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Departments of Nutrition and Food Sciences, Texas Woman’s University, Denton, TX 76383;
*
Pediatrics and Child Health, University of Manitoba, Winnipeg, MB, R3T 2N2 Canada;
Surgical Pathology, University of Texas Southwestern Medical School, Dallas, TX 75235; and
**
Department of Human Nutritional Sciences, University of Manitoba, Winnipeg, MB, R3T 2N2 Canada
4To whom correspondence should be addressed. E-mail: aukema{at}umanitoba.ca.
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ABSTRACT |
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 TOP ABSTRACT MATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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KEY WORDS: • dietary fat level • fish oil • early renal disease • rats
There have been many attempts to modify the progression of chronic renal diseases with diet, including altering the types and levels of dietary fat. We demonstrated recently that a high dietary fat intake using soybean oil as the fat source increases early kidney disease progression, evidenced by greater kidney size, fluid accumulation and cyst growth, and worsened renal function in the Han:SPRD-cy rat model of polycystic kidney disease (PKD)5 (1
). In separate studies, we also demonstrated that feeding flaxseed, enriched in 18:3(n-3), ameliorates early disease progression in Han:SPRD-cy rats with PKD through moderation of the associated chronic interstitial nephritis (2
). Whether these beneficial effects of dietary (n-3) fatty acids in flax seeds also occur with fish oil, however, is not known. In DBA/2FG-pcy/pcy mice, feeding fish oil containing 20:5(n-3) and 22:6(n-3) was beneficial in a short-term early feeding study (3
) but detrimental in a survival study (4
). Diets containing (n-3) polyunsaturated fatty acids (PUFA) appear to be renoprotective in rats with immune and/or inflammatory mediated renal disorders (5
).
PKD is a common genetic renal disease in humans; it is more prevalent than the combined incidences of cystic fibrosis, muscular dystrophy, hemophilia, sickle cell anemia and multiple sclerosis. It encompasses a variety of inherited or acquired cystic disorders characterized primarily by abnormal renal growth and cystogenesis (6
). However, even with the current understanding of the genetic defects that cause PKD, there is no known therapeutic intervention available for this disease. Treatment of PKD patients is confined to alleviation of the secondary complications such as hypertension. The rate of decline in renal function and the age of onset of detectable cysts in patients with PKD demonstrates considerable variability, with approximately half of the patients with the most common form of PKD developing end stage renal disease by the age of 58 y (7
). This indicates that factors other than the primary genetic defect influence the progression of the disease. A growing number of reports demonstrate that diet influences disease progression in animal models with this renal disorder, particularly in the early stages of disease (2
,8
–13
).
Whether the previously observed detrimental effect of a high fat diet in Han:SPRD-cy rats is dependent on the type of dietary fat is not known. Therefore, we used cottonseed oil, rich in (n-6) fatty acids, and menhaden oil, rich in very long-chain (n-3) fatty acids, as well as the previously utilized soybean oil to determine whether the effects of dietary fat level in the early stages of renal disease in Han:SPRD-cy rats with PKD are influenced by the type of fat in the diet. This model of renal disease is an excellent system with which to study how diet can modify early renal injury because it is characterized by progressive dilation of nephrons and marked renal interstitial inflammation and fibrosis in young rats. The results demonstrate that the effects of fat level on renal injury are influenced by the type of fat in the diet.
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MATERIALS AND METHODS |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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The animal experimental protocol was in accordance with the National Institutes of Health Guide for the Care and Use of Laboratory Animals and was approved by the University Animal Care and Use Committee. Han:SPRD-cy rats were obtained from our breeding colony derived from animals provided by Dr. B. D. Cowley (University of Kansas Medical Center). The Han:SPRD-cy rat model is a well-documented animal model of PKD that mimics the main form of PKD in humans (14
). Rats were weaned at 4 wk of age and individually housed at a temperature of 23 ± 2°C, relative humidity of 60–65%, and a 12-h light:dark cycle. Male offspring from heterozygous parents were randomly assigned to dietary groups. Homozygous (cy/cy) rats do not survive to weaning, and the surviving rats are either normal (+/+) or diseased (cy/+). Random assignment of 19 rats to each dietary group resulted in the distribution of 11–14 diseased rats in the dietary groups; the remaining rats in each group were normal. Only rats with renal disease were used for analyses and the specific numbers in each group are detailed in Tables 2
and 4
.
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); the fatty acid compositions of the experimental diets are shown in Table 1
. Body weights were recorded weekly. Forty-eight hours before killing, rats were placed in metabolic cages and 24-h food and water intakes were measured and urine samples collected and stored at -80°C until further analyses.
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Biochemical analyses.
Commercial kits were used to determine serum urea nitrogen (SUN; Sigma #640, Sigma Diagnostics, St. Louis, MO), serum and urine creatinine (Sigma #555, Sigma Diagnostics), serum cholesterol (BioPacific Diagnostics Kit#225, Charlottetown, Canada) and serum triglyceride (BioPacific Diagnostics Kit#210). Creatinine clearance [mL/(min · 100 g body)] was calculated using the following formula: {[(Urine creatinine(mg/dL) x Urine volume per day(mL)/1440(min)]/Serum creatinine(mg/dL)}/Body weight(g) x 100. Lipids from experimental diets and right kidneys from experimental rats were extracted and applied to gas chromatographic analysis using procedures described (15
). Four kidneys from each diet group were randomly chosen for the fatty acid analyses of the kidneys. Fatty acid contents were identified by comparison of retention times between fatty acid methyl esters (FAME) and Supelco 37 component FAME mix (Bellefonte, PA) and expressed as g/100 g total fatty acid.
Histology.
Macrophages are used as a marker of renal inflammation for several reasons, i.e., they are virtually undetectable in healthy kidney, the transient population from normal circulating cells is small, they are invariably present in the chronic interstitial inflammation seen in this model and they are easily and specifically detected by a robust immunohistochemical technique. The use of macrophage infiltration to assess renal infiltration has been previously described by others and by our laboratory (2
,12
,14
,15
). Briefly, macrophages were first identified using a primary monoclonal antibody against a 90- to 100-kDa protein that is expressed on lysosomal membranes and has many characteristics of the human CD68 antigen (Chemicon MAB 1435, Chemicon, Temecula, CA). Sections were incubated at a dilution of 1:100 for 60 min. Secondary detection was performed by using a Vectastain Elite kit with rat absorbed anti-mouse immunoglobulin G derived in goat and with peroxidase-diaminobenzidine color development (Vector Laboratories, Burlingame, CA). Nonspecific binding of goat protein was blocked by a 60-min preincubation with full strength goat serum. Negative controls included both sections without primary or without secondary antibody incubation and normal kidney, which contains very few cells of this lineage. Rat colon, which has a resident macrophage/monocyte population, was used as a positive control. Macrophage numbers were counted using module 2500 of the Imagemeasure software package (Phoenix Biotechnology, Seattle, WA). The counts were reported as a mean per high power video field (40X microscope objective) with at least 50 randomly selected, nonoverlapping fields counted. Because cystic lumens contained no cellular elements, results were corrected for the extent of cystic change in each kidney and thus represented counts per solid tissue area. This correction used the following formula:
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Sections for quantitative analysis of fibrosis were stained using aniline blue as an adaptation of Masson’s trichrome stain (12
,16
). This adaptation demonstrates a perfect concordance of staining with an immunofluorescent detection of collagen type III. Renal fibrous volume was determined using a 20X objective and using the proportion of section areas that had taken up aniline blue stain. The product of the proportion and the reference renal volume, derived from renal weight assuming an average tissue density of 1 g/L, corrected to body weight, gives the final volume occupied by either renal cyst volume or renal fibrous tissue.
Sections for analysis of cyst volume were stained with hematoxylin and eosin as described previously (12
). Measurement of the portion of the tissue section occupied by tubular lumen or cysts was performed through a 2X objective, moving stepwise from a random starting point until 50 measurements were made from each of four separate whole kidneys. Results were expressed as the ratio of the area identified as tubular lumen or cyst by hue and intensity characteristics by an automated measurement subroutine to the total image area, excluding any area of image beyond the renal capsule. An average of 50 measurements from 3–5 different sections was used to determine the cyst area ratio. Cyst volume was calculated from this ratio as described for renal fibrosis.
Statistical analyses.
All data were expressed as least-square means and the pooled SEM. Data were analyzed by two-way ANOVA using JMP statistical software (SAS, Cary, NC). Contrasts were used to determine differences between main effects of oil type, or if there were significant interactions between fat level and type, contrasts were used to determine simple effects. Differences were considered significant if P < 0.05.
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RESULTS |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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) from wk 4 through 10. Rats fed the LF diets ate more than those fed the HF diets, resulting in similar energy intakes in all groups. The feeding study occurred in the period of most rapid early cyst growth in this animal model, with death from renal failure not typically occurring until 6–10 mo of age (14
,16
,17
). Fatty acid compositions of renal tissues.
Generally, the fatty acid compositions of kidneys reflected the compositions of the diets (Tables 1
and 3
). The incorporation of very long-chain (n-3) PUFA, especially 20:5(n-3) and 22:6(n-3), was highest in kidneys from rats fed MO. These rats also had the lowest levels of renal (n-6) fatty acids. Rats fed CO had the highest levels of 20-carbon and 22-carbon (n-6) fatty acids, whereas renal tissues from rats fed SO had the highest contents of 18:2(n-6) and 18:3(n-3), reflecting the relative enrichment of these fatty acids in the diets. Saturated fatty acid compositions were affected less by these diets than were unsaturated fatty acids.
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Overall, HF compared with LF diets resulted in larger kidneys (P = 0.0479) (Table 2)
, higher serum creatinine (P < 0.0001), reduced creatinine clearance (P = 0.0021) and larger renal fibrous volumes (P = 0.0351) (Table 4
). Serum lipids were not affected by fat level (Table 4)
. Fat level effects on SUN concentrations and renal inflammation were influenced by dietary oil type, as evidenced by significant interactions between fat level and type (Table 4)
. HF diets compared with LF diets had higher SUN levels in rats fed CO or MO diets, but not in rats fed SO diets (Table 4)
. As a histological effect, HF diets increased renal fibrosis in rats fed CO diets (Table 4)
. Interestingly, HF diets increased renal inflammation in rats fed CO, but caused less inflammation in those fed MO or SO diets (Table 4
, Fig. 1
).
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There were also overall dietary fat type effects on disease progression in Han:SPRD-cy rats (Tables 2
and 4)
. Rats fed MO rather than CO and SO diets had significantly lower kidney weights, kidney water content, serum cholesterol, triacylglycerol concentrations and cyst volumes (Tables 2
and 4)
. Rats fed all three types of oils had different degrees of renal fibrosis, with those fed the CO diets having the highest and those fed the SO diets having the lowest fibrous volume (Table 4)
. Fat type did not affect creatinine levels or creatinine clearance. Fat type effects on SUN concentrations and renal inflammation were influenced by the level of dietary oil. SUN concentrations were lower in rats fed MO and CO compared with SO only in those fed the LF diets (Table 4)
. The effect of oil type on renal inflammation was not different in LF-fed rats, but in rats fed HF diets, those fed the CO diet had more renal inflammation than those fed the MO and SO diets (Table 4
, Fig. 1
).
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DISCUSSION |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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). Furthermore, this study also demonstrates that the detrimental effects of a HF diet are modulated by the source of dietary lipid. The most damaging effects of the HF diet were observed in rats fed the CO diet, which is virtually devoid of (n-3) fatty acids. In contrast, the MO diet, containing a high amount of very long-chain (n-3) fatty acids, ameliorated the renal injury observed in rats fed the HF diet. When MO was the dietary lipid source, not only was the negative effect of the HF diet abrogated, but renal inflammation was actually lower when a higher level of MO fat was fed. The effects of the SO diet, containing a lower level of (n-3) fatty acids, on the progression of early renal injury varied depending on the marker of disease progression, but were generally intermediate between the effects of CO and MO.
This study adds to the growing number of reports that demonstrate that dietary interventions in rodent models of PKD can alter the early progression of renal injury. Although progress is being made toward understanding the underlying genetic defects in PKD, no known therapeutic interventions for this disease currently exist, and treatment is confined to alleviation of secondary disorders. Dietary manipulations in animal models that retard early disease progression without compromising growth include reducing dietary protein to a low, yet growth-maintaining level, reducing dietary fat, substituting soy protein for casein, adding flaxseed to the diet, and adding citrate to drinking water (1
,2
,9
,12
,13
,18
,19
). Of note in the current study is that reducing the dietary fat level and including a source of (n-3) fatty acids in the diets are dietary interventions that maintain normal body growth and have positive effects on early disease progression. The high and low fat levels consumed by the rats are comparable to very low fat (
10% of total energy from fat) and high fat (40% of total energy from fat) human diets. The level of (n-3) fatty acid in the MO diet would be difficult to achieve in human diets, and the optimal level of (n-3) fatty acids in the diet remains to be determined. However, the improvement in some markers of renal injury in rats consuming the SO diets containing a small amount of 18:3(n-3) suggests that inclusion of even small amounts of (n-3) fatty acids retards early renal disease progression. Intervention studies with purified fatty acids are required to address this issue. These studies are needed to confirm that the beneficial effects of the MO and SO diets are indeed due to their (n-3) fatty acid content and to identify which fatty acids are responsible for these effects.
The Han:SPRD-cy rat model, first described by Kaspareit-Rittinghausen et al. (17
) in 1989, inherits PKD as an autosomal dominant trait and expresses pathologic features consistent with the most common form of PKD in humans. PKD in Han:SPRD-cy rats is characterized by renal inflammation and fibrosis associated with the development of cystic disease, azotemia and protooncogene expression (14
). Because these features are common in most forms of renal injury, Han:SPRD-cy rats comprise an excellent animal model not only of PKD, but also of chronic renal injury in general.
The mechanisms by which dietary fat can influence PKD progression in Han:SPRD-cy rats remain to be determined. However, the current study and a number of our recent studies suggest that eicosanoids may be important in this renal disorder. Dietary flaxseed enriched in 18:3(n-3) and soy protein retard PKD progression in Han:SPRD-cy rats. Both of these interventions alter the fatty acid composition of the kidneys, thus altering the potential pools of eicosanoid precursors (2
,15
). Furthermore, the steady-state levels of the rate-limiting enzymes in eicosanoid synthesis, phospholipase A2, cyclooxygenase-1 and cyclooxygenase-2 are altered in the Han:SPRD-cy rat and pcy mouse models of PKD (20
,21
).
Functional changes in glomerular filtration rate and renal plasma flow in animals consuming high protein diets, which worsen experimental renal injury, also are accompanied by increased kidney synthesis and excretion of eicosanoids (22
–24
). Although the role of eicosanoids in normal renal physiology appears to be minor, in the diseased kidney, eicosanoids appear to play a crucial role in maintaining glomerular filtration rate as well as being involved in inflammatory processes in response to renal injury (22
,24
). In some types of renal disease, a reduction in eicosanoid formation is associated with amelioration of the disease process, whereas in others, it appears to have a protective effect (22
–24
). Increased levels of dietary fat are known to increase eicosanoid synthesis and may be involved in the mechanism by which the HF diets increased disease progression in Han:SPRD-cy rats in this study. The amelioration of renal injury in rats fed the HF diets by (n-3) fatty acids may be due to the fact that the 3-series eicosanoids produced from 20:5(n-3) are generally less bioactive. The (n-6) and (n-3) fatty acids compete for incorporation into and release from cellular phospholipids and for the enzymes that catalyze their conversions to eicosanoids (25
).
In inflammatory renal disease, a marked increase in prostanoids and leukotrienes accompanies increased inflammation (26
–30
). In our study, high dietary CO resulted in higher renal inflammation, whereas high MO and SO led to less renal inflammation in rats fed HF diets. Interstitial inflammation and fibrosis play an important role in the development in renal failure in Han:SPRD-cy rats (14
), and previous studies with flaxseed oil in this model of PKD also have documented reduced interstitial nephritis and macrophage infiltration (2
). Dietary supplementation with (n-3) PUFA also reduces the production of cytokines such as interleukin-1 and tumor necrosis factor, which are principal mediators of inflammation (31
). Studies on other forms of renal disease also demonstrate the benefits of dietary fish oils and their effects on inflammatory mediators [for review, see (5
)], including a study on early renal insufficiency in dogs (32
). Our study demonstrating a beneficial effect on early PKD progression is consistent with these studies; however, the exact mechanism by which (n-3) fatty acids attenuate inflammation and fibrosis in renal tissues remains to be determined.
Hyperlipidemia is a contributing factor in the progression of many forms of chronic renal disease, and patients with renal insufficiency frequently exhibit hyperlipidemia (33
). PKD patients commonly display hyperlipidemia (34
) and we observed elevated lipids both in Han:SPRD-cy rats in this study (data not shown) and previously in the pcy mouse model of PKD (35
). Hyperlipidemia is believed to be followed by lipid accumulation in the renal mesangium with resulting injurious effects such as foam cell formation, cell proliferation, matrix formation and alteration of the charge selectivity in glomerular basement membrane (36
). Although hyperlipidemia initially damages the glomerulus, it is evident that alterations in glomerular function ultimately influence tubulointerstitial injury, inflammation and fibrosis. Tubular function correlates most closely with renal function, even in nephropathies that are traditionally considered to be glomerular diseases (37
). Probucol, a cholesterol-lowering agent prevents the accentuation of kidney enlargement, renal fibrosis, and azotemia in BDF1-pcy mice with PKD (38
). Similarly, the administration of lovastatin, another cholesterol-lowering agent, diminishes the rate of kidney enlargement in male Han:SPRD-cy rats (39
). Therefore, the beneficial effect of (n-3) fatty acids in the MO diet could be due in part to its ability to lower serum lipid levels (40
).
The results of this study are consistent with our previous studies with a high fat diet in which the early progression of disease was examined in growing Han:SPRD-cy rats (1
). The only exception was the SUN concentrations, which were higher in the HF-fed rats in the previous study, but not different in the current study. The reason for this is not clear, but SUN is less reliable than serum creatinine, which was significantly elevated in HF-fed rats in the current study. The detrimental effect of the HF diet is also in agreement with our findings in adult pcy mice with PKD (41
). The effect of the menhaden oil in this study is consistent with the retarding effects of dietary flaxseed (2
,42
) on disease progression in growing Han:SPRD-cy rats. In pcy mice, previous studies also demonstrated that dietary fish oil marginally slows early cyst formation (3
). However, we found no benefit when fish oil was fed during both the growing and adult stages in pcy mice, and that long-term feeding of dietary fish oil fed accelerated disease progression (4
,8
,41
). The reason for this remains to be elucidated, but in addition to effects possibly related to developmental stage, it may also reflect the lesser degree of inflammation in the pcy mouse model because in this model the disease progresses more slowly. It is important, therefore, to determine whether the apparent beneficial effects of fish oil in the early stages of the disease are abrogated by a detrimental effect in the latter stages, and whether the potential benefit of dietary fish oil in PKD is limited to the early stages of disease progression. Given the current lack of treatment modalities for PKD, and the evidence from animal studies that demonstrate that this disease is very sensitive to dietary treatments, it is imperative to delineate when and what dietary treatments have the most beneficial effects.
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FOOTNOTES |
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2 Supported by Texas Foods and Fibers Commission, Manitoba Institute for Child Health and by the Natural Sciences and Engineering Research Council of Canada.
3 Present address: Department of Pediatrics/Research Institute, Northwestern University Medical School, Evanston Northwestern Healthcare, 2650 Ridge Ave., Evanston, IL 60201.
5 Abbreviations used: CO, cottonseed oil; FAME, fatty acid methyl esters; HF, high fat; LF, low fat; MO menhaden oil; PKD, polycystic kidney disease; PUFA, polyunsaturated fatty acids; SO, soybean oil; SUN, serum urea nitrogen.
Manuscript received 27 August 2002. Initial review completed 23 September 2002. Revision accepted 17 October 2002.
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LITERATURE CITED |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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