Departments of 1 Pediatrics and Child Health, 2 Radiology, and 3 Pharmacology and Therapeutics, University of Manitoba, Winnipeg, Manitoba, Canada R3A 1S1
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ABSTRACT |
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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
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INTRODUCTION |
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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 |
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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:
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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.
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 |
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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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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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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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DISCUSSION |
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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 |
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This research was supported by grants from the Children's Hospital Foundation of Manitoba and the Medical Research Council of Canada (MT-13733).
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FOOTNOTES |
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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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