(Hypertension. 2000;35:1009.)
© 2000 American Heart Association, Inc.
Scientific Contributions |
Development of Hypertension in a Rat Model of Diet-Induced Obesity
From the Department of Physiological Sciences, Eastern Virginia Medical School, Norfolk, Virginia.
Correspondence to Anca D. Dobrian, PhD, Department of Physiological Sciences, Eastern Virginia Medical School, PO Box 1980, Norfolk, VA 23501-1980. E-mail dobrian{at}borg.evms.edu
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Abstract |
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Abstract—Although obesity is a risk factor for hypertension, the relationship between these 2 conditions is not well understood. Therefore, we examined some parameters of hypertension and cardiovascular disease in a dietary model of obesity. Male Sprague-Dawley rats were provided either a control diet (C) or a diet containing 32% kcal as fat (similar to a Western diet) for 1, 3, or 10 weeks. Rats in the latter group diverged based on body weight gain into obesity-prone (OP) and obesity-resistant (OR) groups. Systolic blood pressure in OP rats was significantly higher after 10 weeks of the diet (149±4.8 mm Hg) compared with both OR and C groups (131±3.7 and 129±4.5 mm Hg, respectively). The aortic wall area of OP rats was significantly increased, indicating arterial hypertrophy, and a 2-fold increase in plasma renin activity was found in OP rats compared with OR and C rats. The lipid profile showed a significant increase in plasma and VLDL triglycerides of OP versus OR and C groups as early as 3 weeks on the diet. Plasma and LDL-cholesterol levels were increased in the OP group versus the OR and C groups after 3 weeks of the diet, but the difference was blunted after 10 weeks. Lipid peroxidation (thiobarbituric acid–reactive substances) in OP rats was increased 2-fold in LDL and 1.5-fold in aortic wall compared with OR rats, suggesting an increased oxidative stress in these animals. Periodic acid–Schiff staining of the kidney showed mesangial expansion and focal sclerosis that were more prominent in OP rats than in OR rats. The results suggest that hypercholesterolemia, but not hypertriglyceridemia, is linked to the diet; that hypertension and renin-angiotensin system activation are associated with obesity; and that lipid peroxidation and renal damage are the results of both factors.
Key Words: renin • aorta • kidney • lipoproteins • lipids • diet
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Introduction |
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Obesity is a complex, multifactorial disease that is often associated with diabetes, cardiovascular diseases, and stroke. Among other factors, obesity is an important contributor to essential hypertension in humans. Data from the Framingham Heart Study suggest that
78% of essential
hypertension in men and 65% of essential hypertension in women can
be directly attributed to obesity.1 However, the
mechanisms that link obesity with high blood pressure and altered renal
function have not been fully elucidated. One problem in the study of
the mechanisms of obesity hypertension has been the lack of a suitable
animal model. The ideal model would not only have the features of human
hypertension but also allow the study of sequential changes in
cardiovascular and kidney function that occur with
weight gain. The genetic models of obesity may or may not develop
hypertension or do not mimic the changes observed in humans. For
example, Zucker rats have decreased plasma renin activity
(PRA)2 as opposed to the high PRA observed in
humans.3 In contrast, diet-induced obese animal models
appear to be the most relevant with regard to human obesity. Some of
these models, such as the obese dog4 or obese
rabbit5 fed a high-fat diet, are used extensively to study
obesity hypertension because they closely mimic some of the cardiorenal
changes found in obese humans. A particularly interesting model of
diet-induced obesity is one originated by Levin et al6 and
currently developed into a purified diet model.7 In this
model, Sprague-Dawley (SD) rats fed a purified moderately high-fat
(MHF) diet exhibit a bimodal pattern in body weight (BW) gain similar
to that observed in humans. Approximately half of the rats gain weight
rapidly compared with chow-fed rats (obesity prone [OP]), whereas the
other half gain BW at a rate similar to or lower than that of the
chow-fed animals (obesity resistant [OR]).7 This
model enables one to dissociate between the factors related to a
high-fat diet and obesity per se. Some of the major characteristics associated with obesity hypertension in humans are the activation of the renin-angiotensin system (RAS),8 9 high levels of circulating leptin,10 reduced growth hormone (GH) concentration,11 and an activation of the sympathetic nervous system.12 Moreover, obesity hypertension is often associated with dyslipidemia, indicating low levels of HDL-cholesterol13 and higher levels of triglycerides.14 In addition, hyperlipidemia associated with hypertension may induce glomerulosclerosis in the kidney and eventually alter kidney function.15 There also are data that indicate increased oxidative stress in human essential hypertension,16 17 as well as in obese hypertensive patients,18 that may further contribute to the development of atherosclerosis or other cardiovascular diseases.
In the present study, we used a diet-induced obesity model in the rat7 19 that displays some of the characteristics of human obesity hypertension, such as increased plasma norepinephrine response to intravenous glucose,6 20 increased plasma leptin concentration,21 and decreased GH secretion and synthesis.22 23 The purpose of the present study was to document the development of hypertension in this animal model and to partially characterize the model with respect to some factors likely to be involved in the cardiovascular and renal changes associated with obesity hypertension. We consider this model particularly useful in the assessment of the causal relationship among hypertension, obesity per se, and diet.
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Methods |
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Animals
All procedures that involved animals were approved by the Animal Care and Use Committee of Eastern Virginia Medical School. Two separate sets of animals were used to measure short-term and long-term responses to diet-induced obesity. Animals were housed individually in stainless steel cages in a temperature-controlled room (22±2°C) with a 12-hour light/dark cycle. Food and water were provided ad libitum throughout the acclimation and experimental periods.
Short-Term Responses
Forty-two male SD rats (175 to 200 g) were randomly
assigned to receive either an MHF (32% kcal as fat; Research
Diets) or a purified low-fat diet (LF) (10.6% kcal as fat; Research
Diets) for either 1 or 3 weeks. Six rats were sacrificed as baseline
controls for blood pressure and blood lipid profile values. BWs and
body lengths were measured initially and then weekly together with food
intake. At each time point (1 and 3 weeks), the rats with the greatest
and lowest weight gain were selected along with LF-fed animals, and
blood pressures were measured.
Long-Term Responses
Of 32 male SD rats (300 to 350 g), 24 were randomly
selected to be fed the MHF diet, whereas the remaining 8 rats
(controls) were fed a standard rat chow diet (6.5% kcal fat; Harlan
Teklad) for 10 weeks. BW and food intake (corrected for spillage) were
measured weekly. After 10 weeks, rats fed the MHF diverged into
distinct groups based on BW gains. BW gains were analyzed for
frequency distribution with 
2 and Student’s
t test analyses as previously
described.19 24 Rats with the greatest BW gains were
referred to as OP (n=8), whereas those with the lowest BW gains were
referred to as OR (n=8). This analysis demonstrated a
significant difference in BW gain between OP and OR rat populations. At
the end of the study, rats were decapitated, and trunk blood was
collected in EDTA-coated tubes. Plasma was immediately separated
through centrifugation and used for PRA determination,
lipid assays, and lipoprotein isolation. Thoracic aorta, kidney, and
fat depots (retroperitoneal and epididymal) were harvested, weighed,
and either used immediately or snap frozen in liquid nitrogen.
Systolic Blood Pressure
The onset and development of hypertension were assessed with the
tail-cuff method with a Narco Biosystems Electro-Sphygnomanometer after
the rats were warmed at 35°C for 5 minutes, while under slight
restraint. Blood pressure was measured under conscious conditions at
the beginning of the experiment and at 1, 3, 8, and 10 weeks of the
diet. The average of 3 pressure readings was recorded for each
measurement.
Lipid Profile
Blood was collected after decapitation, and plasma was
subjected to density gradient
ultracentrifugation.25 VLDL was isolated
at the plasma density of d<1.006 g/mL, and LDL was collected at
d=1.018 to 1.050 g/mL. Both VLDL and LDL fractions were washed through
centrifugation and extensively dialyzed at 4°C in the
dark against multiple changes of Tris-buffered saline, pH 7.4, with
0.01% EDTA and 0.22 mmol/L BHT (Sigma Chemical Co.).
Cholesterol and triglyceride levels in total
plasma and lipoprotein fractions were assayed with enzymatic kits from
Sigma Chemical Co.
Lipid Peroxidation
Lipid peroxidation in LDL fraction and tissues (thoracic aorta
and kidney) was determined with spectrophotometric measurement of the
amount of malondialdehyde equivalents with thiobarbituric acid and was
expressed as thiobarbituric acid-reactive substances (TBARS; nmol
malondialdehyde/mg protein), according to the method of Fogelman et
al.26 LDL was dialyzed against Tris-HCl buffer,
supplemented with 0.01% EDTA and 0.33 mmol/L BHT, and assayed
within 48 hours on isolation. The thoracic aorta and kidneys were
collected on ice, washed in 0.9% NaCl, and immediately
homogenized in 20 mmol/L Tris-HCl, pH 7.4,
supplemented with 5 mmol/L BHT.27 LDL protein was
assayed according to a modification of the Lowry method,28
and tissue protein was assayed according to the BCA
method29 with BSA as a standard.
Morphological Analysis
To determine the wall area of thoracic aorta as an index of
arterial hypertrophy, thin sections (5
µm thick) of the paraffin-embedded tissue were dehydrated and stained
for 1 minute with toluidine blue to visualize the intima-media of the
vessel wall. The internal and external circumferences of each vessel
were measured with a video-based image system with edge-tracking
software (JAVA; Jandel Scientific). The mean of 3 different
measurements was used to calculate the internal and external diameters
and the intimal-medial area.
Histology
Kidneys were fixed in 10% buffered formalin for 4 hours and
embedded in paraffin. Thin (4- to 5-µm) sections were stained with
periodic acid–Schiff (PAS) reagent and hematoxylin for
counterstaining. To evaluate the degree of segmental sclerosis, 3
independent investigators examined the slides in a blinded fashion,
mixing the slides after covering the protocol numbers. In each case, 10
to 20 glomeruli were examined for each slide and individually graded on
a scale of 0 to 2+ according to the degree of glomerular
sclerosis. Grade 0 indicated a normal-appearing glomerulus; grade 1+
was characterized by mild expansion of mesangial matrix, no
occlusion in the glomerular capillaries, or adhesion to
Bowman’s capsule; and grade 2+ included expansion of the
mesangial matrix, usually focal with adhesion to Bowman’s
capsule, and some degree of capillary occlusion. A score
representing the sum of grades was obtained for each
rat.
Other Assays
PRA was measured through radioimmunoassay with a kit in which
125I-angiotensin (DiaSorin Inc) was
used according to the manufacturer’s instructions.
Statistical Analysis
All data were analyzed for statistical significance with
ANOVA for repeated measures and Student’s t test. The null
hypothesis was rejected at P<0.05.
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Results |
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BW, Food Intake, and Composition Data
The BWs for OP, OR, and C rats were measured weekly. Initial mean BWs of the 3 groups did not differ significantly (Table 1
). At week 3, OP rats had significantly
higher BWs than OR rats, and the BWs remained higher throughout the
10-week dietary period. At week 7, the BWs of OP rats were
significantly greater than those of C rats. In terms of the BW gain,
the short-term (1- and 3-week) study showed a significant difference
after the first week of MHF diet between the OP and OR rats (Table 1). After 3 weeks of the diet, a 25% increase in mean BW was
observed for the OP rats versus the OR and C rats, and in the long-term
study, an even higher (34%) increase was found after 10 weeks of the
diet (Table 1). Epididymal and perirenal fat depot weights were
higher in OP than in OR rats after 10 weeks of the diet (Table 1). The obesity index (the equivalent of the body mass index for
humans) after 10 weeks was significantly increased in OP compared with
both OR and C rats, reflecting the increased body fat content (Table 1). Feed efficiency of weight gain calculated as BW gain (g)
divided by energy consumed (MJ) was 25% higher for OP than for
resisters, suggesting a difference in the metabolic
response to the diet between the 2 groups (Table 1).
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Blood Pressure, PRA, and Thoracic Wall Area in OP, OR, and C
Rats
The average baseline systolic blood pressure,
measured 1 day before the start of the MHF diet, was 114±0.8
mm Hg for all of the rats used in the experiment. After 1 and 3 weeks
of diet, the blood pressure increased slightly in all 3 groups, but it
did not differ among groups (Figure 1).
Starting with week 8, the systolic blood pressure of the OP
rats was significantly increased compared with C rats (Figure 1). After 10 weeks of the diet, the mean blood pressure of OP
rats was 149±4.8 mm Hg, which was significantly higher than that
of either OP (131±3.7 mm Hg) or chow-fed C (129±4.5
mm Hg) groups (Figure 1). PRA was in the normal range for all
groups after both 1 and 3 weeks of diet (Table 2). After 10 weeks, PRA was increased
2-fold in the OP group compared with both OR and C rats (Table 2). The result parallels the increase in blood pressure observed
in the OP group versus the OR and C rats. Moreover, there is a good
correlation in all 3 groups between blood pressure and PRA
(r=0.794, P<0.05), suggesting that activation of
the RAS is important in the development of hypertension in this model.
To assess whether the high blood pressure in the OP group of animals
had any effect on the morphology of the arteries, we measured the wall
area of thoracic aorta in the 3 groups of rats after 1, 3, and 10 weeks
of the diet. The results showed no differences among the 3 groups after
1 and 3 weeks of the diet (Table 2). After 10 weeks of the diet,
the OP rats displayed a 30% increase in the aortic wall compared with
OR rats (Table 2), suggesting that structural changes already
occurred in the arteries of hypertensive rats. In addition, there is a
good correlation between wall area and blood pressure in OP, OR, and C
rats (r=0.861, P<0.01), suggesting that the
structural arterial changes observed are in close
connection to the blood pressure in these animals.
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Plasma Lipid Profile in OP, OR, and C Rats
After 1 week of the diet, there were no differences in the
cholesterol and triglyceride levels in both
plasma and lipoprotein (LDL and VLDL) fractions among the OP, OR, and C
groups (data not shown). After 3 weeks of the diet, the
cholesterol values for the OP group were significantly
increased compared with OR and C groups in plasma, LDL, and VLDL
fractions, whereas only the LDL-cholesterol level was
higher in OR than in C rats (Figure 2A).
The difference in the total cholesterol and LDL- and
VLDL-cholesterol levels was blunted between OP and OR rats
after 10 weeks of the MHF diet but remained significantly increased in
both groups compared with the chow-fed C group (Figure 2B). The
total, LDL, and VLDL triglyceride levels were significantly
increased after 3 weeks of the MHF diet in OP compared with both OR and
C groups (Figure 2C). The same differences for plasma and VLDL
triglycerides were also observed after 10 weeks of the
diet, with a further increase in the VLDL triglycerides in
the OP group and a correspondent decrease in LDL
triglycerides that abolished the difference among the OP,
OR, and C groups in this latter fraction (Figure 2D). The data
suggest that hypercholesterolemia in OP and OR
rats was a direct consequence of the MHF diet, whereas the elevated
level of triglycerides in OP group may be attributable to
the obese state and not to the high-fat diet.
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Lipid Peroxidation in Plasma and Tissues of OP, OR, and C
Rats
The level of lipid peroxides expressed as TBARS was assessed in
LDL fraction (known to be the most prone to oxidative modification) and
in the homogenates of thoracic aorta in the 3 groups. After
1 week of the diet, TBARS levels for the LDL fraction are very low,
consistent with data reported for normal adult rats, whereas
the aortic peroxides were not detectable (Table 3). After 3 weeks of the diet, the LDL
TBARS exhibited a 3-fold increase in both OP and OR groups compared
with the C animals. Aortic TBARS were low for OP rats and were still
not detectable for OR and C rats (Table 3). After 10 weeks of
the MHF diet, the LDL TBARS in OP rats showed a further 3-fold increase
compared with those on the 3-week diet and was significantly higher
than that for both OR and C groups. Aortic TBARS were detectable in all
3 groups, showing a substantial increase for the OP group that was
significantly higher than that for both OR and C groups (Table 3). In addition, the OR group had a 2-fold higher level of TBARS
versus the chow-fed group. The data suggest increased oxidative stress
in both the plasma and aortic wall of OP rats versus OR and C rats.
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Renal Morphology Changes in OP, OR, and C Rats
To address the possible morphological changes in the kidney, we
used PAS-hematoxylin staining and morphometric analysis of the
kidneys of OP, OR, and C rats after 10 weeks of their respective diets.
Figure 3 illustrates the mild sclerosis
noticed in the OP (Figure 3C) and OR (Figure 3B) rats compared with C
rats (Figure 3A). The lesions were in various stages of development,
with most of them in a relatively early stage, displaying capillary
loop collapse, moderate mesangial expansion, and sometimes
adhesion between the affected segments and Bowman’s capsule (Figure 3C). Morphometric analysis indicated a mean±SE
mesangial score of 11.8±0.9 for the OP group, which was
higher than that for the OR (9.2±1.2) and C (8.4±1.2) groups. Still,
the difference was significant only between the OP and C groups. The
data suggest a combined role of diet and obesity per se in the kidney
injury in this rat model.
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Discussion |
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This model of diet-induced obesity developed mild hypertension accompanied by vascular and renal changes similar to those observed in obese hypertensive humans. The MHF diet that we used contains 32% kcal fat, a value similar to the average Western diet, as opposed to many other models that have very high levels of fat.30 In addition, similar to humans, not all rats fed the MHF diet become obese, with the BW displaying a bimodal distribution. The increased BW reflects an increase in the adipose mass in the OP rats versus the C rats as measured with the obesity index. This mimics the increased body mass index associated with human obesity. The experiments enabled us to assess early (1 to 3 weeks after the beginning of the MHF diet) and late (10 weeks) changes induced by diet and obese state. One of the earliest changes measured is a drastic modification in the lipid profile among OP, OR, and C groups after 3 weeks of diet. Total plasma cholesterol is significantly increased in OP rats only, because of a cholesterol enrichment in both LDL and VLDL fractions (Figure 2A
). Results are consistent with other
reports of diet-induced obesity but only after 8 weeks of a
hypercholesterolemic diet.31 After 10
weeks of the diet, both OP and OR rats had significantly higher levels
of total and LDL-cholesterol but not
VLDL-cholesterol. These data suggest that the clearance of
cholesterol is impaired in OP rats, whereas in OR rats the
cholesterol loading of LDL is decreased. Therefore, OP rats
are exposed to high cholesterol levels for a longer time
period, which may lead to vascular complications that may appear later
in time. Some preliminary data from our group indicate that the OP rats
have a lower HDL-cholesterol level throughout the diet
compared with OR and C groups (unpublished data). This is
consistent with other reports showing a decrease in
HDL-cholesterol level in
hypercholesterolemic rats.32
Triglycerides are also increased in OP rats after 3 weeks
of the MHF diet in plasma, LDL, and VLDL fractions (Figure 2C).
As opposed to cholesterol content, this difference is even
greater after 10 weeks of the diet, indicating that factors other than
diet are also responsible for the high levels of
triglycerides in OP rats. One possible factor may be the
reduced GH secretion reported in OP rats.22 23 Impaired GH
secretion may lead to an abnormal lipid profile in rats, with high
levels of triglycerides and low levels of
HDL-cholesterol.33 Dyslipidemia,
which occurs in this model of diet-induced obesity, is also a common
feature of obesity in humans and is frequently associated with
hypertension.34
Another early detectable parameter in our model is
lipid peroxidation. Free radicals are known to be involved in a variety
of human pathologies, including
atherosclerosis,35 obesity,18
and hypertension.16 17 36 In addition, increased oxidative
stress was reported for various animal models of hypertension, such as
spontaneously hypertensive rats,37 the Dahl hypertensive
rat,38 39 or angiotensin-induced hypertension
in the rat.40 In this study, peroxides associated with the
native LDL fraction were elevated in both OP and OR rats compared with
C rats by 3 weeks. This may be due to the increase in the overall
cholesterol loading of LDL particles caused by the MHF
diet. However, the values do not exceed the normal values reported for
the physiological levels of peroxides associated
with LDL particles. The aortic homogenates of OP rats
displayed a low level of TBARS compared with OR and C rats, in which
the peroxides, if present, were not detectable with our method
(Table 3). After 10 weeks of the diet, the level of lipid
peroxides in the LDL fraction was significantly increased in OP rats
compared with both OR and C rats, and the TBARS associated with LDL
indicated the presence of a minimally modified LDL level. This was
shown to be a potentially atherogenic state of LDL that is also common
with other diseases, such as diabetes.41 The level of
lipid peroxides in the aortic wall was also significantly increased in
OP versus OR and C rats and in OR versus C rats, suggesting that both
the diet and the obese state are responsible for the induction of the
increased oxidative stress. A potential mechanism for the generation of
free radicals may be the activation of ß-adrenergic receptors
reported for OP rats.19 This could increase lipolysis to
yield free fatty acids that are able to uncouple the mitochondrial
phosphorylation and further generate free
radicals.42 Another possibility is that increased leptin
reported for OP21 is able to generate oxidative stress, as
was recently reported for endothelial cells in
culture.43
The most important associated pathology that was detected late in
the diet was hypertension. A significant increase in blood pressure
that exceeds the normal threshold (systolic blood pressure
>140 mm Hg) was measured only after 8 weeks of the diet and
became significant in OP versus OR and C rats only after 10 weeks of
the diet (Figure 1). Hypertension developed in OP, but not OR,
rats, suggesting that diet is not the major factor that causes the high
blood pressure in this model. The hypertension is also well correlated
to PRA, indicating that activation of the RAS may be one of the major
causes of the increase in blood pressure in OP rats. There is a
consensus that sympathetic overactivity in obese subjects may
predispose to cardiovascular disease in general and to
hypertension in particular.44
The hypertension and obesity in this rat model are also
accompanied by changes in the vascular and renal morphology. The aortic
wall area of the OP rats is significantly increased compared with OR
and C rats. In consideration of the significant correlation between
blood pressure and wall area in all 3 groups, arterial
hypertrophy is most likely caused directly by hypertension.
High blood pressure is known to induce vascular hypertrophy
in animal models of experimental hypertension,45 46 and
the elevated pressure may initiate a growth response through elevations
in wall stress.47 The hypertrophy of the wall
and the increased lipid peroxidation detected are potential candidates
to contribute to further complications in OP rats, such as
atherosclerosis. The kidney morphology indicated a
moderate glomerulosclerosis in OP rats and some
mild changes in the glomerular structure in OR rats
compared with C rats (Figure 3). The alterations in kidney
structure are apparently a combined effect of diet and other
aggravating factors associated with the obese state.
Hypertriglyceridemia present in the OP
rats may contribute to glomerulosclerosis, as
shown in other animal models.48 49 50 In addition, reactive
oxygen species, which are apparently increased in our model, were shown
to induce glomerular sclerosis and altered tubular cell
function.51 Although we did not measure any renal
functional parameters, we expect the sclerosis in the OP
rat kidney to increase tubular reabsorption, which may raise
glomerular filtration rate and stimulate renin secretion.
On the other hand, the increased perirenal fat depots measured in OP
rats may generate medullary pressure, which is also known to cause
renin release.4 Further investigation is needed to assess
the renal function in our model. One possible scenario, based on the
present results and supported by data reported by other authors, is
that increased perirenal fat and
hypertriglyceridemia associated with
obesity, together with the increased oxidative stress generated by both
the obese state and diet, may induce augmented renin release by the
kidney due to glomerulosclerosis or other
mechanisms, which ultimately induce the increase in blood pressure.
In conclusion, we partially characterized a rat model of diet-induced obesity that also develops hypertension. The advantages over other similar animal models are the close similarity to human obesity hypertension, namely activation of RAS, dyslipidemia, increased oxidative stress, and associated vascular and renal pathology, and the ability to dissociate between the effect of MHF diet (specific differences between OP, OR, and chow-fed C rats) and other factors specifically related to obese state (differences between OP and OR rats). With the latter differential analysis, we can conclude that diet induces hypercholesterolemia, but not hypertriglyceridemia; that obesity is responsible for the development of hypertension and RAS activation; and that lipid peroxidation and the renal changes are apparently the result of the combined effect of dietary factors and obesity state per se. The model may also be useful to study other pathologies associated with obesity, such as atherosclerosis.
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Acknowledgments |
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This work was supported by NIH grants HL-54810 and DK-46832. The authors wish to acknowledge the excellent technical assistance of Suzanne Schriver.
Received October 19, 1999; first decision November 11, 1999; accepted December 8, 1999.
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