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Department of Physiological Sciences, Eastern Virginia Medical School, Norfolk, Virginia 23507
Submitted 31 October 2002 ; accepted in final form 6 June 2003
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONREFERENCES |
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glomerulosclerosis; kidney; leptin; sodium dietary
78% of men and 65% of women, as
indicated by the data from the Framingham Heart Study
(25). Another important
contributor to hypertension in humans is the excessive consumption of dietary
salt, and epidemiological studies have demonstrated a significant but weak
relation between salt intake and hypertension
(32,
33). Some, but not all,
interventional studies have shown that salt restriction may lower blood
pressure (BP) (19,
33). Some recent studies
report correlation among hypertension, salt sensitivity, and insulin
resistance in obese humans
(38), whereas others fail to
observe a significant relationship
(8). Animal models of obesity,
hypertension, and insulin resistance display differences with respect to salt
sensitivity. In Zucker rats, there is a clear correlation between salt intake
and the severity of hypertension
(4,
47), whereas in chronic
hyperinsulinemic Sprague-Dawley (SD) rats, hypertension is not salt sensitive,
albeit a shift in pressure-natriuresis relationship was reported
(2). One important contributor
to hypertension in salt-sensitive animal models and humans seems to be the
endothelial dysfunction, in particular the altered vascular reactivity due to
an impairment in nitric oxide (NO) production
(22,
31,
36). High-salt intake is able
to decrease both plasma levels and urinary excretion of nitrates
(3,
16). One possible explanation
is a reduced availability rather than decreased production of NO. The ability
of NO to quickly interact with superoxide anion, forming the potent oxidant
peroxynitrite, is well documented
(43). Increased superoxide
production in both vasculature and kidney was extensively reported in various
forms of hypertension in experimental models and humans
(40–42,
46). Moreover, we reported
that obese hypertensive rats on high-fat diet also display increased oxidative
stress and reduced NO bioavailability
(12). Also, salt sensitivity
was associated with increased oxidative stress in rats
(5,
49). Apart from the effects on
BP regulation, elevated salt intake was associated with cardiovascular and
renal changes leading to end-organ damage
(6). Moreover, a recent report
connects salt intake with oxidative stress and nephrosclerosis in
Dahl-sensitive hypertensive rats
(48). Another important factor
involved in BP regulation in obesity is leptin
(24). Leptin was shown to have
both a vasopressor effect at peripheral level and, infused in high doses, a
hypertensive effect acting at central level
(24). However, a recent report
suggests that leptin may not contribute to arterial pressure sensitivity to
salt in hyperleptinemic obese rats
(7). The aim of our study was
to assess the effect of high-fat, high-salt diets on the development of
hypertension and oxidative stress in a rat model of diet-induced obesity.
Moreover, the effect on vascular hypertrophy and kidney sclerosis was
assessed. Additionally, the effect of salt on adiposity and leptin production
was also measured. |
METHODS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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All procedures involving animals were approved by the Institutional Animal Care and Use Committee of Eastern Virginia Medical School. Eighteen male SD rats (300–350 g) individually caged were randomly selected to be fed a moderately high-fat diet (MHF) with 0.8% sodium (32% kcal as fat, Research Diets, New Brunswick, NJ), whereas six rats (controls) were fed purified low-fat (LF) diet with 0.8% sodium (10.6% kcal as fat, Research Diets) for 10 wk. An identical number of rats was placed on MHF and LF diets, each containing either 2 or 4% sodium (high-salt diets). Food and water were provided ad libitum throughout the experiment. Body weights (BW) and lengths were measured initially and then weekly together with food intake. Rats fed the MHF diet on both low and high salt diverged into distinct groups based on BW gains. Assignment of rats into obesityprone (OP) (n = 8) and obesity-resistant (OR) (n = 8) groups was performed as described previously (12).
Systolic BP
The onset and development of hypertension were assessed by using the tail-cuff method with a Narco Biosystems Electro-Sphygnomanometer (Houston, TX). BP was measured under conscious conditions at the beginning of the experiment and at 1, 5, 8, and 10 wk of diet. The average of five pressure readings was recorded for each measurement.
Assessment of Oxidative Stress
Superoxide anion production was measured in isolated aortic rings using a method previously described (12, 21). Briefly, 5-mm aortic rings were preincubated in Krebs-bicarbonate buffer, at 37°C, for 30 min and then transferred to a cocktail containing 5 µmol/l lucigenin and immediately measured, every 2 min, for 15 min total, using a scintillation counter set in the out-of-coincidence mode. The readings were plotted and the area under the curve was integrated. Results were normalized per milligram of DNA measured using the Hoechst 33258 dye as described (27). The specificity of the reaction was tested by the ability of 50 U/ml of SOD to quench the chemiluminescence at the end of the measurement.
Free 8-isoprostane F2
. Isoprostanes
were measured by EIA using a kit from Cayman Chemicals as previously described
(12). Urine collected in
metabolic cages over a 24-h period was supplemented with 0.05% butylated
hydroxytoluene and spiked with 8-[3H]isoprostane. The samples (1
ml) were passed on an affinity column (Cayman Chemicals) and only the free
isoprostanes were eluted using 95% methanol. The eluate was evaporated to
dryness under a stream of N2 and the pellet was resuspended in a
1-ml assay buffer. Each sample was assayed in duplicate at two different
dilutions and corrected for individual recovery of
8-[3H]isoprostane, and the results were averaged. Nitrate/nitrite
was assayed both in plasma and urine (diluted 1:50 in PBS) using a LDH
colorimetric method with a kit from Cayman Chemicals.
Immunohistochemistry for 4-hydroxy-2-nonenal. Kidneys were fixed in 10% buffered formaline for 3 h and paraffin embedded. The sections were incubated with a polyclonal antibody recognizing 1:1 Cys, His, Lys-4 hydroxy-2-nonenal "Michael" adducts (Calbiochem, dilution 1:750). The slides were then reacted with biotinylated secondary goat anti-rabbit antibody (1:500 dilution; Vector Laboratories, Burlin-game, CA), with the ABC-Elite avidin reagent (Vector Laboratories), and finally with the Immuno Pure Metal Enhanced DAB Substrate kit (Pierce, Rockford, IL).
Vascular Hypertrophy and Kidney Sclerosis
Aortic wall area. Thin sections of the paraffin-embedded tissue were stained for 1 min with toluidine blue and analyzed as described previously (10).
Kidney histology. Kidneys were fixed in 10% buffered formalin for 4 h and embedded in paraffin. Sections were stained using the periodic acid-Schiff (PAS) reagent and counterstained with hematoxylin. To evaluate the degree of segmental sclerosis, three independent investigators examined the slides in a blind fashion, mixing the slides after covering the protocol numbers. In each case, 80–100 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 was a normal looking 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.
Adipocyte Morphometry
Adipose tissues from the same depot and group were pooled and collagenase
was digested according to Rodbell and Krishna
(39). Adipocytes were washed
several times to remove collagenase and centrifuged to separate adipocytes
from preadipocytes, stromal cells, and vascular membranes. Cell diameter of
1,200 cells was measured with the Image 1 Analysis System (Universal
Image, West Chester, PA). Mean cell diameter was used to estimate mean cell
volume. Cell size (µg lipid/cell) was calculated by multiplying cell volume
(pl) by lipid density (0.915 g/ml). Cell lipid content was determined
according to the method of Dole
(14). Cell lipid content and
cell size were used to calculate cell number.
Statistics
Data are means ± SE. To determine the significance between different groups, two-way or three-way ANOVA was performed followed by Tukey's post hoc test. P < 0.05 was considered statistically significant.
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RESULTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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After 10 wk of diet, BW in the OP groups on both high- and regular-salt
diets was significantly higher than those in the corresponding OR and control
(C) groups (Table 1). In
addition, no significant difference in BWs was detected between each of the
OP, OR, and C groups on 0.8, 2, and 4% NaCl, respectively
(Table 1). The result is in
accordance with daily food intake data, indicating that high-salt diets did
not result in increased food consumption in OP, OR, or C rats on the
respective diets vs. their counterparts on the low-salt diet
(Fig. 1, A and
B). However, from the beginning of the experiment until
week 8, the OP rats ate significantly more than OR rats on a similar
diet (Fig. 1, A and
B). Also, the average food intake in all experimental
groups reaches a peak after 3 wk on the respective diets, followed by a
decrease by week 5 and a subsequent relatively stable level until the
end of the experiment (Fig. 1, A
and B), indicating that the highest salt intakes occurred
in the first 3–5 wk on the diet. The increased BWs in the OP groups
compared with OR and C groups were also mirrored by the elevated adiposity.
Both the epididymal and retroperitoneal fat depots were significantly
increased in the OP groups compared with OR and C, but no significant
differences were recorded between the high- and low-salt groups
(Table 1). Furthermore, the
obesity index was higher in the OP groups compared with OR and C and was not
influenced by the salt intake (Table
1). In contradistinction, the adipocyte morphometry and number
were different among the OP, OR, and C groups placed on low- vs. high-salt
diets. For all OP, OR, and C, the 2% NaCl diet induced an increase by
12–20% in cell volume and 12–15% in cell size with the highest
effect on OP adipocytes (Table
2). Also, a decrease in adipocyte number was measured for OP
(30%) and OR (12%) groups on 2 vs. 0.8% NaCl diet, with no
difference for C adipocytes (Table
2). This indicates hypertrophy of adipocytes from the OP rats,
significantly exacerbated by the high-salt intake. In accordance with previous
findings (29), our results
indicate an increase in circulating leptin for OP rats compared with OR and C
after 10–14 wk of diet (Table
2). Interestingly, both the 2 and 4% NaCl diets significantly
increased, by 40%, plasma leptin in the OP rats, and only the 4% NaCl
diet induced a significant increase in the leptin levels in OR and C rats,
compared with their counterparts on 0.8% NaCl
(Table 2). The latter result
suggests that obesity and high salt are both important in regulation of leptin
levels. Moreover, the finding that the 4% NaCl, but not 2% NaCl, diet
increased leptin levels in both OR and C lean groups of rats suggests that
even in the absence of obesity, and independently of the amount of fat in the
diet, a high enough content of NaCl (in our particular experiment 4 vs. 2%)
could modulate the leptin levels.
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Effect of High-Salt Diet on BP and Plasma Renin Activity in OP, OR, and C Rats
Systolic BP measured in the conscious rats at the beginning of the diet
indicated an average of 122 ± 3.9 mmHg. Starting with week 5,
the OP rats on both 2 and 4% NaCl displayed a significant increase in BP with
an average of 160.2 ± 5.2 and 156.5 ± 4.4 mmHg, respectively, as
opposed to all the other groups that were either normotensive or borderline
hypertensive (Fig. 2, A and
B). At week 8, the OP rats on 0.8% NaCl diet
were moderately hypertensive with an average BP of 154 ± 3.2 mmHg,
whereas the OP rats on both 2 and 4% NaCl did not show a further significant
increase in their systolic BP compared with week 5
(Fig. 2, A and
B). By the end of the experiment (week 10), all
three OP groups (on 0.8, 2, and 4% salt) had a similar increase in BP that
averaged 158 mmHg. Also, the OR and C groups on high- and normal-salt
diets were normotensive (Fig. 2, A
and B). In the OP rats on 0.8% NaCl, the increase in
systolic BP was paralleled by an approximately twofold increase in plasma
renin activity (PRA), as measured at the end of the experiment
(Fig. 2C). The 2% NaCl
diet induced a 40% reduction in PRA in the OP rats and slightly decreased
PRA in the OR and C rats (Fig.
2C). In addition, the 4% NaCl diet induced a significant
reduction in PRA in OP, OR, and C groups compared with their respective
counterparts on 0.8 and 2% NaCl diets (Fig.
2C). The ability of the OP rat groups to adequately
respond to the different increase in dietary salt at week 10 may
explain the lack of difference in the systolic BP between the three OP groups
at that time point.
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Oxidative Stress in Rats Fed Regular- and High-Salt Diets
The systemic oxidative stress measured as the excreted free 8-isoprostane
F2 in 24-h urine samples indicated an
2.5-fold increase in the OP groups on both normal (0.8% NaCl)- and high
(2 and 4% NaCl)-salt diets, compared with the respective OR and C groups
(Fig. 3A), indicating
that high salt does not further increase systemic oxidative stress in the
obese rats. However, the ability of thoracic aortic rings to generate
superoxide anions, measured as lucigenin chemiluminescence, is double in OP
rats on both 2 and 4% NaCl vs. OP rats on regular salt, indicating an increase
in oxidative stress in the large vessels of obese animals
(Fig. 3B). Also, a
significant increase induced in response to high salt was measured in C rats
and the same trend was present in the OR rats
(Fig. 3B). The latter
result indicates that high salt increased superoxide formation independent of
obese state and the amount of dietary fat. In addition, the high-salt intake
and obesity, but not dietary fat, seem to have a synergistic effect on
superoxide generation. Also, the urinary nitrate/nitrite is four- to fivefold
decreased in OP rats on both regular and salt-supplemented diets, compared
with the OR and C counterparts (Fig.
3C). The result indicates that salt intake does not
further decrease nitrite/nitrate excretion, despite its significant effect on
superoxide generation in the vasculature. Therefore, nitrite/nitrite formation
seems to be modulated mainly by the obese state per se and not critically by
the high-fat or high-salt content in the diets. Kidney immunohistochemistry
using a polyclonal antibody for 2-hydroxy-4-nonenal protein adducts indicates
a similar staining pattern in all groups on both regularand high-salt diets;
however, the intensity of the staining is much higher in the OP, OR, and C
rats on 4% vs. regular-salt diets (Fig. 4,
G–L). The most intense staining is noticed
in the distal tubules, thick ascending limb, and to a lesser extent in the
cortical proximal tubules, whereas it is virtually absent in the glomeruli. As
shown in Fig. 4,
G–L, the staining is more prominent in all
OP, OR, and C rats on high salt (Fig. 4,
G–I) vs. regular salt
(Fig. 4,
J–L), suggesting an increased local free
radical production in the kidney cortex induced by high-sodium intake. The
control in which the primary antibody was replaced with nonimmune serum shows
no staining (Fig.
4M).
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Effect of Salt on Vascular Hypertrophy, Kidney Sclerosis, and Excretory Function
Vascular hypertrophy was measured as aortic cross-sectional wall area. Results indicated that in all the OP groups (0.8% NaCl, 2% NaCl, and 4% NaCl), there is a significant increase in wall area compared with the respective OR and C groups (Fig. 5A). However, high salt did not induce a further increase in wall area in OP rats, suggesting no additional effect on vascular hypertrophy (Fig. 5A). To address the possible morphological changes in the kidney, we used PAS-hematoxylin staining followed by morphometric analysis. In accordance with our previous data (11), in OP rats on regular-salt diet, a mild sclerosis with most of the lesions in a relatively early stage was noticed, as opposed to OR and C rats that displayed a normal kidney histology (Fig. 4, D–F). The OP rats on 4% NaCl displayed numerous and more advanced lesions of the glomeruli as well as significant matrix deposition throughout the cortex (Fig. 4A). The glomerular lesions displayed capillary loop collapse, mesangial matrix expansion, and sometimes adhesion to Bowman's capsule. In addition, interstitial fibrosis and glomerular membrane thickening were noticed (Fig. 4A). The changes noticed in the 2% NaCl groups were somewhat intermediate between the 4 and 0.8% NaCl counterparts (not shown). In OR and C rats, a normal histological appearance was observed regardless of the amount of NaCl in the diets. Morphometric analysis indicated a mean ± SE mesangial score of 16.9 ± 1.4 for the OP rats on 4% NaCl compared with 14.2 ± 0.8 and 10.9 ± 1.2 for the OP rats on 2% NaCl and 0.8% NaCl, respectively. The scores for the OR rats on 4, 2, and 0.8% NaCl were 9.4 ± 1.1, 8.7 ± 1.2, and 8.4 ± 1.3, respectively, and the scores for the C rats on 4, 2, and 0.8% NaCl were 8.8 ± 1.4, 8.2 ± 1.2, and 8.4 ± 1.3, respectively. To test the possible changes in the renal function, protein, creatinine, and albumin excretion were measured. OP rats on both high-salt diets did not display overt proteinuria or significantly increased protein excretion compared with OP rats on low salt. Also, the creatinine values were similar among all groups. However, OP rats on 2% NaCl had mild albuminuria (5.6 ± 0.42 mg/24 h) compared with OP on regular salt (2.12 ± 0.47 mg/24 h) (Fig. 5B). In addition, the OP group on 4% NaCl had a significantly higher albumin excretion (7.8 ± 0.53 mg/24 h) compared with both 2% NaCl and 0.8% NaCl counterparts (Fig. 5B). The results indicate that the changes in renal morphology, paralleled by albuminuria, are dependent on the salt content in OP rats only, suggesting a synergistic effect for salt and obesity but not for the dietary fat.
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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Also, high-salt diet induced a significant increase in the adipocyte size, especially in the OP rats. Adipocyte hypertrophy may potentiate the insulin resistance in OP rats, due to the increased fatty acids efflux and increased circulating triglycerides. It was shown that salt increases circulating levels of fatty acids (17), and our data indicating adipocyte hypertrophy suggest a possible increase in circulating fatty acids.
Oxidative stress was reported previously for this animal model in both
prehypertensive (11) stage and
after the development of moderate hypertension
(12). In the present study, we
tested whether salt has an effect on free radicals formation in the obese
rats. Data indicated that 2 and 4% NaCl diets did not enhance free
isoprostanes excretion in OP, OR, or C rat groups compared with their
counterparts on 0.8% NaCl diet. However, the superoxide production by aortic
rings is significantly increased in OP rats on both high-salt diets vs. 0.8%
NaCl group. Urine isoprostanes are considered a reliable marker to quantify
systemic oxidative stress
(30). However, recent reports
indicate that in rats, under certain conditions such as increased oxygen
tension (26) or
NADPH-stimulated free radical production
(15),
F2 isoprostanes were not increased, although
other oxidative stress parameters were elevated. Although this study does not
provide data to support this hypothesis, it is possible that the increased
vascular superoxide production mainly originates from a vascular NAD(P)H
oxidase (18,
35) and hence isoprostanes
F2 could not accurately reflect the increased
aortic oxidative stress. Nevertheless, increased superoxide production in the
aorta does not seem to affect vascular hypertrophy. The wall area in OP rat
groups on high- and regular-salt diets is increased vs. the OR and C, but no
differences were measured among the three OP groups on 4, 2, and 0.8% NaCl.
The results suggest that vascular remodeling is due to the elevation in BP
rather than directly related to free radicals production in rats on high-salt
diet. The presence of increased hydroxynonenal protein adducts in the kidneys
of OP rats on high-salt vs. normal-salt diets indicates elevated free radicals
production in the renal tissue in the former. One possible source of free
radicals in the kidney may originate from high-leptin production by the local
infiltrates of adipose tissue. Leptin was shown to induce oxidative stress in
the endothelial cells in culture
(1). Therefore, it is possible
that increased local leptin production may contribute to reactive oxygen
species generation. High dietary fat does not appear to have a direct effect,
because both the OR and C groups displayed similar levels of lipid
peroxidation. Conversely, high-salt intake (4% NaCl) induced increased renal
lipid peroxidation in all study groups (OP, OR, and C), suggesting a role for
high salt independent from obesity and dietary fat. However, the higher lipid
peroxidation in the OP group on 4% NaCl vs. 0.8% NaCl and the higher
peroxidation in all OP groups compared with their OR and C counterparts on
similar diets indicate a possible synergistic effect of obesity and salt on
renal lipid peroxidation.
A direct or indirect effect of high-salt intake, possibly via free radicals production, could be responsible for the kidney glomerulosclerosis in the OP rats. Salt was shown to induce smooth muscle cells and myoblasts hypertrophy in vitro (20). Also, oxidative stress seems to be directly involved in the renal dysfunction in Dahl salt-sensitive rats (48). Therefore, it is reasonable to assume that the higher degree of renal damage in the OP rats on high salt vs. normal salt is likely to be independent of a pressor effect and rather due to the production of local excess leptin and/or free radicals. In conclusion, our results indicate that 1) high-salt diet induces an earlier increase in systolic BP in OP rats (5 wk on 4 and 2% NaCl vs. 8 wk on 0.8% NaCl), possibly due to the inability of OP rats to reduce their renin production in response to increased NaCl intake early in the diet; 2) salt does not affect fat accretion, but it induces adipocyte hypertrophy and increased leptin production, independently from dietary fat and in synergy with obese state; 3) high-NaCl intake induces increased vascular and renal oxidative stress, independently from dietary fat and synergistically to obesity; and 4) high-salt diet accelerates kidney sclerosis, which correlates with renal oxidative stress, but it is, at least in part, independent of a direct pressor effect and does not affect vascular hypertrophy, which is probably the direct result of high arterial pressure. In this model, the concurrent effect of metabolic factors related to obese state and high-salt intake seems to induce kidney sclerosis and moderate hypertension. The finding could be relevant for human pathology, indicating that increased salt intake in obese individuals with moderate hypertension may lead to accelerated end-organ damage.
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DISCLOSURES |
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FOOTNOTES |
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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.
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REFERENCES |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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) in isolated rat kidney glomeruli by a radical-independent
mechanism. Br J Pharmacol 133:
643–650, 2001.[Web of Science][Medline]
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