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Nutrient Metabolism
Research Communication

Dietary Soy Protein Attenuates Renal Disease Progression After 1 and 3 Weeks in Han:SPRD-cy Weanling Rats^1,2

Denise E. Fair^*, Malcolm R. Ogborn^*,, Hope A. Weiler^*,, Neda Bankovic-Calic, Evan P. Nitschmann, Shirley C. Fitzpatrick-Wong^* and Harold M. Aukema^*,,3

Departments of ^* Human Nutritional Sciences and Pediatrics and Child Health, University of Manitoba, Winnipeg, Manitoba, R3T 2N2, Canada

³To whom correspondence should be addressed. E-mail: aukema{at}umanitoba.ca.

	ABSTRACT

TOP ABSTRACT METHODS AND MATERIALS RESULTS DISCUSSION LITERATURE CITED

 
Compared with casein, dietary soy protein slows disease progression in animal models of chronic renal injury. To determine whether dietary soy protein feeding can alter early disease progression, male Han:SPRD-cy rats (n = 87) in a very early stage of chronic kidney disease were fed soy protein compared with casein-based diets for 1 or 3 wk. Kidneys were assessed for fibrosis, cyst growth, fatty acid composition and prostaglandin E₂ (PGE₂) production. Soy protein feeding significantly reduced renal fibrosis by 22% (P = 0.0347) and 38% (P = 0.0102) after 1 and 3 wk of diet, and cyst growth was 34% lower after 3 wk (P < 0.0001). Kidney 18:2(n-6) levels were reduced in normal and diseased rats after as little as 1 wk of consuming the soy protein diet. Dietary soy protein also partially ameliorated the suppression of PGE₂ production observed in diseased kidneys. Compared with diseased kidneys from casein-fed rats, ex vivo PGE₂ release was 31–32% higher after 1 (P = 0.0281) and 3 (P = 0.0189) wk of dietary soy protein consumption. Hence, the first signs of a beneficial soy protein effect were observed after 1 wk of feeding, with further improvements evident after 3 wk. These data demonstrate that dietary soy protein compared with casein delays disease progression in an early stage of chronic kidney disease.

KEY WORDS: • dietary soy protein • chronic kidney disease • early intervention

Chronic kidney disease (CKD)⁴ is a public health problem affecting 11% of the adult population. The presence of CKD increases the risk of kidney failure, cardiovascular disease, and premature death (1,2). Although there are no treatments to reverse renal failure once it occurs, early detection and treatment of CKD are effective in delaying progression to kidney failure and preventing the complications associated with this condition (3). Current therapeutic strategies to slow disease progression include treatment of blood pressure using angiotensin-converting enzyme inhibitors and angiotensin receptor blockers, glycemic control in the case of diabetes, and dietary protein restriction (1,3). The use of dietary protein restriction has been controversial, due to the risk of protein malnutrition and the difficulty in maintaining a low-protein diet in the long term. Hence, there is interest in determining whether altering the type of protein may be beneficial in slowing renal disease progression.

Soy protein compared with casein has been recognized as having beneficial effects in several models of chronic renal disease, including subtotally nephrectomized rats given soy protein for 10–13 wk (4,5), db/db mice with type II diabetic nephropathy studied for 21–26 wk (6), and in rats with chronic nephritic syndrome with 9 wk of feeding (7,8). In long-term studies of normal Fischer 344 rats, lifespan was extended and the incidence of chronic nephropathy was lower in rats fed soy protein compared with casein-based diets (9,10). We used rat and mouse models of polycystic kidney disease to examine the effect of soy protein compared with casein on genetically determined chronic renal disease. In the Han:SPRD-cy rat model, 6–8 wk of soy protein feeding reduced renal fibrosis, cyst growth, and inflammation and attenuated the elevated levels of serum creatinine (11–13). In pcy mice, characterized by progressive renal fibrosis and cyst growth, soy protein feeding for 3–4 mo also slowed disease progression (14,15). In 1 of these studies, the histologic benefit was associated with changes in fatty acid composition (12). We also observed that prostaglandin E₂ (PGE₂) production is altered in this model of renal disease (unpublished observations).

These studies demonstrated that dietary soy protein compared with casein reduces renal disease severity and alters fatty acid composition after longer-term feeding when initiated early in the disease, but they do not address early effects. The purpose of this short-term study, therefore, was to determine whether as little as 1–3 wk of feeding in weanling Han:SPRD-cy rats would alter renal disease progression, fatty acid composition, and PGE₂ production. The stage of disease in these rats is analogous to the 5.9 million individuals in the United States with stage 1 CKD, as defined by the National Kidney Foundation CKD criteria. In this stage, there is evidence of kidney damage but the glomerular filtration rate (GFR) is normal or higher (1).

	METHODS AND MATERIALS

TOP ABSTRACT METHODS AND MATERIALS RESULTS DISCUSSION LITERATURE CITED

 
Han:SPRD-cy rats were obtained from our own breeding colony, which originated from the colony of Dr. Benjamin Cowley (University of Kansas Medical Center, Kansas City, KS). Surviving weanling male offspring (n = 87) of known heterozygous Han:SPRD-cy rats were randomly divided into 2 groups and given a 20 g/100 g soy protein diet or a 20 g/100 g casein protein diet for 1 or 3 wk. The 2 diets were identical in composition with the exception of the protein source⁵ as previously described for our 8-wk study (12). This diet is based on the AIN-76A diet (16); the only difference is the source of carbohydrate, which was 52 g cornstarch and 13 g dextrose/100 g diet. The experimental protocol was approved by the University of Manitoba Animal Care Committee.

One day before killing, rats were placed in metabolic cages for a period of 6 h to obtain urine samples beginning at 0700 h. During this time, food and water were withheld to prevent sample contamination. Mineral oil was used in the urine collection to prevent evaporation. Once samples were collected, the oil was removed and samples were weighed and frozen at –20°C. All rats were killed by exsanguination under sodium pentobarbital anesthesia (65 mg/kg, i.p.), blood samples were drawn via heart puncture, and both kidneys were excised and weighed. The right kidney was sectioned into thirds and the center section was placed in formalin for histopathology. The lower pole was incubated immediately for PGE₂ analysis (see below). The remaining portion of the right kidney and the left kidney were immediately frozen in liquid nitrogen and stored at –80°C.

Quantitative histologic analysis of the right kidney was performed using our previously described methods, using hematoxylin and eosin staining of kidney sections for cyst area and aniline blue for fibrosis (11,12). Diagnosis of diseased and normal rats was made postmortem under 200X magnification of sections by an experienced observer (N.B.C.) who was unaware of the dietary intervention. Rats were classified as diseased if examination of a single longitudinal cross section of renal tissue contained >10 areas of tubular dilation and an increase in extracellular matrix. Images captured by a Spot Junior CCD camera by random stage movement through the sections were subsequently analyzed using Image Pro version 4.5 Package (Media Cybernetics), to determine the ratios of cyst and fibrous area to normal tissue, as previously described (11,12). Measurements of fibrosis were corrected to solid tissue areas of sections so that the presence of empty cystic areas on the section did not lead to an underestimation of these variables.

Serum and urine creatinine were measured using a commercial kit (#555-A, Sigma-Aldrich), and results were used to calculate creatinine clearance. Lipids from a portion of the right kidney were solvent extracted and analyzed for fatty acid composition by GC as described (12,17,18). The lower pole of the right kidney was incubated in HBSS to measure ex vivo PGE₂ production by ELISA using a commercial kit (#DEO100, R&D Systems) as previously described (17).

Results were analyzed by 2-way [diet, duration of feeding (time)] ANOVA using JMP statistical software (SAS) to determine diet and time effects. To determine genotype effects in PGE₂ production, data from each feeding time were analyzed by 2-way (diet, genotype) ANOVA. Differences in main effects or interactions were considered significant if P < 0.05. Contrasts were used to determine simple effect differences.

	RESULTS

TOP ABSTRACT METHODS AND MATERIALS RESULTS DISCUSSION LITERATURE CITED

 
Compared with casein, dietary soy protein resulted in 30% less renal fibrosis overall (P = 0.0011) (Table 1). Further comparisons of the diet effects at each time point using simple contrasts revealed that renal fibrosis was reduced by 22% (P = 0.0318) after the diet was fed for 1 wk and by 38% (P = 0.0102) after 3 wk. Soy protein also resulted in less cyst growth, but the diet effect was significant only after 3 wk of consuming the diets (34% lower cyst volume in soy-fed rats, P < 0.0001). Normal and diseased rats that consumed the 2 diets thrived, and their significant increases in body weight with time did not differ due to diet. The effect of growth and of the soy protein diet on histology was reflected in the kidney sizes. The lower kidney weights relative to body weights observed in the normal rats at 3 wk of feeding were maintained only in diseased rats fed the soy diet. The opposite trend was observed in casein-fed rats with kidney disease in which the relative kidney size was 12% higher (P = 0.0189) in rats fed casein for 3 compared with 1 wk postweaning. In normal rats, creatinine clearance increased with time (P = 0.0018); this trend was maintained in the diseased rats fed soy diets (P = 0.0004), but in the casein-fed rats, creatinine clearance was not different in the 3 compared with 1 wk postweaning group.

Ex vivo production of PGE₂ from diseased compared with normal kidneys was 26% (P = 0.0021) lower in rats after 1 wk of feeding. This genotype effect was maintained after 3 wk of feeding in casein- (36% lower, P = 0.0057) but not soy-fed rats. Dietary soy protein compared with casein increased PGE₂ levels in diseased kidneys overall by 32% (P = 0.0017), and at both 1 (by 31%, P = 0.0281) and 3 wk (by 32%, P = 0.0189) of feeding (Table 1).

	DISCUSSION

TOP ABSTRACT METHODS AND MATERIALS RESULTS DISCUSSION LITERATURE CITED

 
This study demonstrates that dietary intervention using soy protein compared with casein alters disease progression as early as 1 wk after it was fed to postweaning Han:SPRD-cy rats with early renal disease. Soy-fed rats had less renal fibrosis after as little as 1 wk of feeding, whereas the effect on cyst growth was not observed until after 3 wk of feeding soy protein. Slowing of disease progression by substituting dietary soy protein for casein also was evidenced by lower kidney weight relative to body weights and by higher creatinine clearance rates.

These results of early soy effects are consistent with longer-term dietary interventions in this model (11–13), as well as other models of renal disease (4–10,14,15). In 1 of our previous studies with Han:SPRD-cy rats, the histologic benefit of soy protein feeding was associated with changes in the fatty acid composition of the kidney after 8 wk of feeding (12). In that study, the concentrations of renal 18:1(n-7) were lower and the concentrations of 18:2(n-6) were higher, whereas the concentrations of the remaining major fatty acids were unchanged. In conjunction with the current study, the changes in renal 18:1(n-7) and 18:2(n-6) concentrations associated with soy protein feeding are the fatty acid changes that appear to remain consistent over the longer feeding period, whereas other changes appear to be transitory.

The elevated levels of 18:2(n-6) in soy-fed rats may be a reflection of increased fatty acid metabolism to 20:4(n-6) and its availability for subsequent conversion to eicosanoids. PGE₂ is the major prostaglandin produced in the kidney, and its reduced production by diseased kidneys was partially ameliorated by soy protein feeding, particularly in the rats fed soy protein for 3 wk. The kidney is a relatively rich source of eicosanoids, which regulate renal processes such as hemodynamics, water and solute transport, and renin secretion (19–21). In diseased kidneys, eicosanoids appear to play a role in maintaining GFR, as well as being involved in inflammatory processes in response to renal injury (19,21). Soy protein feeding may be beneficial in the early stages of renal disease in Han:SPRD-cy rats by enhancing PGE₂ production and maintaining renal function because there is little renal inflammation early in the disease.

Although eicosanoids appear to have a protective effect in this study and in some other forms of renal disease, a reduction in eicosanoid formation is associated with amelioration of the disease process in renal diseases with an inflammatory component [for reviews see (21–23)]. In a recent study in 11-wk-old Han:SPRD-cy rats, dietary conjugated linoleic acid reduced PGE₂ levels, renal inflammation, and the progression of disease (17). In Han:SPRD-cy rats, alterations in eicosanoid synthesizing enzymes are observed at 10 wk, but not in 4-wk-old rats (24), suggesting that inflammatory eicosanoids play a greater role in the later stages of the disease. Other dietary interventions in 10- to 12-wk-old Han:SPRD-cy rats using diets containing (n-3) compared with (n-6) fatty acids, which would be expected to reduce the production of inflammatory eicosanoids, also were associated with slower disease progression (18,25). In addition, in the pcy mouse model of polycystic kidney disease in which inflammation is much less a part of the pathology, dietary fish oil is not as beneficial and may be detrimental in the long term (26–28). It also should be noted that an increase in 18:2(n-6) does not necessarily increase eicosanoid synthesis and could reflect impaired elongation/desaturation activity. Indeed, 18:2(n-6) was elevated after 6–8 wk of soy protein feeding but reduced disease progression (11–13). It is important to elucidate the effect of soy protein on eicosanoid production in this stage of disease in which inflammation is a significant factor.

The specific ingredient(s) in soy protein compared with casein that is responsible for these dietary effects is not understood. Much attention has been focused on the biological effects of soy isoflavones, but genistein does not appear to be the active ingredient here (14). A recent study demonstrated that soyasaponins derived from soy protein significantly delay cyst growth in this model of renal disease (29). Soyasaponins were reported to be present at levels of 3.4–7.6 mg/g in soy protein isolates (29,30). Studies utilizing soyasaponin extracts in Han:SPRD-cy rats are required to determine whether this ingredient also is effective in this model of renal disease and whether the effects are manifested as early as with soy protein isolate. Studies with purified amino acid diets also are warranted to address how differences in the amino acid composition influence the dietary effect on kidney disease progression. This may be useful in determining whether the different protein effect is due to a beneficial effect of soy protein or a detrimental effect of casein.

Many individuals choose to follow vegetarian eating patterns or use specialty products to maintain a reduced level of dietary protein. The beneficial effects of dietary soy protein were shown in normal and diseased kidneys in humans (31,32), as well as in animal studies (4–15,33). Given the high numbers of individuals with CKD and the risk factors associated with this, any dietary treatment that slows renal disease progression will have beneficial health effects. This study demonstrates that protein effects on renal disease occur after as little as 1 wk of dietary intervention and in the very early stages of renal disease. An estimated 5.9 million individuals in the United States have stage 1 CKD (1). In addition to determining whether the benefits observed in this rat model occur in humans, it also will be important to examine the effects of other protein sources in early renal disease.

	FOOTNOTES

 
¹ Presented in part in abstract form at the 5th International Symposium on the Role of Soy in Preventing and Treating Chronic Disease, September 2003,Orlando, FL [Fair, D. E., Nitschmann, E., Bankovic-Calic, N., Ogborn, M. R., Weiler, H. A. & Aukema, H. M. (2003) Attenuation of early renal injury in rats with chronic renal disease is observed after only 1 wk of soy protein feeding].

² Supported by the Natural Sciences and Engineering Research Council of Canada, the Children’s Hospital Foundation of Manitoba, and a fellowship from the Kidney Foundation of Canada to D.E.F. H.A.W. holds a CIHR New Investigator Award.

⁴ Abbreviations used: CKD, chronic kidney disease; GFR, glomerular filtration rate; PGE₂, prostaglandin E₂.

⁵ The amino acid composition (g/100 g) for the casein and soy protein isolates (Harland Teklad) were as follows: alanine (3.0, 4.1); arginine (3.7, 7.5); aspartic acid (6.9, 11.9); cyst(e)ine (0.4, 1.3); glutamic acid (20.9, 21.5); glycine (1.8, 4.2); histidine (2.9, 2.6); isoleucine (4.6, 4.9); leucine (9.1, 8.1); lysine (7.7, 6.3); methionine (2.9, 1.3); phenylalanine (5.1, 5.4); proline (10.4, 5.5); serine (5.8, 5.2); threonine (4.3, 3.7); tryptophan (1.2, 1.5); tyrosine (5.5, 4.0); and valine (5.7, 4.5), respectively (all L-isomers). The isoflavone content of the soy protein isolate was 1.5–3 mg/g.

Manuscript received 7 January 2004. Initial review completed 15 February 2004. Revision accepted 9 March 2004.

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TOP ABSTRACT METHODS AND MATERIALS RESULTS DISCUSSION LITERATURE CITED

 

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This Article Abstract Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Fair, D. E. Articles by Aukema, H. M. Search for Related Content PubMed PubMed Citation Articles by Fair, D. E. Articles by Aukema, H. M.