90, 0.09, respectively). In contrast log renin,
square root serum aldosterone, square root plasma angiotensinogen, and log urinary angiotensinogen/creat values showed
a distribution closer to normality (skewness: 0.21, −0.09, 0.11,
−0.65; kurtosis: 0.27, 0.23, 2.83, −0.33; Shapiro–Wilk statistic: 0.99, 0.98, 0.95, 0.93).
Relationship Between Indexes of Salt Intake and
Measures of the Circulating Renin–Angiotensin–
Aldosterone System
angiotensinogen/creat (Table 2), and urinary angiotensinogen/
creat increased across quartiles of plasma angiotensinogen
concentrations (Figure 1). However, neither plasma renin
nor serum aldosterone concentrations, estimated glomerular
filtration rate, or indexes of salt intake (24-hour urinary Na+
excretion or Na+/K+; Table 2) were correlated with urinary
angiotensinogen/creat. Moreover, no differences in urinary
angiotensinogen/creat were noted across quartiles of urinary
Na+/K+, an index of salt intake (Figure 1), or 24-hour urinary
Na+ (data not shown).
Relationships Between Circulating or Urinary RAS
Activity and BP
In keeping with a salt-sensitive population, plasma renin
concentrations were inversely associated with office and
24-hour SBP (Table 3), and both office (Figure 2) and 24-hour
(Figure 3) SBP decreased across quartiles of plasma renin
concentrations. Neither plasma angiotensinogen nor serum
aldosterone concentrations were associated with either office
or 24-hour BP (Table 3; Figures 2 and 3). However, urinary
angiotensinogen/creat was independently associated with
office and 24-hour SBP, and office or 24-hour SBP increased
across quartiles of urinary angiotensinogen/creat (Table 3;
Figures 2 and 3). An 8.2-mm Hg greater office and 4.6-mm Hg
24-hour SBP was noted in the highest compared with the lowest quartile of urinary angiotensinogen/creat (Figures 2 and
3). The relationships between urinary angiotensinogen/creat
and office or 24-hour SBP were noted to be independent of
the circulating RAS, including plasma angiotensinogen concentrations, as well as of indexes of salt intake (urinary Na+/K+
and 24-hour urinary Na+ excretion; Table 4).
Dependence of the Relationship Between
Urinary Angiotensinogen and BP on
Na+ Intake, Sex, or BMI
No positive interaction between urinary angiotensinogen/creat
and 24-hour urinary Na+ excretion or urinary Na+/K+ (indexes
of Na+ intake) was associated with either office or 24-hour
SBP (data not shown). Moreover, no interactions between urinary angiotensinogen/creat and sex or BMI were associated
with either office or 24-hour SBP (data not shown).
Table 2. Factors Independently Associated With Urinary
Angiotensinogen Excretion in a Group of African Ancestry
Never Having Received Antihypertensive Therapy (n=425)
In keeping with a salt-sensitive population, 24-hour urinary
Na+/K+, an index of Na+ intake, but not 24-hour urinary Na+
excretion was inversely correlated with plasma renin (r=−0.13;
P<0.01) and serum aldosterone (r=−0.25; P<0.0001) concentrations. However, neither 24-hour urinary Na+ excretion nor
24-hour urinary Na+/K+ was correlated with plasma angiotensinogen concentrations (P=0.98).
Log Urinary Angiotensinogen/Creatinine vs
Factors Independently Associated With Urinary
Angiotensinogen Excretion
CI indicates confidence interval; GFR, glomerular filtration rate; K+, potassium;
and Na+, sodium.
*With adjustments for age, sex, body mass index, diabetes mellitus or an
hemoglobin A1c>6.1%, regular tobacco use, and regular alcohol consumption.
Probability values are further adjusted for nonindependence of family members.
In a multivariate model, plasma angiotensinogen concentrations were positively associated with the urinary
Partial r* (CI)
P Value
0.17 (0.08 to 0.26)
<0.0005
−0.03 (−0.12 to 0.07)
0.60
−0.003 (−0.10 to 0.09)
0.94
−0.07 (−0.16 to 0.03)
0.17
Log urinary Na+/K+
0.08 (−0.01 to 0.18)
0.09
Estimated GFR
0.07 (−0.02 to 0.17)
0.13
Square root plasma angiotensinogen
Log plasma renin
Square root serum aldosterone
Log 24-h urinary Na+
152 Hypertension July 2014
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Figure 1. Multivariate-adjusted urinary angiotensinogen (AGT)
excretion (log urinary AGT/creatinine) across quartiles of plasma
AGT concentrations and urinary sodium (Na+)/potassium (K+),
an index of Na+ intake in a group of African ancestry. *P<0.05,
**P<0.0005 vs quartile 1 of plasma AGT concentrations. Adjust­
ments are for age, sex, body mass index, diabetes mellitus
or a hemoglobin A1c>6.1%, regular tobacco use, and regular
alcohol consumption. Probability values are further adjusted for
nonindependence of family members.
Discussion
In the present study, we explored the relationship between
urinary angiotensinogen excretion and BP in a community
sample of African ancestry (none of whom had received
antihypertensive drug therapy) with typical salt sensitivity
(as indexed by strong inverse relationships between plasma
renin concentrations and both BP and urinary Na+/K+). In this
regard, despite a lack of positive association between the systemic RAS and BP, urinary angiotensinogen excretion (angiotensinogen/creat) was independently associated with both
office and 24-hour SBP. Moreover, relationships between urinary angiotensinogen/creat and BP were independent of circulating angiotensinogen, renin, and aldosterone concentrations,
as well as of indexes of Na+ intake.
The results of the present study provide the first evidence to
show in a relatively large, randomly selected study sample that
urinary angiotensinogen/creat is associated with BP in a group
of black African descent with typical salt sensitivity (inverse
relationships between plasma renin concentrations and both
BP and an index of salt intake). In this regard, relationships
between urinary angiotensinogen/creat and BP in groups of
African ancestry have previously been demonstrated in only
12 selected black men20 and in a small study sample (n=106)
consisting of a combination of selected white, Asian, and
blacks, only 56 of whom were black.19 The present findings,
therefore, lend support for the previously suggested notion
that despite poor BP responses to RAS blocker monotherapy7,8
and inverse relationships between Na+ intake and circulating
RAS concentrations and between plasma renin concentrations
and BP in groups of African ancestry, the renal RAS may play
an important role in BP regulation in this ethnic group.24
Although in the present study we demonstrated relationships between urinary angiotensinogen/creat and BP but not
24-hour urinary Na+ excretion, in a prior study21 relationships between urinary angiotensinogen/creat and both BP
and 24-hour urinary Na+ excretion were noted. In this regard,
the authors of this prior study21 suggested that these relationships indicated a role for the intrarenal RAS in mediating
salt-sensitive hypertension, a conclusion not supported by the
present study. An explanation for the discrepancies between
studies is that previously reported21 relationships between urinary angiotensinogen/creat and 24-hour urinary Na+ excretion
were over a range of 24-hour urinary Na+ excretion values that
Table 3. Independent Relationships Between Circulating or Renal Indices of RAS Activity and BP in a Group of
African Ancestry Never Having Received Antihypertensive Therapy
Office BP (n=425)
Indices of RAS Activity
Partial r* (CI)
24-h BP (n=340)
P Value
Partial r* (CI)
P Value
Systolic BP
Log plasma renin
−0.21 (−0.30 to −0.12)
<0.0001
−0.14 (−0.25 to −0.04)
<0.01
Square root serum aldosterone
0.01 (−0.09 to 0.11)
0.85
0.01 (−0.10 to 0.11)
0.98
Square root plasma angiotensinogen
0.07 (−0.02 to 0.17)
0.14
0.09 (−0.02 to 0.19)
0.11
Log urinary angiotensinogen/creatinine
0.16 (0.07 to 0.25)
<0.001
0.11 (0.01 to 0.22)
<0.05
Log plasma renin
−0.24 (−0.33 to −0.15)
<0.0001
−0.16 (−0.27 to −0.06)
<0.005
Square root serum aldosterone
−0.02 (−0.12 to 0.07)
0.64
0.06 (−0.05 to 0.16)
0.31
Square root plasma angiotensinogen
0.08 (−0.02 to 0.17)
0.11
0.03 (−0.08 to 0.14)
0.59
Log urinary angiotensinogen/creatinine
0.06 (−0.04 to 0.16)
0.22
0.09 (−0.02 to 0.20)
0.10
Diastolic BP
BP indicates blood pressure; CI, confidence intervals; and RAS, renin–angiotensin system.
*With adjustments for age, sex, body mass index, diabetes mellitus or an hemoglobin A1c>6.1%, regular tobacco use, and regular alcohol
consumption. Probability values are further adjusted for nonindependence of family members.
Michel et al Urinary Angiotensinogen and BP 153
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Figure 2. Multivariate-adjusted office systolic blood pressure across quartiles of circulating concentrations of renin, angiotensinogen
(AGT), and aldosterone or urinary AGT excretion (log urinary AGT/creatinine) in a group of African ancestry. *P<0.05, **P<0.0005 vs
quartile 1; †P<0.01 vs quartile 2. Adjustments are for age, sex, body mass index, diabetes mellitus or an hemoglobin A1c>6.1%, regular
tobacco use, and regular alcohol consumption. Probability values are further adjusted for nonindependence of family members.
by far exceeded the maximal Na+ consumption in the present community sample. Yet, in the present study, relationships
between urinary angiotensinogen/creat and BP were still
noted. Importantly, whether Na+ intake has an effect on urinary angiotensinogen and whether intrarenal angiotensinogen
contributes toward salt-sensitive hypertension remains controversial. Intrarenal or urinary angiotensinogen may increase32–34
or renal angiotensinogen mRNA levels may decrease with a
high salt load.35,36 Moreover, in transgenic mice models, overexpression of proximal tubular angiotensinogen causes hypertension regardless of salt intake, whereas overexpression of
liver angiotensinogen causes salt-sensitive hypertension.37
Despite inconsistencies in the ability to show relationships
between urinary angiotensinogen/creat and 24-hour urinary
Na+ intake in the present and a prior21 study, in both studies
relationships between urinary angiotensinogen/creat and BP
remained after further adjustments for indexes of Na+ intake.
Although several studies have demonstrated that urinary
angiotensinogen/creat is associated with BP in white or Asian
samples,18–21 whether these relationships are better than or independent of the previously described relationships between plasma
angiotensinogen concentrations22–24 or the circulating RAS25–29
and BP is uncertain.18–21 In the present study, we show associations between urinary angiotensinogen/creat and BP, whereas no
significant relationships between plasma angiotensinogen and
BP were noted, despite a relationship observed between plasma
angiotensinogen concentrations and urinary angiotensinogen/
creat. Importantly, the urinary angiotensinogen excretion–BP
relationships were noted in a typically salt-sensitive group where
plasma renin concentrations were inversely correlated with BP.
In keeping with one prior study,21 we also show that the associations between urinary angiotensinogen/creat and BP persisted
with adjustments for plasma angiotensinogen concentrations.
Moreover, despite relationships noted between urinary angiotensinogen/creat and BP in the present study, no relationships
between serum aldosterone concentrations and BP were noted,
and relationships between urinary angiotensinogen/creat and
BP were independent of circulating aldosterone concentrations.
Hence, in the present study, associations between renal RAS
activity, as indexed by urinary angiotensinogen/creat and BP,
were independent of indexes of the systemic RAS.
In the present study, plasma angiotensinogen concentrations
were correlated with urinary angiotensinogen excretion, a finding that is likely to be explained by augmentation of intrarenal angiotensinogen production by the extrarenal RAS,13–15,38
rather than by filtration of angiotensinogen at the glomerulus.
Because of its molecular size (50–60 kDa), little angiotensinogen is expected to cross the glomerular membrane and systemic infusion of angiotensinogen does not result in detectable
angiotensinogen in the urine.17 Consistent with this notion, in
154 Hypertension July 2014
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Figure 3. Multivariate-adjusted 24-hour systolic blood pressure across quartiles of circulating concentrations of renin, angiotensinogen
(AGT), and aldosterone or urinary angiotensinogen excretion (log urinary AGT/creatinine) in a group of African ancestry. *P=0.01, **P<0.005
vs quartile 1; †P=0.01 vs quartile 2. Adjustments are for age, sex, body mass index, diabetes mellitus or an hemoglobin A1c>6.1%, regular
tobacco use, and regular alcohol consumption. Probability values are further adjusted for nonindependence of family members.
the present study, we show no relationship between urinary
angiotensinogen excretion and estimated glomerular filtration rate. Although circulating angiotensinogen concentrations
were correlated with urinary angiotensinogen/creat, urinary
angiotensinogen excretion, but not plasma angiotensinogen
Table 4. Relationships Between Urinary Angiotensinogen
Excretion and Office SBP in a Group of African Ancestry Never
Having Received Antihypertensive Therapy, With Adjustments
for Measures of the Circulating RAS, Na+ Intake, or GFR
Adjustments
Partial r* (CI)
P Value
Log urinary angiotensinogen/creatinine vs office SBP (n=425)
*and Square root plasma angiotensinogen
0.15 (0.06–0.24)
*and Log plasma renin
0.16 (0.06–0.25)
<0.005
*and Square root serum aldosterone
0.16 (0.06–0.25)
<0.005
*and Log 24-h urinary Na+
0.16 (0.07–0.25)
<0.001
*and Log urinary Na /K
0.15 (0.06–0.24)
<0.005
*and Estimated GFR
0.16 (0.06–0.25)
+
+
<0.005
<0.005
CI indicates confidence intervals; GFR, glomerular filtration rate; K , potassium;
Na+, sodium; RAS, renin–angiotensin system; and SBP, systolic blood pressure.
*Adjustments are for age, sex, body mass index, diabetes mellitus or an
hemoglobin A1c>6.1%, regular tobacco use, regular alcohol consumption and
circulating measure of RAS, indexes of Na+ intake, or estimated GFR as indicated.
Probability values are further adjusted for nonindependence of family members.
+
concentrations, was associated with BP. This may reflect the
more important role of the renal as opposed to the systemic
RAS in BP control over the relatively low range of Na+ intake
values observed in the present population. As we have previously reported,24 it is nevertheless possible that at a higher
Na+ intake, systemic rather than renal angiotensinogen plays a
more important role in BP control.
Although speculative, the clinical implications of the present study warrant consideration. In this regard, although the
effect of RAS blockers on BP in salt-sensitive populations
such as those of African ancestry are limited,7,8 the present
results suggest that irrespective of a suppressed systemic
RAS, the intrarenal RAS may play an important role in BP
regulation in a proportion of these individuals. Hence, in contrast to the recommendations by some guidelines that RAS
blockers should not be first-line therapy in black African populations,9,10 targeting the renal RAS may be an important therapeutic approach in a subgroup of these patients even in the
presence of systemic RAS suppression. Further studies are,
therefore, required to evaluate whether RAS blockers produce
enhanced antihypertensive effects in groups of African descent
with increased urinary angiotensinogen excretion rates.
There are several limitations to the present study. First, the
present study was cross-sectional, and hence no conclusions
about cause and effect can be drawn. It is, therefore, possible
Michel et al Urinary Angiotensinogen and BP 155
that the independent relationships between urinary angiotensinogen excretion and BP reflect reverse causality, where as a
compensatory response to an elevated BP, and after a reduced
renin release, less renal angiotensinogen is converted to angiotensin II and hence more appears in the urine. However, the
relationships noted between urinary angiotensinogen and BP
in the present study were independent of plasma renin concentrations, despite the strong inverse relationships between
plasma renin concentrations and BP. Moreover, plasma renin
concentrations were not associated with urinary angiotensinogen excretion. Second, a high proportion of participants were
women and obese, and we were not statistically powered to
perform sex-specific analysis or analysis in categories of obesity. Thus, the relationships noted may relate specifically to
women or obese individuals only.
Perspectives
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The role of the RAS in salt-sensitive populations, such as those
of African ancestry, is currently uncertain. In the present study,
we show in a group of South Africans of African ancestry having never received antihypertensive therapy that despite strong
inverse relationships between plasma renin concentrations and
BP and a lack of relationship between circulating angiotensinogen or aldosterone concentrations and BP, urinary angiotensinogen excretion, as indexed by urinary angiotensinogen/creat, is
associated with both office and 24-hour BP. Importantly, these
relationships were independent of urinary indexes of Na+ intake
and of the circulating RAS. The present study, therefore, provides evidence to suggest that in salt-sensitive groups of African
ancestry, despite suppression of the circulating RAS, the intrarenal RAS may contribute toward BP control and that this effect
is independent of both Na+ intake and the circulating RAS.
Acknowledgments
This study would not have been possible without the voluntary collaboration of the participants and the excellent technical assistance of
Mthuthuzeli Kiviet, Nomonde Molebatsi, and Nkele Maseko.
Sources of Funding
This study was supported by the Medical Research Council of
South Africa, the University Research Council of the University
of the Witwatersrand, the National Research Foundation (Women
in Research and the Thuthuka Program), the Circulatory Disorders
Research Trust, the Carnegie Corporation, and the South African
National Foundation for Research.
Disclosures
None.
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Novelty and Significance
What Is New?
• The role of the intrarenal renin–angiotensin system (RAS), independent
of the systemic RAS, in blood pressure (BP) control in salt-sensitive,
­low-renin groups of African ancestry is unknown.
What Is Relevant?
• Because the systemic RAS is suppressed in salt-sensitive groups of
­African ancestry, RAS blockers are not recommended as first-line therapy for BP reduction in these populations. However, it has been suggested
that the intrarenal RAS is associated with BP.
Summary
In a community sample of African ancestry, which demonstrated typical
characteristics of salt sensitivity (inverse relationships between plasma
renin concentrations and both BP and an index of salt intake), independent of the systemic RAS (including plasma angiotensinogen concentrations), urinary angiotensinogen/creatinine (an index of urinary angiotensinogen excretion) was associated with both office and 24-hour systolic
BP. Hence, despite suppression of the systemic RAS, the intrarenal RAS
may play a role in BP control in salt-sensitive groups of African ancestry.
Urinary Angiotensinogen Excretion Is Associated With Blood Pressure Independent of the
Circulating Renin −Angiotensin System in a Group of African Ancestry
Frederic S. Michel, Gavin R. Norton, Muzi J. Maseko, Olebogeng H.I. Majane, Pinhas Sareli
and Angela J. Woodiwiss
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Hypertension. 2014;64:149-156; originally published online April 28, 2014;
doi: 10.1161/HYPERTENSIONAHA.114.03336
Hypertension is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231
Copyright © 2014 American Heart Association, Inc. All rights reserved.
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