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3
*
Department of Physiology and Department of Internal Medicine and
The Combined Program in Nephrology and Renal Physiology, Texas Tech University Health Sciences Center, Lubbock, Texas
3To whom correspondence and reprint requests should be addressed.
 |
ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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KEY WORDS: • food restriction • renal membrane lipids • renal function • F344 x BNF1 rats
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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, Keenan et al. 1998
, Sprott 1997
). Such food restriction
(FR)4
was also reported to maintain tissue integrity, reducing the
incidence of myocardial fibrosis, some endocrinopathies, carcinoma and
environmental diseases (Cornwell et al. 1991
,
Frame et al. 1998
, Keenan et al. 1998
,
Sprott 1997
). Plasma glucose and insulin concentrations
in food-restricted rats was 15 and 50% lower, respectively, than
in those with free access to food (Masoro et al. 1992
).
Metabolic rate was only transiently altered by energy restriction
(McCarter 1989
).
Although the mechanism underlying these findings is not completely
understood, short-term food restriction (40%, for 8 wk) has been
shown to increase the capacity for enzymatic decomposition of
hydroperoxides and to decrease oxidative stress in murine kidneys
(Cadenas et al. 1994
).
Chronic food restriction in male Fischer 344 rats (40%, from 6 wk of
age) suppressed the age-associated increase in malondialdehyde
production and lipid hydroperoxide formation in liver mitochondrial and
microsomal membranes (Laganiere and Yu 1987
).
Restricting intake also modified fatty acid composition in hepatocyte
membranes such that linoleic acid content was increased and
docosapentaenoic acid content was decreased (Laganiere and Yu 1987
). A higher unsaturation/saturation index was indicative of
the membrane's resistance to peroxidation (Laganiere and Yu 1987
). Food restriction also prevented the
age-induced hyperparathyroidism and decreased the incidence of
chronic glomerulonephritis that occur in rats (Kalu et al. 1984
). Despite these observations, studies of the effects
of food restriction on renal membrane lipid metabolism as it relates to
renal transport have not been examined in detail. Such studies are
relevant because alterations in renal tubular membrane lipids, per se,
may hasten the progression of chronic renal failure (Mackenzie and Brenner 1998
, Remuzzi et al. 1997
).
In the present experiments we examined the effects of 6 wk of food restriction (60% of ad libitum [AL] intake) on selected aspects of renal function and on cortical brush border membrane (BBM) and basolateral (BLM) membrane lipid concentration in young male Fischer 344 x Brown-Norway F1 rats (F344 x BNF1). We compared the results we obtained to those of their age-matched littermates who consumed food AL. We postulated that if beneficial changes occurred, they would be associated with a decrease in renal work, measured by a fall in cortical membrane Na,K-ATPase activity and membrane transport. We further predicted that decreases in BBM and BLM phospholipid and cholesterol concentrations would occur. Such effects should render the renal membranes more resistant to oxidative injury.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Male Fischer 344 x Brown-Norway F1 rats were obtained at 16 wk
of age from the National Institute of Aging (NIA). At 14 wk of age, the
NIA randomly separated the rats into two groups: one group was allowed
free access to food (AL), while the other was subjected to food
restriction (90% of the AL consumption). Over the subsequent 2 wk, the
amount of food provided was gradually reduced so that by 16 wk of age,
the FR group consumed 60% of that consumed by the AL rats.
These rats (n = 10/group) were fed their respective
diets throughout the experiment (an additional 6 wk). Both the decrease
in energy and the amount of food given daily by us was prescribed by
weight according to guidelines provided by the NIA (Sprott and Austad 1996
). The nutrient NIH-31 diet (NIH Rat and Mouse/Auto
4F; Purina Mills, Richmond, IN) was used in this
study5
. The FR rats were fed 60% (11.5–12.0 g/d, 20.95–21.86 kJ/d) of the
amount given to the AL rats (19.16–20.0 g/d, 34.89–36.43 kJ/d). All
rats were allowed free access to tap water and were housed in the
animal facility with 12 h of daylight and 12 h of darkness.
The protocol was approved by the Animal Care and Use Committee at our
institution.
On the last day of the diet-treatment period, the rats were placed
in metabolic cages (free access to water) for a 24-h urine collection
as we have described previously (Sabatini et al. 1990
).
On the day they were killed, the rats were anesthetized, and blood
samples were obtained from the aortas for measurement of pH,
pCO2 and electrolytes. The kidneys were then removed for
the biochemical studies described below. Urine and plasma electrolytes
were measured for calculation of renal function by using the standard
methods previously described (Sabatini et al. 1990
).
Plasma glucose and cholesterol concentrations were determined by
CIBA-CORNING, Express Plus (Medfield, MA). Urine ammonium (after
conversion to ammonia) was measured by an ion analyzer (Model 255,
CIBA- CORNING) and an ammonia gas-sensing electrode (Model 95–12,
Orion Research, Boston, MA). Titratable acid concentration was
assessed by the amount of 0.1 mol/L NaOH used to titrate 1 mL of urine
from urine pH to pH 7.4.
Renal cortical membrane preparations.
Vesicles from brush border and basolateral membranes were prepared from
rat renal cortex by previously described methods (Eiam-Ong and
Sabatini 1999a
and 1999b
, Grassl and Aronson 1986
, Hilden et al. 1989
). In brief, the rats
were killed with pentobarbital sodium anesthesia (50 mg/kg body weight,
intraperitoneal). The kidneys were removed and immediately placed in
isotonic buffered solution containing 200 mmol sucrose/L, 25 mmol
potassium-gluconate/L, 2 mmol disodium EDTA/L, and 10 mmol HEPES/L; the
buffer was adjusted to pH 7.6 with tetra-methylammonium hydroxide
(4°C). The cortex of each kidney was first separated from the
medulla, and the tissue from the two kidneys were pooled. The cortical
tissue was then added to the above solution (5 mL/g kidney wt.) and
homogenized with a Teflon pestle-glass homogenizer. The homogenate
was centrifuged at 40,525 x g (Beckman SW 28
rotor; Fullerton, CA) for 30 min (4°C). When making BLM, a
preliminary centrifugation of the homogenate at 1,000 x g (Beckman SW 28) for 10 min was performed and the
pellet discarded (Eiam-Ong and Sabatini 1999a
and 1999b
,
Grassl and Aronson 1986
). The 40,525 x g precipitate was used to make BBM or BLM as outlined
below.
BBM.
The pellet was resuspended in 25 mmol potassium-gluconate/L, 2 mmol
EGTA/L, and 10 mmol HEPES/L (pH 7.6, with KOH) and homogenized with
three strokes of a Teflon pestle-glass homogenizer (4°C)
(Eiam-Ong and Sabatini 1999 a
and b
, Hilden et al. 1989
). Subsequently, 0.3 mL of 1 mol MnCl2/L
was added and the homogenate was diluted to 30 mL with the resuspension
medium. After stirring on ice for 20 min, the solution was centrifuged
at 2,117 x g (Beckman SW 28) for 10 min and the
pellet discarded. The supernate was again centrifuged at
47,770 x g (Beckman SW 28) for 30 min. The
resulting pellet contained the purified BBM (Eiam-Ong and
Sabatini 1999 a
and b
, Hilden et al. 1989
).
Average enrichment in specific activity (final pellet/initial
homogenate) of 
-Glutamyltransferase, a brush border membrane marker,
was 10.68 ± 0.45 (n = 10), a value not
different from one reported by others (Glossmann and Neville 1971
). The protein concentration of BBM ranged from 9 to 13 g/L
(n = 10).
BLM.
The lower, brown part of the 40,525 x g pellet was
discarded, and the upper part was suspended in the homogenizing
solution (Eiam-Ong and Sabatini 1999a
and 1999b
,
Grassl and Aronson 1986
). This mixture was
centrifuged at 45,289 x g (Beckman SW 28) for 30
min. The upper part of the pellet containing the crude membrane was
resuspended in an aliquot of the homogenizing medium. A solution
containing 4 g Percoll and 19 g homogenizing medium was
prepared to which 2 mL of the crude membrane suspension was added. This
was followed by centrifugation at 32,811 x g
(Beckman Ti 50.2 rotor) for 40 min to form a gradient (4°C). The
distinct upper band in the upper half of the gradient was aspirated and
pooled. These pooled fractions were centrifuged at 184,048 x g (Beckman Ti 50.2) for 60 min to remove the Percoll.
The purified BLM was found above a hard Percoll pellet (Eiam-Ong
and Sabatini 1999a
and 1999b
, Grassl and Aronson 1986
). Average enrichment of Na,K-ATPase
specific activity, a basolateral membrane marker, was 11.59 ± 0.89 (n = 10), a value not different from that
reported by others (Grassl and Aronson 1986
).
The protein concentration of BLM ranged from 3 to 5 g/L
(n = 10).
Enzyme measurements.
Na,K-ATPase activity was measured in the BLM vesicles as the difference
in activity found in the presence and absence of ouabain
(Sabatini et al. 1990
). -Glutamyltransferase activity
in the BBM vesicles was measured by a standard method of the
International Federation of Clinical Chemistry (IFCC) (CIBA-CORNING,
Express Plus). Protein concentration was measured according to the
Biuret method (CIBA-CORNING, Express Plus) after precipitation with
0.612 mol trichloroacetic acid/L and hydrolyzed in 0.5 mol NaOH/L.
Lipid measurements.
Total lipids were extracted from both BBM and BLM based on a method
(Davison and Wajda-Spohn 1961
) that we modified
(Eiam-Ong and Sabatini 1999a
). The pelleted fractions
were extracted with chloroform-methanol (2:1, v/v), filtered to
remove nonlipid substances, and the filtrates were washed by
partitioning between the nonlipid phase (upper, aqueous) and the
lipid-containing phase (lower, chloroform rich). The proportion of
solvents was maintained at four parts chloroform-methanol (2:1,
v/v) mixture to one part water. This procedure, which removes the
nonlipid, water-soluble compounds from the chloroform-soluble
lipids, was then divided into aliquots for the determination of
cholesterol, total lipids, and the subsequent separation of the
individual phospholipids.
To measure cholesterol, the sample was first evaporated under nitrogen
gas, and the residue was hydrolyzed with alcoholic KOH, followed by
precipitation with digitonin (0.5 g digitonin in 50% aqueous ethanol).
The precipitate was resuspended in glacial acetic acid, and the
cholesterol concentration was determined colorimetrically after the
addition of the Lieberman-Burchard reagent (20 parts ice-cold
acetic anhydride: one part concentrated sulfuric acid) (Sperry and Webb 1950
).
The individual phospholipids were separated by TLC (Cuzner and Davison 1967
). The nitrogen-dried lipid residues, resuspended in 20
µL of chloroform methanol (2:1, v/v), were applied as narrow streaks
to Silica Gel G plates (250 µm thick; Fisher, Houston, TX).
The plates were developed in chloroform/methanol/ammonia (17:7:1,
v/v/v). This system results in the quantitative separation of
sphingomyelin (Spm), phosphatidylcholine (PC), phosphatidylethanolamine
(PE), and phosphatidylserine (PS). After development, the chromatograms
were allowed to dry and then were exposed to iodine vapor. The
individual phospholipids were identified by using cochromatography of
authentic standards (Sigma, St. Louis, MO). The phospholipids were
scraped from the silica gel plates and ashed with 9.95 mol perchloric
acid/L.
Phospholipid calculations were based on the assumption that, after
converting lipid phosphorus to inorganic phosphate (Pi) by ashing, each
phospholipid molecule yields 1 atom of Pi (Davison and Wajda-Spohn 1961
). The clear digests were diluted with
water and used for the determination of inorganic phosphorus by the
method of Daly and Ertingshausen (CIBA-CORNING, Express Plus) according
to IFCC standards by using H2SO4 and ammonium
molybdate reagents after 9.95 mol perchloric acid/L digestion.
Materials.
All chemicals and reagents were obtained from Sigma Chemical and were of highest quality.
Statistical analyses.
All the data are expressed as means ± SEM Statistical significance of differences (P-values < 0.05) was assessed using two-tailed, unpaired Student's t-test.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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At the beginning of the experiment, the AL rats weighed 404 ± 7 g, and the FR rats weighed 294 ± 12 g, a 28%
difference (P < 0.001). On the day of killing, 6 wk
later, weight gain was 3 (P > 0.05) and 8%
(P > 0.05) in the AL and FR groups, respectively
(Table 1
). Following 6 wk of FR, this group of rats maintained a body weight
lower than that of the AL rats (P < 0.001). Plasma
glucose, cholesterol and blood urea nitrogen were 12, 9 and 11% lower
(P < 0.05), respectively, in FR rats than in AL rats
(Table 1)
.
|
. Arterial pH was not altered by FR (data not shown). Effects of food restriction on urinary excretion of ions and solutes.
Food restricted rats had a 50% lower fractional excretion of sodium,
potassium, chloride as well as urinary excretion of ammonium,
titratable acid, and phosphate (P < 0.001)
(Table 2
). By contrast, urine HCO3 excretion did not
differ between groups (3.77 ± 0.55 vs. 5.42 ± 0.87 mmol/L,
FR vs. AL, respectively; P = 0.12). Daily urine volume
in FR rats was 66% lower than that in the AL rats (P
< 0.001), whereas, urine osmolality was unaffected, presumably
reflecting the same ability to concentrate urine. Interestingly, the FR
rats had a 12% lower creatinine clearance (P < 0.05)
than did the AL rats (Table 2)
.
|
Na,K-ATPase activity in the basolateral membrane of FR rats was approximately one-half that of the AL group (P < 0.001). The enzyme activity was 14.44 ± 1.05 and 26.72 ± 1.85 µmol Pi/(mg protein · h) in FR and AL rats, respectively.
In the BBM (Fig. 1
), 6 wk of FR significantly reduced the concentration of all
phospholipids (phosphatidylserine, phosphatidylcholine,
phosphatidylethanolamine and sphingomyelin) by ~50–60% compared to
the AL group (P < 0.001). In the BLM (Fig. 2
), FR lowered only phosphatidylcholine concentration by 50%
(P < 0.01). Renal membrane cholesterol concentration
was 50–60% lower in FR rats than in AL rats, both in the BBM (0.49
± 0.02 vs. 1.22 ± 0.03 µmol/mg protein, FR vs. AL,
respectively, P < 0.001) and in the BLM (0.30 ± 0.02 vs. 0.64 ± 0.03 µmol/mg protein, FR vs. AL, respectively,
P < 0.05).
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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, Keenan et al. 1998
, Sprott 1997
) because a delayed onset of several diseases was
documented (Cornwell et al. 1991
, Frame et al. 1998
, Keenan et al. 1998
, Sprott 1997
). Such observations have profound implications for humans,
however, the mechanisms underlying these effects are not completely
understood. Our study was designed to examine the potential benefits of
FR on the kidney, as regards aspects of renal function and cortical
brush border and basolateral membrane lipid concentrations. Our results
show that the changes that occurred with FR could be exploited to delay
the onset of some renal diseases observed in overfed animals. These
beneficial effects may also retard the progression to uremia
(Mackenzie and Brenner 1998
, Remuzzi et al. 1997
).
In the present study, 6 wk of FR (60%) in young F344 x BNF1 rats
significantly lowered renal membrane cholesterol (BBM & BLM) and
phospholipid concentrations (BBM > BLM). FR rats were not
malnourished because plasma albumin concentration did not differ
between groups. The changes found in this study were permanent, as most
are also noted in 3-y-old FR rats (Eiam-Ong and Sabatini
1999a
and b
).
Manipulation of food intake has the positive effects of
decreasing the incidence, severity and progression of some renal
diseases (Gumprecht et al. 1993
, Keenan et al. 1995
, MacConi et al. 1997
). SCG/Kj mice exhibit
clinical and histological evidence of acute crescentic
glomerulonephritis, including proteinuria and hematuria, beginning as
early as 3–4 wk of age and die as 16-wk-old young adults with severe
glomerular lesions (Kinjoh et al. 1993
). Food
restriction (68%) in SCG/Kj mice (from 7 wk of age) delayed the onset
of crescentic glomerulonephritis and extended the medium of the life
span by 25% compared to overfed mice (Cherry et al. 1998
). While the restricting carbohydrate, fat, and minerals
(except for calcium and phosphorus) by 64% retarded growth in rats, it
also prevented the development of end-stage renal pathology in the
remnant kidney model of chronic renal failure (21 wk postablation)
(Tapp et al. 1989
). This occurred independent of the
amount of protein in the diet. Twenty-one weeks after 5/6
nephrectomy in rats, FR (40%) ameliorated the well known increase in
single nephron glomerular filtration rate; it also lessened the
occurrence of tubulointerstitial pathology (Kobayashi and Venkatachalam 1992
). Careful morphologic analysis by light
(Maeda et al. 1985
) and electron microscopy
(Hayashida et al. 1986
) showed that FR (40% of normal
rats, from 6 wk of age) inhibited the age-related increase in the
thickness of the renal basement membrane; it also prevented the
enlargement and fusion of the mesangium, deposition of
lipofuscin-like secondary lysosomes in the proximal epithelium, and
ameliorated the destructive changes that occur in the foot processes
(Hayashida et al. 1986
).
Food restriction has a therapeutic effect on spontaneously occurring
autoimmune diseases related to the kidney. The NZB x NZW F1 strain of
mice spontaneously develops systemic lupus erythematosus (SLE); most
animals die of severe immune complex-type glomerulonephritis at
about 10 mo of age (Urao et al. 1995
). FR (40%, from 2
mo of age) in these mice affected immunoglobulin metabolism, a maneuver
critical in the pathogenesis of SLE (Urao et al. 1995
).
FR diminished the age-related onset of T cell subset abnormalities,
including activation of autoreactive T cells (Urao et al. 1995
).
Two months of FR (50%) in MWF rats (an animal that develops
spontaneous glomerular injury) significantly decreased urine protein
excretion compared to the overfed rats (18 ± 8 mg/d vs. 104
± 32 mg/d, respectively) (MacConi et al. 1997
).
Glomerulosclerosis and tubulointerstitial changes were completely
absent in the FR group (MacConi et al. 1997
). The
potential applicability of nutritional control for the treatment of
autoimmune diseases in humans was suggested. Both fasting and a
long-term, vegetarian diet were reported to be successful in
treating rheumatoid arthritis in some patients (Kjeldsen-Kragh et al. 1991
).
Mechanisms by which energy restriction may delay the loss of
age-associated immune function include modulation of the fatty acyl
composition of plasma membrane lipids or alterations in the
concentration of phospholipids (Venkatraman and Fernandes 1992
). Spleen cell membranes from FR rats (60%) showed higher
linoleic acid (18:2) levels; significant decreases of arachidonic acid
(20:4), docosatetraenoic acid (22:4) in phosphatidylcholine and
phosphatidylethanolamine fractions were also noted (Venkatraman and Fernandes 1992
). The same membranes had more binding sites
for interleukin-2 (IL-2) and insulin and enhanced IL-2 production. Such
modifications in membrane lipid may facilitate binding of IL-2 and
insulin to their receptors, thus improving T cell function. Food
restriction (60%, from 6 mo of age) in aged rats significantly
increased levels of essential fatty acids and attenuated levels of
long-chain polyunsaturated fatty acids in both phosphatidylcholine
and phosphatidylethanolamine fractions from liver mitochondrial and
microsomal membranes (Laganiere and Yu 1993
). Despite
changes in these fatty acids, the concentration of the major
phospholipids (i.e., phosphatidylcholine, phosphatidylethanolamine or
phosphatidylinositol) in the membranes did not vary significantly with
diet (Laganiere and Yu 1993
). These results may be
relevant to our data on renal cortical membranes in that at least
phosphatidylethanolamine in BLM, the site of Na,K-ATPase, did not
differ. In both membranes (BBM and BLM), however, phosphatidylcholine
was lower in FR rats. We did not measure the effect of FR on renal
mitochondrial or microsomal membranes, thus, we do not know whether it
affects phospholipid concentration. No measure of fatty acyl
composition was made in the renal tissue of FR rats. In addition, a
lower fat intake by FR rats may explain the reduction in renal cortical
membrane phospholipid deposition. If this were the sole reason,
however, we would expect the phospholipids to be depressed equally in
BBM and in BLM. This did not occur in our study. The lower amount of
dietary fat consumed in FR rats could more easily explain the fall in
BBM and BLM cholesterol concentration, but even here, the BBM seemed
the more affected (i.e., it fell 75%, whereas BLM was ~50% lower).
Sphingomyelin is noted to be higher in atherosclerotic lesions than
in normal arterial tissue (Schissel et al. 1996
). Ceramide, a second messenger of sphingomyelin, is an
important signal for renal injury and apoptotic response
(Shayman 1998
). There are no studies in renal membrane
sphingomyelin or phosphatidylserine concentration in response to FR.
Our study documented the first evidence that FR significantly
decreases sphingomyelin and phosphatidylserine concentration in renal
BBM. Such a fall in the deposition of sphingomyelin may reduce the
propensity of the BBM to be injured. Further experiments are
required to determine whether or not this is true.
Food restriction was shown to reduce the membrane rigidity that is
induced with normal aging. It was noted in aged rats that FR (60%,
from 16 wk of age) limited oxy-radical production in rat brain
mitochondria (Gabbita et al. 1997
). The fluidity of
erythrocyte membranes derived from FR rats (60%) is higher
(Levin et al. 1992
), thus protecting the
membranes against hemolysis (Pieri et al. 1996
). These protective effects may be the consequence of
decreased lipid peroxidation. The lower in membrane
cholesterol concentration, a maneuver that also increases membrane
fluidity, and as we noted in our studies, would be beneficial to
prolonged and optimum cellular function in the renal tubules, both in
BBM and BLM.
Basal Ca-ATPase activity in red blood cell membranes from aged rats
was shown to be significantly reduced with FR (60%, from 16 wk of
age), but responses to selected other stimuli were not changed,
indicating that certain enzymes were operating more efficiently
(Davis et al. 1991
). Our data show that FR significantly
lowered renal work that is required for proton secretion by 50%. This
occurred along with a fall in BLM Na,K-ATPase activity and a reduction
in the fractional excretion of Na+, K+, and
Cl-. A reduction in Na+ and K+
intake (and possibly other electrolytes) in FR rats could explain the
fall in the Na,K-ATPase enzyme. We believe the enzyme to be
functioning more efficiently; however, were it not, more Na and K, not
less, would appear in the urine. Despite a fall in membrane Na,K-ATPase
activity, both AL and FR rats showed identical levels of
Na+ and K+ in plasma and muscle tissue
(Eiam-Ong and Sabatini 1999b
). We suggest that the lower
energy expenditure by the kidney may reduce the accumulation of
oxidatively damaged cell components. This would decrease renal membrane
destruction, because of a favorable effect on phospholipid
concentration. In the BBM, this adaptive change would affect the apical
transporters, such as the proton-translocating -ATPase, the
Na+/glucose and the
Na+/PO4-2 cotransporters. In the
BLM, the Na,K-ATPase would be affected. In the kidney, this enzyme
provides virtually all of the energy for maintaining electrochemical
gradients, secondary active transport and metabolism (Burckhardt and Gerger 1992
). To document that the proximal tubule is more
efficient, however, studies showing increased glucose or bicarbonate
re-absorption would be required. It should be noted that urine
HCO3 excretion did not differ between groups, despite the
reduced Na,K-ATPase in FR rats.
Our study also showed that FR rats had lower plasma levels of glucose
and cholesterol as well as 25% lower body weight. These data are
consistent with evidence in animals and humans (Hansen and Bodkin 1993
, Kemnitz et al. 1994
, Lane et al. 1995
, Ruhe et al. 1996
, Walford et al. 1992
, Wang et al. 1997
). The lower blood
glucose and decreased body weight improve insulin sensitivity
(Kemnitz et al. 1994
, Lane et al. 1995
,
Ruhe et al. 1996
, Wang et al. 1997
), both
of which prevent diabetes mellitus (Hansen and Bodkin 1993
). We have reported that blood glucose concentration and
body weight in the 3-y-old FR rats did not differ from the 4-mo-old FR
rats (Eiam-Ong and Sabatini 1999a
and 1999b
).
Prolonged food restriction produces a wide array of effects on the
cardiovascular system (Herlihy and Thomas 1992
). FR
(50%) lowered blood pressure in rats made hypertensive either by
combined nephrectomy-deoxycorticosterone acetate treatment or by
abdominal aortic coarctation (Swoap et al. 1995
).
Recently, Overton et al. (1997)
showed that FR (40%, from 5 wk of age)
decreased the development of hypertension in spontaneously hypertensive
rats by reducing the activity of the sympathetic nervous system. Such a
fall in the sympathetic nervous system activity may account for the
lower creatinine clearance noted in the FR rats in our study. Such a
reduction should result in a decrease in glomerular hyperperfusion, a
factor known to cause glomerulosclerosis (Mackenzie and Brenner 1998
). In the present study, our FR rats were not azotemic
because of a reduction in creatinine clearance. Moreover, FR
significantly lowered blood urea nitrogen concentration, indicating
that the rats were not catabolic. The low blood urea nitrogen also may
explain the reduced proton excretion in the FR rats. In addition, a
lower protein intake may decrease creatinine clearance and phosphate
excretion in the FR rats. Collectively, these observations document
some of the mechanisms for the beneficial effects of FR on the kidney.
That FR causes lower renal membrane lipid deposition, glomerular
hyperfiltration, renal energy expenditure and plasma cholesterol are
all evidence that FR should delay either the onset or the
progression of renal disease.
There are no studies of food restriction as related to the preservation
of renal function in humans. The beneficial effects of protein
restriction on the kidney were documented (Levey et al. 1996a and b
, Pedrini et al. 1996
). Clinical trials of
energy restriction in renal disease patients need to be examined. The
results may elucidate an additional noninvasive form of therapy to
prevent the progressive nephropathy of aging.
In summary, the present study provides additional data as to the
benefits of food restriction on the kidney. Six weeks of food
restriction, without malnutrition, in F344 x BNF1 rats improved renal
function and prevented renal membrane lipid deposition. These
alterations might attenuate the incidence of renal disease related to
the onset of diabetes mellitus and to the progression of
glomerulosclerosis in humans. Clinical trials as to the efficacy of
such an approach should be performed. Studies should be performed to
determine which component of the diet; which (i.e., carbohydrate, fat
or protein), if restricted, is beneficial (Kobayashi and Venkatachalam 1992
, MacConi et al. 1997
).
|
ACKNOWLEDGMENTS |
|---|
|
FOOTNOTES |
|---|
2 This work was supported in part by a grant from
the National Institutes of Health (#R0I-KD-36199).
4 Abbreviations used: AL, ad libitum; BBM, brush
border membrane; BLM, basolateral membrane; F344 x BNF1, Fischer
344 x Brown Norway F1; FR, food restriction; IFCC, International
Federation of Clinical Chemistry; IL-2, interleukin-2; NIA, National
Institute of Aging; PC, phosphatidylcholine; PE,
phosphatidylethanolamine; Pi, inorganic phosphate; PS,
phosphatidylserine; SLE, systemic lupus erythematosus; Spm,
sphingomyelin.
5 Natural ingredient diet is composed mainly of a
mixture of wheat, corn gluten meal, oats, fish meal, soybean meal,
alfalfa meal and soybean oil. The major nutrient composition (per g of
pellet) as determined by the manufacturer is as follows: protein,
0.18 g; carbohydrate, 0.55 g; fat, 0.04 g; fiber,
0.05 g, ash, 0.08 g; moisture, 0.1 g; vitamins (vitamin
A acetate, 104.5 µg; cyanocobalomin, 0.05 µg; cholecalciferol, 0.16
µg; 
-tocopheryl acetate, 0.8 mg; biotin, 0.66 µg; choline
chloride, 3.56 mg; folic acid, 3.8 µg; niacin, 1.45 mg; pantothenic
acid, 20.48 mg; pyridoxin, 13.4 µg; riboflavin, 12.9 µg;
thiamin, 73.0 mg); minerals (Ca, 11.5 mg; Cl, 6.1 mg; Co, 0.26 µg;
Cu, 12.3 µg; F, 15.0 µg; I, 1.8 µg; Fe, 2.63 mg; Mg, 1.5 mg; Mn,
1.24 mg; P, 8.5 mg; K, 7.5 mg; Se, 0.43 µg; Na, 3.0 mg; Zn, 97.3
µg). Nutrient content represents average nutrient content based on
the latest ingredient analysis. This diet is fortified with additional
nutrients such that only energy is limiting (The Bionetics, Jefferson,
AR). All lots were analyzed prior to feeding, and this analysis did not
differ from the average values. Source: A. Shepherd, Purina Mills,
(Richmond, IN).
Manuscript received February 2, 1999. Initial review completed March 10, 1999. Revision accepted May 14, 1999.
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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