Vol. 279, Issue 6, G1162-G1168, December 2000
Dietary betaine modifies hepatic metabolism but not renal
injury in rat polycystic kidney disease
Malcolm R.
Ogborn1,
Evan
Nitschmann1,
Neda
Bankovic-Calic1,
Richard
Buist2, and
James
Peeling2,3
Departments of 1 Pediatrics and Child Health,
2 Radiology, and 3 Pharmacology and Therapeutics,
University of Manitoba, Winnipeg, Manitoba, Canada R3A 1S1
 |
ABSTRACT |
We undertook a morphometric and
proton nuclear magnetic resonance (1H-NMR) study to test
the hypothesis that 1% dietary betaine supplementation would
ameliorate renal disease in the heterozygous Han:SPRD-cy rat, a model of polycystic kidney disease (PKD) and progressive chronic
renal failure. After 8 wk of pair feeding, betaine had no effect on
renal cystic change, renal interstitial fibrosis, serum creatinine,
serum cholesterol, or serum triglycerides. 1H-NMR
spectroscopy of renal tissue revealed no change in renal osmolytes,
including betaine, or renal content of other organic anions in response
to diet. 1H-NMR spectroscopy of hepatic tissue performed to
explore the metabolic fate of ingested betaine revealed that
heterozygous animals fed the control diet had elevated hepatic levels
of gluconeogenic amino acids, increased 
-hydroxybutyrate, and
increased levels of some citric acid cycle metabolites compared with
animals without renal disease. Betaine supplementation eliminated these
changes. Chronic renal failure in the Han:SPRD-cy rat is
associated with disturbances of hepatic metabolism that can be
corrected with betaine therapy, suggesting the presence of a reversible
methylation defect in this form of chronic renal failure.
liver; nuclear magnetic resonance; uremia; methylation
| |
INTRODUCTION |
CHRONIC RENAL
FAILURE FROM all causes represents one of the most expensive and
rapidly growing demands on the health care systems of developed
countries. The final pathophysiological pathway to renal failure and
the clinical uremic state that follows seem to be remarkably similar in
most patients despite diverse etiologies of the original renal injury.
The failing kidney is characterized by expansion of the interstitial
compartment by inflammation and fibrosis with obliteration of the
vascular bed and loss of tubular tissue (32).
The Han:SPRD-cy rat is an autosomal dominant model of
polycystic kidney disease (PKD) and progressive chronic renal failure (4). The model is characterized by marked sexual
dimorphism, with affected male animals developing terminal uremia in
6-9 mo, whereas female animals have renal function preserved into
the second year of life. In previous studies in this model, we
(18, 20-22) have demonstrated that the histological
course of renal injury and the decline of renal function may be
modified by dietary changes. These include reduction in total protein
intake, substitution of soy protein for casein, or supplementation with
flaxseed (18, 20-22). Our (23) previous
proton nuclear magnetic resonance (1H-NMR) studies noted
that disease progression was associated with renal depletion of betaine
and citric acid cycle intermediaries. Our (18, 19)
subsequent studies found that dietary strategies associated with
amelioration of disease were associated with renal enrichment of
betaine beyond the normal level present in healthy animals on control diets.
In a renal context, betaine is usually considered only in its role as
an osmolyte in protection of renal cells from the extreme osmolar
environment of the kidney (2). Dietary betaine has, however, been successfully employed as a therapy for inborn errors of
metabolism characterized by disturbance of critical methylation pathways, and as treatment for hyperhomocysteinemia, a state associated with accelerated risk of atherosclerosis (11, 12). Betaine acts as alternate methyl donor through the generation of
methionine from homocysteine via betaine-homocysteine
methyltransferase (6). Betaine has metabolic effects in
healthy human volunteers at quite modest intake levels
(36). In rats, betaine is effective at preventing a
variety of toxic injuries to the liver (1, 14, 17). We
therefore undertook a morphometric study to test the hypothesis that a
dietary betaine supplement would ameliorate renal injury in the
Han:SPRD-cy rat. Subsequent to the morphometric study, we
undertook 1H-NMR spectroscopic studies to explore the
metabolic fate of ingested betaine and the biochemical consequences of
dietary betaine supplementation on renal and hepatic biochemistry of
the Han:SPRD-cy rat.
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METHODS |
Han:SPRD-cy rats.
Han:SPRD-cy rats were obtained from our own breeding colony,
which is derived from animals kindly provided by Dr. Benjamin Cowley
(University of Kansas Medical Center, Kansas City, KS). All animal
procedures and care were examined by the University of Manitoba
Committee on Animal Use and certified to be within the guidelines of
the Canadian Council on Animal Care. Surviving male offspring of known
Han:SPRD-cy heterozygotes were used in this study.
Two-thirds of these animals would be expected to be heterozygous, as
homozygotes in our colony rarely survive beyond weaning.
Animals were randomly assigned to either control diet or control diet
supplemented with 1% betaine (Sigma Chemical, St. Louis, MO). This
dose is comparable to that reported in previous rat studies
(1). The control diet consisted of 20% casein (80% protein, 72 kcal/100 g), 5% corn oil (45 kcal/100 g), 65% corn starch and dextrose (260 kcal/100 g), 5% fiber, 3.5% AIN-93 mineral mix, 1.0% AIN-76 vitamin mix, 0.3% methionine, and 0.2% choline bitartarate. The control diet was manufactured in the Department of
Food and Nutrition Science, Faculty of Human Ecology, University of
Manitoba, under the supervision of Dr. Ranjana Bird. Diet was initiated
at weaning and continued for 8 wk using a pair feeding protocol. The
animals were killed by pentobarbital (pentobarbitone) overdose after 8 wk on the diet, and blood, liver, and kidneys were collected for study.
Histology.
Tissue from the left kidney was used for histological analysis. This
tissue was fixed in 10% formalin for 120 min before embedding in
paraffin and sectioning at 5 µm. Sections for measurement of cystic
volume and qualitative study of renal histology were stained with
hematoxylin and eosin. Sections for quantitative analysis of fibrosis
were stained using aniline blue alone in adaptation of Masson's
trichrome stain. This staining demonstrates perfect concordance with
the distribution of type III collagen (20).
Image analysis.
Image analysis procedures were performed with a system consisting of a
Cohu high-resolution black-and-white camera connected to a computer via
a PCVisionPlus video capture board. Images were captured using the
Image Pro software package (Phoenix Biotechnology, Seattle, WA).
Renal volume was determined using the Cavalieri principle as we
(22) have described previously. Measurement of relative tubular luminal area, i.e., the fraction of tissue section occupied by
tubular lumen, was performed fluorometrically using the IM4100 module
of the Imagemeasure software package (Phoenix Biotechnology) using
low-power microscopic images captured via a Cohu high-resolution black-and-white video camera. Sections were viewed through a ×2 objective and Nikon television relay lens. The samples were illuminated with a wide-aperture condenser to ensure uniform lighting conditions. The profiling tool within the program was used to ensure uniform lighting of the captured video image. A 64 pixel by 64 pixel rectangle was moved in an alternating horizontal and vertical path through the
section from a random starting point until 50 measurements from each of
four separate whole kidney tissue cross sections had been collected.
The inner fluorometric threshold was adjusted for each slide to include
all gray scale values equal to or greater than open tubular lumen. The
outer threshold was set to one (black) to include all stained areas of
tissue and the relative tubular luminal area was calculated according
to the following formula:
where A is the relative area ratio and
Xi and Xo are the number
of pixels within the inner and outer threshold, respectively. An
average of 50 measurements from three to five different sections was
used to determine the cyst area ratio. A measurement was accepted if
the 95% confidence intervals of the mean were within 2% of the mean.
Renal fibrous volume was measured in a similar way, using the
proportion of section areas that had taken up aniline blue stain as
measured in densitometry mode of module 4100 of the Imagemeasure
software package. In densitometry mode, the thresholds are reversed,
with the outer threshold set to 255 (white) and the inner threshold set
1 gray scale unit over the actual measured value of an area of
interstitial aniline blue staining. For both sets of measurements, the
proportion was then multiplied by the reference renal volume corrected
to body weight to give the final volume occupied by either renal cyst
volume or renal fibrous tissue (18, 20, 21).
1H-NMR spectroscopy.
The right kidney and left lobe of the liver were quickly removed when
the animals were killed and then placed immediately in liquid nitrogen
before storage at 
70°C. Frozen whole kidney tissue was weighed,
lyophilized, and then reweighed to determine water content. The dried
tissue was pulverized under liquid nitrogen and then homogenized on ice
in 0.5 M perchloric acid (PCA, 10:1 vol/tissue wt) (26).
Tissue debris was removed by centrifugation at 20,000 g for
10 min at 4°C to precipitate insoluble components. The supernatant
from this procedure was adjusted to a pH of 7.2 with KOH and HCl. The
sample was centrifuged at 20,000 g for 10 min at 4°C to
precipitate KClO4. The supernatant was frozen at 70°C
and then lyophilized. The lyophilized sample was reconstituted in 1.5 ml of D2O, containing known amounts of
sodium-d4-(trimethylsilyl)propionate (TSP) as an internal
standard of concentration and chemical shift. The pH was
adjusted to 7.25 with appropriate deuterated compounds. Samples were
refrigerated at 4°C for 1 h, then centrifuged at 4°C for 25 min at 16,000 g to remove additional salt. Samples were then
transferred to 5-mm NMR tubes.
1H-NMR spectra of tissue extracts were obtained at 500 MHz
(11.7 T) using a Bruker AMX500 spectrometer locked to the
D2O deuterium resonance and operating with a probe
temperature of 310 K. Each spectrum was accumulated as the sum of 160 free induction decays acquired into 16,384 data points following an
80° pulse, using a sweep width of 7,042 Hz, an acquisition time of
1.16 s, and a relaxation delay of 10 s for a total pulse
recycle time of 11.16 s. The water signal was suppressed by
presaturation during the relaxation delay. An exponential line
broadening of 0.5 Hz was applied before Fourier transformation to yield
the spectrum. Spectral peak positions were measured relative to the TSP
peak (0 ppm).
Peak assignments were based on previously published spectra and by
comparison with spectra of authentic compounds. For each metabolite of
interest, an isolated peak or group of peaks was selected and the
integral of peak area was measured relative to that of the TSP peak.
The concentration of the metabolite in each sample was determined from
this ratio and the known concentration of TSP, after correcting for the
relative number of protons contributing to the resonances and for the
dry tissue weight used.
Serum biochemistry.
Serum creatinine, total cholesterol, and triglycerides were measured
using spectrophotometric methods and Sigma Chemical kits.
Statistical analysis.
Data from affected and normal animals were compared with respect to
dietary intervention using one-way ANOVA with Bonferroni post hoc tests
using the Prism2 software package (Graphpad Software, San Diego, CA).
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RESULTS |
Both Han:SPRD-cy rats and unaffected littermates
thrived on either control or betaine-supplemented diets. Serum
biochemistry confirmed that affected animals were becoming uremic to an
extent consistent with our (18, 21) previous studies in
animals receiving a casein-based diet (Table
1).
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Table 1.
Physical, biochemical, and histochemical data from Han:SPRD-cy rats
fed control or betaine-supplemented diet
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Betaine supplementation was not associated with any change in renal
histology manifest as either cystic change or interstitial fibrosis,
the predominant phenotypic abnormalities in Han:SPRD-cy rat
polycystic kidney disease (Table 1). Betaine supplementation was not
associated with any change in serum creatinine in either normal or
affected animals (Table 1). Neither dietary treatment nor the observed
degree of renal failure was associated with significant change in total
serum cholesterol or triglycerides (Table 1).
Dietary betaine supplementation had minimal influence on renal
biochemistry as assessed by 1H-NMR spectroscopy of PCA
tissue extracts (Table 2).
Notably, renal betaine content demonstrated no relationship to dietary intake. Disease expression was associated with changes in lactate and
allantoin content, but this was not influenced by diet. Representative 1H-NMR spectra of PCA renal extracts from affected animals
on control or betaine-supplemented diet are shown in Fig.
1.
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Table 2.
1H-NMR spectroscopic analysis of kidney extracts from
Han:SPRD-cy rats fed control or betaine-supplemented diet
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Fig. 1.
Representative proton nuclear magnetic resonance
(1H-NMR) spectra from renal perchloric acid (PCA) tissue
extracts from Han:SPRD-cy rats receiving control
(A) or betaine-supplemented (B) diets. Peak
assignments are as follows: 1, hippurate; 2,
allantoin; 3, inositol; 4, betaine; 5,
taurine; 6, cholines, including contributions from
glycerophosphocholine, phosphocholine, and choline; 7,
succinate; 8, glutamate; 9, alanine;
10, lactate; 11, hydroxybutyrate.
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1H-NMR spectroscopy of liver tissue revealed that animals
receiving the control diet already demonstrated significant changes in
a broad range of metabolites at a relatively modest degree of uremia
(Table 3) compared with unaffected
animals on the same diet. Compounds involved in gluconeogenesis,
ketogenesis, ureagenesis, and the citric acid cycle all demonstrated
perturbations consistent with previous descriptions (3, 5, 7, 24,
33) of disturbed metabolism in uremia in both liver and
nonhepatic tissues. Betaine supplementation had no effect on hepatic
metabolism in unaffected animals, although there was a trend to higher
hepatic betaine content that did not reach statistical significance.
Affected animals receiving the betaine-supplemented diet demonstrated a hepatic metabolic profile that was indistinguishable from unaffected, nonuremic animals (Table 3). Representative 1H-NMR spectra
of PCA hepatic extracts from affected animals receiving control or
betaine-supplemented diets are shown in Fig.
2.
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Table 3.
1H-NMR spectroscopic analysis of liver extracts from
Han:SPRD-cy rats fed control or betaine-supplemented diet
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Fig. 2.
Representative 1H-NMR spectra from hepatic PCA tissue
extracts from Han:SPRD-cy rats receiving control
(A) or betaine-supplemented (B) diets. Peak
assignments are as follows: 1, formate; 2,
allantoin; 3, inositol; 4, betaine; 5,
taurine; 6, cholines, including contributions from
glycerophosphocholine, phosphocholine, and choline; 7,
succinate; 8, glutamate; 9, alanine;
10, lactate; 11, hydroxybutyrate; 12,
valine.
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DISCUSSION |
A successful pharmacological approach to the modification of the
course of PKD in humans has yet to be determined. Indeed, nonspecific
approaches to slowing the course of human renal failure through
vasoactive drugs or diet have produced disappointing results compared
with animal studies (15). Our (18, 19, 23)
previous studies suggested that Han:SPRD-cy rat PKD
progression was associated with renal betaine depletion and that
dietary manipulations such as soy protein or flaxseed feeding that
ameliorated the disease restored or enriched renal betaine content.
Although specific phamacokinetic data about oral absorption and
systemic distribution of orally absorbed betaine is scant, studies of
choline and choline metabolites suggest that levels of choline-derived
compounds may be influenced by dietary intake in both mature and fetal
organisms (8, 30, 31). A trial of dietary betaine
supplementation therefore seemed a reasonable means to test whether a
causal link existed between renal betaine levels and the
progression of renal injury in the Han:SPRD-cy rat. As
this maneuver did not achieve a change in renal betaine content, the
hypothesis that betaine is protective against renal injury remains
untested. Our data do indicate, however, that renal betaine content is
independent of dietary intake and thus that dietary modification of
renal betaine content seen in our previous studies must occur through a
secondary mechanism. A possible explanation of altered renal betaine
content in our previous studies might be that those interventions reduced renal content of other osmolytes, a trend that was observed, causing a reciprocal increase in betaine to maintain intracellular osmolality (2). Moeckel et al. (16) showed
that endogenous renal synthesis is the major source of renal betaine
and that this synthesis was influenced by hydration status and urine
osmolality. Amelioration of Han:SPRD-cy rat PKD is
associated with preservation of concentrating ability
(23). A component of increased renal betaine in situations
of dietary amelioration may be an epiphenomenon of a partially
preserved urinary concentrating mechanism.
PKD has been proposed as an example of disordered renal regeneration
and repair, supported by histological studies that demonstrate both
apoptosis and disappearance of noncystic tubules at one end of the
injury spectrum to massive epithelial proliferation in cysts at the
other end (38). The ubiquitous association of this injury
with progressive interstitial fibrosis has caused investigators to draw
parallels between PKD and the hepatic response to chronic injury of
cell death, disregulated proliferation, and fibrosis that characterizes
cirrhosis. Such an analogy may be germane to the role of
betaine in preventing renal injury. Betaine has been shown to be an
effective agent in protecting liver tissue from the toxic insults of
ethanol, carbon tetrachloride, and chloroform, probably through the
preservation of S-adenosyl methionine through its role as an
alternate methyl donor (1, 13, 17). It has also been
protective in ischemic injury in the same organ (37). Although the nature of progressive injury in PKD remains undetermined, the possibility of a metabolic disturbance that can be reversed by an
alternate methylation source is at least tenable as structural renal
disease secondary to metabolic derangement is well described. Alteration of renal histology to a cystic and fibrotic phenotype may be
seen with a variety of toxins (9) and may be seen with inborn errors of metabolism such as Zellweger's syndrome
(10). Determination of whether betaine has a direct role
in the modification of this type of renal injury will require different
manipulations that directly modify intrarenal synthesis or retention of betaine.
Although we could not demonstrate hepatic accumulation of betaine as a
cause for the failure of the diet to change renal betaine content, the
extensive metabolic changes seen in the liver in response to betaine
imply a metabolic fate for the ingested compound in that organ. The
metabolic abnormalities seen in animals on the control diet are
consistent with other reports (24, 25, 34, 35) in the
literature. Patterson and Cohn (25) demonstrated inhibition of cytosolic, microsomal, and mitochondrial enzymes relevant
to drug metabolism in uremic rats. Riegel and Horl (34) found that acute uremia was associated with a move of mitochondrial metabolism toward reduction, whereas cytoplasmic metabolism moved to a
more oxidative state. Stepinski et al. (35) noted that acute uremia influenced gluconeogenesis from L-serine,
pyruvate, and hydroxyacetone, but the precise nature of that influence
varied with the method of inducing uremia. Pastoris et al.
(24) found evidence of a "hypermetabolic" citric acid
cycle in stable predialysis chronic renal failure patients, although
oxidative phosphorylation seemed impaired. Our observed increase in
hepatic succinate in Han:SPRD-cy rats receiving the control
diet would be consistent with this observation. Cano et al.
(3) studied hepatic metabolism in isolated hepatocytes
from rats with chronic renal failure secondary to renal ablation. They
found decreased gluconeogenesis and ureagenesis but no change in ketone
generation from oleate and octanoate. Oxygen uptake did not change in
response to a variety of energy substrates, but mitochondrial
ATP-to-ADP ratios decreased, possibly suggesting increased hepatocyte
ATP demand. Our observed elevation of alanine and valine in
Han:SPRD-cy rats receiving control diet would be consistent
with decreased use of these compounds in gluconeogenesis. A similar
explanation might apply to the accumulation of glutamate, which might
also increase if glutamate conversion to aspartate as part of the urea
cycle was reduced. Our methodology does not explore individual pathways
but the observed 1H-NMR spectroscopic profiles are
consistent with disturbances previously described in the literature.
The response to betaine that we have demonstrated is unique as a
strategy to modify uremic metabolism without correcting the uremic
state. The findings suggest a role for a methylation disturbance in the
pathogenesis of the biochemical perturbations in this model. Perna et
al. (27-29) have identified such a defect in red
blood cell membranes in uremia and have linked this observation to the
hyperhomocysteinemia that is commonly found in uremia. Our experimental
design does not rule out the possibility that the hepatic response to
betaine is a specific remedy to the hepatic expression of the
Han:SPRD-cy rat gene, the product of which is yet to be
identified. Further experiments in other models of chronic renal
failure are required to test whether observations can be generalized.
Dialysis is an efficient means of correcting electrolyte and fluid
imbalances in renal failure but does not eliminate nonspecific uremic
symptoms of anorexia or fatigue or correct disturbances of lipid
and homocysteine metabolism that contribute to the excess nonrenal
morbidity that plagues dialysis patients. Our finding of normalization
of a variety of metabolic intermediaries in the liver by dietary
betaine therapy provides a basis to further explore pharmacological or
dietary correction of the metabolic consequences of uremia.
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ACKNOWLEDGEMENTS |
This research was supported by grants from the Children's Hospital
Foundation of Manitoba and the Medical Research Council of Canada
(MT-13733).
| |
FOOTNOTES |
Address for reprint requests and other correspondence: M. R. Ogborn, AE 208-840 Sherbrook St., Winnipeg, Manitoba R3A 1S1, Canada
(E-mail:mogborn{at}hsc.mb.ca).
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.
Received 21 October 1999; accepted in final form 15 June 2000.
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