Am J Physiol Heart Circ Physiol 293: H1327–H1333, 2007.
First published July 6, 2007; doi:10.1152/ajpheart.00457.2007.
CALL FOR PAPERS
Cardiovascular Aging
Long-term AT1 receptor blockade improves metabolic function and provides
renoprotection in Fischer-344 rats
Shea Gilliam-Davis,1,3 Valerie S. Payne,4 Sherry O. Kasper,1,3 Ellen N. Tommasi,1,2 Michael E. Robbins,3,4
and Debra I. Diz1,2,3
1
The Hypertension and Vascular Research Center, 2General Surgery, 3Department of Physiology and Pharmacology and
Department of Radiation Oncology, Wake Forest University School of Medicine, Winston-Salem, North Carolina
4
Submitted 13 April 2007; accepted in final form 2 July 2007
exhibit increases in systolic
blood pressure (SBP) (42), insulin resistance, body weight (13,
30, 31, 41), and serum leptin (30, 39) as they age. Similar
changes occur in the aging human population, and a clustering
of these factors is consistent with the metabolic syndrome
(MetS) (22, 41a). MetS, a collection of cardiovascular risk
factors, is an intermediate state between normal metabolism
and Type 2 diabetes (22, 43). Clinical trials have shown that
renin-angiotensin (ANG) system (RAS) blockade, either by
ANG-converting enzyme (ACE) inhibitors (4, 57) or ANG II
type 1 (AT1) receptor blockers (17, 27), may substantially
lower the risk for Type 2 diabetes in hypertensive subjects.
However, the exact mechanism underlying this effect is unknown. Moreover, long-term ACE inhibition or AT1 receptor
blockade in rodents protects against most of these age-related
changes, including the increase in blood pressure (5, 18),
weight gain (11), and decline in cognitive, mitochondrial,
cardiac, and renal function (19).
Circulating, cardiac, and intrarenal RASs are dissimilarly
regulated in the aging rat (9, 21, 28, 29) and during short- and
long-term RAS blockade (9, 29). Previous studies have suggested that plasma renin concentrations and kidney renin
mRNA are decreased in aging rats (28) and associated with a
decrease in plasma ANG peptides in aging Sprague-Dawley
(SD) rats (42); plasma renin is decreased in aging humans (54).
In contrast, there is an increase in intrarenal tissue ANG II with
aging (3) as well as an increase in the excretion of ANG
peptides (42), an indicator of activation of the intrarenal RAS.
Cardiac ANG peptides are also elevated in aging animals (21).
These observations, suggesting activation of the cardiac and
intrarenal RASs during aging in the face of a decline in the
circulating RAS, raise questions about the mechanisms underlying the beneficial effects of RAS blockade during aging.
The activation of the intrarenal RAS during aging occurs
over the same time frame as many of the features of MetS, but
it is not clear to what extent the different components of MetS
are interdependent. The Fischer-344 (F344) rat represents an
interesting model since insulin resistance and kidney damage
occur without an increase in blood pressure during the aging
process (53). Previous studies in normotensive rats have indicated that RAS blockade will prevent many age-related renal
pathologies, including the increase in blood pressure that
occurs with age (5, 18, 19). Furthermore, urinary ANG peptides remained low in animals treated long term (22 mo) with
RAS blockers (29). However, the extent to which the protective effects on the kidney are a result of the maintenance of low
blood pressure are unclear. Therefore, we assessed the time
course of changes in indexes of metabolic function, blood
pressure, and activation of the intrarenal RAS in older animals
compared with young F344 rats and in the presence of longterm (1 yr) RAS blockade to provide information on the
interdependence of many of the features of MetS.
Address for reprint requests and other correspondence: D. I. Diz, The
Hypertension and Vascular Disease Center, Wake Forest Univ. School of
Medicine, Medical Center Blvd., Winston-Salem, NC 27157-1032 (e-mail:
[email protected]).
The costs of publication of this article were defrayed in part by the payment
of page charges. The article must therefore be hereby marked “advertisement”
in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
angiotensin type 1 receptor blockade; glucose metabolosim; aging
MANY NORMOTENSIVE RAT STRAINS
http://www.ajpheart.org
0363-6135/07 $8.00 Copyright © 2007 the American Physiological Society
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Gilliam-Davis S, Payne VS, Kasper SO, Tommasi EN, Robbins
ME, Diz DI. Long-term AT1 receptor blockade improves metabolic
function and provides renoprotection in Fischer-344 rats. Am J
Physiol Heart Circ Physiol 293: H1327–H1333, 2007. First published
July 6, 2007; doi:10.1152/ajpheart.00457.2007.—Fischer-344 (F344)
rats exhibit proteinuria and insulin resistance in the absence of
hypertension as they age. We determined the effects of long-term (1
yr) treatment with the angiotensin (ANG) II type 1 (AT1) receptor
blocker L-158,809 on plasma and urinary ANG peptide levels, systolic blood pressure (SBP), and indexes of glucose metabolism in
15-mo-old male F344 rats. Young rats at 3 mo of age (n ⫽ 8) were
compared with two separate groups of older rats: one control group
(n ⫽ 7) and one group treated with L-158,809 (n ⫽ 6) orally (20 mg/l)
for 1 yr. SBP was not different between control and treated rats but
was higher in young rats. Serum leptin, insulin, and glucose levels
were comparable between treated and young rats, whereas controls
had higher glucose and leptin with a similar trend for insulin. Plasma
ANG I and ANG II were higher in treated than untreated young or
older rats, as evidence of effective AT1 receptor blockade. Urinary
ANG II and ANG-(1-7) were higher in controls compared with young
animals, and treated rats failed to show age-related increases. Protein
excretion was markedly lower in treated and young rats compared
with control rats (young: 8 ⫾ 2 mg/day vs. control: 129 ⫾ 51 mg/day
vs. treated: 9 ⫾ 3 mg/day, P ⬍ 0.05). Long-term AT1 receptor
blockade improves metabolic parameters and provides renoprotection.
Differential regulation of systemic and intrarenal (urinary) ANG
systems occurs during blockade, and suppression of the intrarenal
system may contribute to reduced proteinuria. Thus, insulin resistance, renal injury, and activation of the intrarenal ANG system
during early aging in normotensive animals can be averted by reninANG system blockade.
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AT1 RECEPTOR BLOCKADE IMPROVES METABOLISM AND RENAL FUNCTION
METHODS
RESULTS
Mean SBP was not different between older control and
treated rats, but both were significantly lower (P ⬍ 0.001) than
the young group (Fig. 1). We observed similar food intake
Fig. 1. Systolic blood pressure in young, control, and L-158,809-treated rats.
After 1 yr of treatment, L-158,809-treated rats had a similar blood pressure to
older control rats, and both older groups were lower than the young group.
*P ⬍ 0.001 vs. young rats.
AJP-Heart Circ Physiol • VOL
Fig. 2. Food intake and body weight in young, control, and L-158,809-treated
rats. Food intake was similar between the two older groups of rats, and both were
statistically higher than the young group. The older treated group maintained a
significantly lower body weight than the older control group. *P ⬍ 0.05 vs. young
rats; ⫹P ⬍ 0.001 vs. young rats; #P ⬍ 0.001 vs. control rats.
between the two older groups of rats, and both were statistically higher than that in young rats (P ⬍ 0.05). While both
older groups gained weight over the course of the study, the
older treated group maintained a significantly lower body
weight (P ⬍ 0.001) than the older control group (Fig. 2). Water
intake was significantly higher (P ⬍ 0.05) in treated rats
compared with young and control rats (Fig. 3). Urine volume
was higher (P ⬍ 0.01) in the two older groups of rats compared
with young animals (Fig. 3).
As expected in this model of aging, there was a significant
increase (P ⬍ 0.001) in serum leptin in older control rats
relative to the young and treated groups with a similar trend for
serum insulin (Fig. 4). Serum glucose in the older control
group was significantly higher (P ⬍ 0.001) than the young
group, whereas values in the treated group were not different
from the younger group (Fig. 4). The older control group had
a significantly lower QUICKI value and higher HOMA value
compared with the young group, and there were no differences
between young and treated rats (Fig. 5). This suggests that
older control animals have insulin resistance and that blockade
of the AT1 receptor may delay this from occurring.
Plasma ANG I (P ⬍ 0.05) and ANG II (P ⬍ 0.001) were
higher in older treated animals than in young or older control
animals (Fig. 6). However, plasma ANG-(1-7) was not significantly different among the three groups (data not shown).
Creatinine excretion was similar among the groups (young:
23 ⫾ 1 mg䡠kg⫺1 䡠day⫺1 vs. control: 19 ⫾ 2 mg䡠kg⫺1 䡠day⫺1
vs. treated: 25 ⫾ 3 mg䡠kg⫺1 䡠day⫺1). Serum creatinine was not
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Twenty-one male F344 rats were obtained from Harlan Laboratories (Indianapolis, IN) and housed under controlled conditions of light
(12:12-h light-dark cycle) and temperature with free access to food
and water. At 3 mo of age, one group of 8 rats (young animals) were
subjected to the measurements. Separate groups of animals were used
as vehicle controls (n ⫽ 7) or treated with 20 mg/l L-158,809 (n ⫽ 6)
in their drinking water for a period of 1 yr. SBP was measured using
the tail-cuff procedure at ⬃3 mo of age for the group of young rats
and at ⬃15 mo of age for the groups of control and L-158,809-treated
rats. There were at least three training sessions with the tail-cuff
procedure to acclimate the animals to the device. The mean of at least
five blood pressure measurements was determined for each animal.
Animals were then weighed and placed in metabolic cages for 24-h
urine collections on dry ice. Food and water intake were also determined. Rats were euthanized at least 3– 4 h after the removal of food
and water by quick decapitation, and trunk blood was collected in the
presence of inhibitors as previously described (26). Serum insulin and
leptin were measured using radioimmunoassays (Linco) and serum
glucose using a Freestyle glucose monitor (TheraSense). The quantitative insulin sensitivity check index (QUICKI) and homeostasis
model assessment (HOMA) were used as indexes of insulin sensitivity
as previously described (7, 15, 25, 31, 32). We used nanograms per
milliter for insulin and milligrams per decaliter for glucose as the units
for calculating these values (31). Plasma and urinary ANG I, ANG II,
and ANG-(1-7) were analyzed using radioimmunoassay (1, 26).
Protein in urine was measured using reagent strips (Multistix 10 SG,
Bayer, Elkhart, IN). Urine was analyzed for creatinine (Metra creatinine assay kit, Quidel), and urinary peptide data are expressed as 24-h
excretion rates normalized to creatinine excretion as detailed elsewhere (20). Serum creatinine was analyzed using the Quantichrom
creatinine assay kit (BioAssay System). The glomerular filtration rate
(GFR) was determined from serum and urine creatinine values. All
animal protocols were reviewed and approved by the Institutional
Animal Care and Use Committee.
Statistical analysis. All data are presented as means ⫾ SE, and P
values of ⬍0.05 were considered significant. One-way ANOVA with
Tukey’s multiple-comparison post hoc tests was performed using
Graphpad Prism.
AT1 RECEPTOR BLOCKADE IMPROVES METABOLISM AND RENAL FUNCTION
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19, 29, 40, 52) in rat strains where aging is accompanied by
increases in SBP.
There are reports that RAS blockade improves components
of, or reduces the onset of, MetS and Type 2 diabetes (4, 17,
23, 57). Our study demonstrates the advantageous effects of
RAS blockade independent of blood pressure-lowering actions
in accordance with previous studies (48, 50). However, the
precise mechanisms underlying the beneficial effects are not
entirely known, and mechanisms may involve actions at the
skeletal muscle (24, 48), brain, and autonomic nervous system
(30, 31) or other organs such as the liver and pancreas (18,
19, 51).
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Fig. 3. Water intake and urine volume in young, control, and L-158,809treated rats. Water intake was significantly higher in treated rats compared with
young and control rats. Urine volume was higher in the two older groups of
rats. *P ⬍ 0.05 vs. L-158,809-treated rats; **P ⬍ 0.01 vs. L-158,809-treated
rats; ␪P ⬍ 0.01 vs. young rats; ⫹⫹⫹P ⬍ 0.001 vs. young rats.
different among the groups (young: 0.5 ⫾ 0.0 mg/dl vs.
control: 0.6 ⫾ 0.1 mg/dl vs. treated: 0.7 ⫾ 0.1 mg/dl). GFR,
calculated from serum and urinary creatinine levels, was similar among the groups (young: 1.0 ⫾ 0.2 ml/min vs. control:
1.2 ⫾ 0.3 ml/min vs. treated: 1.1 ⫾ 0.3 ml/min). Urinary
excretion of ANG I (P ⬍ 0.001), ANG-(1-7) (P ⬍ 0.01), and
ANG II (P ⬍ 0.05) was greater in the older control group
compared with the young group. Urinary ANG peptide excretion in the older treated group was not different from the young
group (Fig. 7). The urinary ANG-(1-7)-to-ANG I ratio revealed
that the young group had a significantly higher ratio compared
with the two older groups (young: 4.4 ⫾ 1.1 vs. control: 0.95 ⫾
0.16 vs. treated: 2.5 ⫾ 0.64, P ⬍ 0.05). Protein excretion was
markedly elevated in older rats (P ⬍ 0.05) compared with
young animals, and this was completely prevented in AT1
receptor-blocked animals (Fig. 8).
DISCUSSION
Long-term AT1 receptor blockade prevented the increases in
insulin, leptin, and glucose observed in older F344 rats associated
with reduced weight gain. It is important to note that there were no
significant differences in blood pressure between the older control
and treated groups, associated with the improvements in metabolism. Proteinuria, a marker of renal damage, was completely
prevented in older treated rats compared with older controls, and,
in treated rats, ANG peptide excretion, an indicator of intrarenal
RAS activity, was maintained at levels not different from those
seen in younger animals. The results are consistent with previous
studies showing protective effects of long-term RAS blockade on
age-related changes in kidney and metabolic function (5, 10, 11,
AJP-Heart Circ Physiol • VOL
Fig. 4. Serum insulin, glucose, and leptin levels in young, control, and
L-158,809-treated rats. The young and treated groups had lower levels of
serum glucose and leptin, with a similar trend for insulin. **P ⬍ 0.01 vs.
young rats; ***P ⬍ 0.001 vs. young and L-158,809-treated rats.
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AT1 RECEPTOR BLOCKADE IMPROVES METABOLISM AND RENAL FUNCTION
Fig. 5. Quantitative insulin sensitivity check index (QUICKI) and homeostasis
model assessment (HOMA) values in young, control, and L-158,809-treated
rats. The older control group had a significantly lower QUICKI value and
higher HOMA value compared with the young group. *P ⬍ 0.05 vs. young
rats.
As expected, AT1 receptor blockade led to increases in
plasma ANG I and ANG II, consistent with previous findings
(29) and the known feedback mechanism of the system. This
implies that the dosing of the blocker was effective, even with
the absence of a blood pressure-lowering effect in these normotensive animals. Plasma ANG-(1-7) levels were not different between the two older groups of animals. Although a
previous study (29) has shown an increase in the levels of this
peptide with AT1 receptor blockade or ACE inhibition, the
failure to increase ANG-(1-7) levels in the circulation may
result from the reported decline in neprilysin activity in the
circulation and kidney of older animals (44). Interestingly,
plasma levels of ANG I and ANG II were not lower in older
F344 rats relative to younger animals. This was a surprising
finding since older F344 rats exhibited proteinuria with increased age, and renal damage has been suggested to contribute
to the loss of renin-producing cells in the kidney. However,
there was no reduction in GFR in older rats in this study, and
the reduction in circulating levels of ANG II in other models of
aging occurs coincident with the increase in SBP (31) rather
than the onset of kidney damage as assessed by proteinuria or
activation of the intrarenal RAS. As F344 rats do not have an
increase in blood pressure, the maintenance of normal circulating levels of RAS peptides may reflect the absence of a
pressure-mediated inhibition of renin release in these animals.
ANG II excretion was lower in older treated animals relative
to older controls, suggesting a role for increased intrarenal
ANG II production in the deleterious changes seen in renal and
metabolic function with aging. The lower level of ANG II
excretion in treated animals is similar to previous studies of
AJP-Heart Circ Physiol • VOL
Fig. 6. Plasma angiotensin (ANG) peptides in young, control, and L-158,809treated rats. Levels of plasma ANG I and ANG II peptides were higher in the
treated group. ⫹P ⬍ 0.05 vs. control rats; ***P ⬍ 0.001 vs. young and control
rats.
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long-term RAS blockade in older animals (29) or tissue ACE
knockout mice (38). Our findings further suggest that the
systemic and kidney RASs are differentially regulated, given
increases in circulating peptides in this and a previous study
(29) persisting for the duration of treatment while urinary
peptides remain low. The decrease in ANG peptide excretion
in the treated group may reflect tubular RAS suppression (29),
consistent with the differential regulation of the systemic and
kidney RASs (9, 38). GFR was similar among the groups. F344
rats develop age-related nephropathy while serum creatinine
levels do not change until the latter stages of nephropathy (8,
16, 35, 56). However, F344 rats develop proteinuria, which
may manifest as protein overload nephropathy, and there may
be slight changes in the glomeruli in the first couple of stages
(grades) of renal disease (8, 56). Proteinuria is decreased in the
presence of AT1 receptor blockers (37, 47): our study suggests
that this may result from reduced activation of the intrarenal
RAS as well as effects to correct hyperinsulinemia and elevated serum glucose.
Serum glucose in the older control group was significantly
higher than the young group and the profile for serum insulin
was similar, suggesting insulin resistance is present at this time
point in older control rats. The older treated group was indistinguishable from the young group. QUICKI and HOMA
values were significantly different in the older control group
AT1 RECEPTOR BLOCKADE IMPROVES METABOLISM AND RENAL FUNCTION
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#
Fig. 7. Urinary ANG peptide excretion in young, control, and L-158,809treated rats. Young and treated rats exhibited lower urinary ANG peptide levels
compared with control rats. The excretion values shown are normalized for
creatinine excretion. *P ⬍ 0.05 vs. young rats; ***P ⬍ 0.001 vs. young and
L-158,809-treated rats; ⫹P ⬍ 0.01 vs. young rats; #P ⬍ 0.05 vs. L-158,809treated rats.
compared with the young group, suggestive of insulin resistance, which is a known feature of the F344 rat at this age. Both
are established methods used to assess insulin resistance and
correlate well with the glucose-clamp technique (7, 25, 32).
Rats with decreased glial angiotensinogen (ASrAogen rats)
have lower levels of glucose and insulin during aging compared with age-matched SD rats associated with reduced sympathetic nervous system activity, suggesting a role for glialAJP-Heart Circ Physiol • VOL
Fig. 8. Protein excretion in young, control, and L-158,809-treated rats. Protein
excretion was elevated in control rats, and this was completely prevented in
treated rats. *P ⬍ 0.05 vs. young and L-158,809-treated rats.
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produced ANG II in the metabolic impairments that occur
during aging (30). Insulin and leptin interact in the rat hypothalamus at the phosphatidylinositol 3-kinase (PI3K) and
MAPK pathways to decrease feeding and maintain an appropriate metabolism (12). Aged Fischer ⫻ Brown Norway rats on
ad libitum and restricted diets showed a greater tendency to
develop insulin resistance in association with greater adiposity
compared with younger animals, suggesting that abdominal
obesity during aging may contribute to insulin resistance (13).
While the exact mechanisms of the beneficial effects of RAS
blockade on insulin and glucose are not known, it may be
partly due to the decreased actions of ANG II at the kinase
pathways as well as actions in the central nervous system on
autonomic pathway controlling insulin and glucose metabolism.
In the F344 rat, aging is associated with an increase in serum
leptin (39), as is the case with other rat strains (30). Our study
confirms this as there was a significant increase in serum leptin
in older control rats relative to young and L-158,809-treated
animals. Leptin regulates weight loss by suppressing the appetite and food intake and enhancing energy expenditure (36,
55). Food intake was similar between the two older groups of
rats, and both were statistically higher than that in young rats,
but the treated group maintained a significantly lower body
weight than the control group. This is consistent with a report
(55) showing that leptin is primarily released from adipose
tissue and serves as an index of the amount of body fat mass.
We did not measure physical activity in this study, and it is
possible that changes in activity levels may accompany the
overall improvement in metabolic function. In ASrAogen rats,
leptin levels and body weight are lower and food intake higher
than in SD and (mRen2)27 rats (30), suggesting that interruption of the brain RAS may be part of the beneficial effects seen
with RAS blockade. Leptin, like insulin, via actions in the
brain, activates the sympathetic nervous system. Activation of
the sympathetic nervous system can lead to a reduction in GFR
and salt and water retention. This may lead to activation of the
renal RAS and kidney damage. F344 rats are known to have
leptin and insulin resistance (33, 34), as appears to be the case
with our animals. Thus, elevated levels of insulin and leptin
may also contribute to the declining renal function that occurs
during aging.
L-158,809 is a competitive and specific AT1 receptor antagonist (14, 49), and, in this study, it deceased indexes of MetS
and Type 2 diabetes after treatment for 1 yr, similar to the
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AT1 RECEPTOR BLOCKADE IMPROVES METABOLISM AND RENAL FUNCTION
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
ACKNOWLEDGMENTS
The authors thank Dr. Ron Smith of Merck for kindly providing L-158,809.
21.
GRANTS
We acknowledge support from National Institutes of Health Grants HL51952, HL-51952S1, and CA-122318. Unifi (Greensboro, NC) and the FarleyHudson Foundation (Jacksonville, NC) also provided partial support for this
work.
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effects of other RAS antagonists or inhibitors and consistent
with what has been shown in previous studies (18, 19, 24, 29,
40, 48, 52). The mechanisms behind the antidiabetic effects are
not well understood, and there are reports that a certain subset
of AT1 receptor antagonists may have such effects by acting as
a partial agonist of peroxisome proliferator-activated receptor-␥ (PPAR-␥) (6, 45, 46). Other AT1 receptor antagonists
tested, including valsartan, had no effect on PPAR-␥. However, in the Valsartan Antihypertensive Long-term Use Evaluation trial (27), valsartan reduced new onset diabetes, suggesting that the antidiabetic effect of this AT1 receptor antagonist is mediated indeed through the AT1 receptor, not
necessarily by interactions with PPAR-␥. Valsartan treatment
in KK-Ay mice, a model of Type 2 diabetes, did not affect SBP
but improved insulin sensitivity, PI3K activity, and glucose
transporter 4 translocation while decreasing TNF-␣ expression
in skeletal muscle (48). It is also important to note that
interruption of the RAS at levels other than AT1 receptor
blockade has proven beneficial in reducing the new onset of
diabetes (57).
We conclude that aging is associated with activation of the
intrarenal RAS independent of age-related increases in SBP.
Moreover, the decline in circulating RAS during aging may be
a consequence of the age-related increase in SBP, since animals without the increase in SBP have no reduction in ANG II
in plasma, despite the development of MetS. Long-term blockade of the RAS reduces the onset of indexes of MetS and
kidney damage that occur during aging in F344 rats independent of blood pressure-lowering effects. Moreover, intrarenal
RAS activity was decreased in the presence of the blockade,
suggesting that local tissue RAS blockade may contribute to
the protective effects on metabolic, kidney, and cardiovascular
function during aging. Further investigation is needed to determine the full complement of mechanisms and other tissue
RASs that may be involved in the deleterious changes that
occur in the normotensive population as they age and may
contribute to the beneficial effects of RAS blockade.
AT1 RECEPTOR BLOCKADE IMPROVES METABOLISM AND RENAL FUNCTION
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