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Division of Nutritional Sciences, University of Illinois at Urbana-Champaign, Urbana, IL 61801
3To whom correspondence and reprint requests should be addressed. E-mail: jwerdman{at}uiuc.edu.
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ABSTRACT |
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 TOP ABSTRACT MATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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KEY WORDS: • soy protein • low protein diet • diabetic mice • urinary albumin excretion
More than six decades ago, Chanutin et al. (1 ) and Farr et al. (2 ) showed that in rats with induced chronic renal failure (CRF),4 a high protein diet led to increases in proteinuria, renal histological damage and mortality, whereas dietary protein restriction protected the kidney from further damage. Since then, protein restriction has been advocated by some as a preventive measure for kidney disease (3 ), but refuted by others (4 ). The lack of a consensus may be due to the fact that dietary protein restriction does not have as strong an effect on kidney disease prevention as other therapeutic measures, such as tight blood pressure control. Nevertheless, a beneficial effect is consistently seen with protein restriction if the patients are shown to follow the prescribed diets (3 ,5 –8 ). This effect seems to be even stronger in patients with diabetic nephropathy (7 ,8 ). However, the disadvantage of protein restriction is that low protein diets are typically associated with poor compliance and the risk of malnutrition (3 ). Although most studies did not show a significant deleterious effect on nutritional status (3 ), close nutritional and compliance monitoring is essential for a successful outcome. This is particularly important for diabetic patients, who may require other dietary modifications as well (9 ).
Over the past two decades, the possibility of maintaining the quantity of protein intake while changing its type has been investigated. In particular, the work of Williams and Walls in the late 1980s (10 –12 ) sparked considerable interest in studying the effects of soy protein. The authors showed that in the remnant kidney rat model, soy protein diets at 12 or 24% led to higher survival, lower urinary protein excretion, less renal hypertrophy and less histological damage than casein diets with equivalent quantities of protein. Although considerable attention has focused on the effects of soy protein in the remnant kidney rat model and in animal models of polycystic kidney disease (PKD) (13 ), studies in animal models of diabetic nephropathy are presently lacking. Thus, the objective of this study was to investigate the effects of protein type and quantity on diabetic nephropathy in male BKS.cg-m +Leprdb/+Leprdb diabetic mice, which are commonly used as a model of type 2 diabetes mellitus (14 ) and diabetic nephropathy (15 –20 ). We hypothesized that soy protein consumption, compared with casein, would result in lower urinary albumin excretion throughout the study, which would suggest protection from diabetic nephropathy. We expected the effect of protein type to be more pronounced at the higher protein intake.
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MATERIALS AND METHODS |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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Male BKS.cg-m mice (n = 48; formerly designated as C57BLKS/j-m +/+ Leprdb), comprising 24 diabetic (+Leprdb/+Leprdb) and 24 control (m+/m+), were obtained from Jackson Laboratory (Bar Harbor, ME) at 
4 wk of age (27 ± 3 d). On arrival, each diabetic mouse (DB) was matched to a control mouse (CON) on the basis of body weight. Mice were housed individually in sterile conditions in a humidity- and temperature-controlled (21–22°F) facility with a 12-h light:dark cycle for the duration of the study. Principles of laboratory animal care were followed and the study was approved by the University of Illinois Laboratory Animal Care Advisory Committee.
Experimental design.
Mice were fed an AIN-93G (21
) pelleted diet for acclimation from the arrival day (time point designated as dA) until age 35 ± 4 d. During this period, mice were maintained in metabolic cages to collect urine for glucose measurement. At age 35 ± 4 d (designated as d 0), mice were randomly assigned to one of four dietary treatments, casein or soy protein at 20 or 12% energy, and followed for 180 d or until terminal stage, whichever occurred first (185–215 ± 4 d of age). The duration of the study was decided on the basis of the average lifespan of the DB mice (8 mo). The final time point was designated as the final day (dF) and was determined for each DB mouse if two of the following three findings were observed: body weight (BW) loss of >30%, persistent urinary ketone bodies or straightened hind-limb pose indicative of neuropathy. Each DB mouse and its paired control were killed at the same time. During the intervention period, the mice were maintained in plastic shoebox cages and placed in metabolic cages every 30 d (d 30, 60, 90, 120, 150 and dF of intervention) for 24-h urine collections. At d 0, 30, 60, 120 and dF of intervention, 50 µL of blood was collected from the saphenous vein for blood glucose measurements. BW was measured twice a week up to age 166 ± 4 d and daily thereafter.
Diets.
During the dietary intervention period, mice were fed one of four semipurified, pelleted and isoenergetic diets (Table 1 ). The diets were modifications of the AIN-93G (21 ) containing different types and amounts of protein. They were designated as 20C (20% casein), 20S (20% soy protein), 12C (12% casein) and 12S (12% soy protein). The percentages were energy based. Fat content was the same in all diets. The amounts of disaccharides (sucrose) and tetrasaccharides (dextrinized cornstarch) were approximately the same in all diets; only the amount of complex carbohydrates (cornstarch) varied. DL-Methionine and L-cysteine were added to all diets. The AIN-93G vitamin mix was used and the AIN-93G mineral mix was adjusted to provide similar mineral content in all diets. Food and water were consumed ad libitum. Food intake (FI) was measured twice a week throughout the study, by placing a known amount of food in the cages and measuring the remaining amount after 3 or 4 d.
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Isolated soy protein (ISP) was used as the source of soy protein (Clinical 670 Blend, Protein Technologies International, St. Louis, MO) and was obtained as a gift from Protein Technologies International. The total aglycone amount (genistein, daidzein and glycitein) in the ISP was 2.55 mg/g protein. Diets were formulated (Table 1) and prepared by Dyets (Bethlehem, PA) and stored at -20°C throughout the study to limit nutrient loss.
Diet analysis.
Treatment diets were analyzed in duplicate for dry and organic matter (22
), crude protein and amino acids. Crude protein was determined using the Kjeldahl procedure (22
,23
). Amino acid composition was determined by ion-exchange chromatography, and sample preparation was performed according to Spitz (24
). Total and bioavailable phosphorus was calculated for the four diets. The ISP was supplemented with 300 mg bioavailable phosphorus (calcium phosphate)/100 g ISP, making 50% of the total phosphorus bioavailable. All of the phosphorus in casein was bioavailable.
Blood analyses.
At d 0, 30, 60, 120 and dF of intervention, 50 µL of blood was collected from the saphenous vein, and blood glucose was measured in duplicate using a glucose meter (ONE TOUCH Basic, LifeScan, Milpitas, CA). All blood collections were performed in the afternoon from fed rats, except for dF, which was performed in the afternoon after a 7-h period of food deprivation. Blood glucose concentrations were converted to plasma glucose (PGLUC) concentrations according to Weitagasser et al. (25 ). Because the ONE TOUCH Basic glucose meter measured concentrations only up to 33.3 mmol/L, any blood with glucose concentrations above the maximum was diluted 1:2 with saline and reanalyzed in duplicate. The dilution method was verified in a preliminary study and the dilution was found not to have any considerable effect on the glucose measurements (CV <5%).
At the final time point (dF), mice were food deprived for 7 h, weighed and anesthetized by intraperitoneal injection of pentobarbital (40–90 mg/kg body) followed by cardiac puncture for blood collection. Blood was collected into evacuated tubes without preservatives, allowed to clot for 60 min and centrifuged at 550 x g for 20 min at 4°C to obtain serum. Aliquots of serum samples were placed into storage tubes and stored at -70°C until analysis. Concentrations of serum urea (SU), total cholesterol (TC) and albumin (SALB) were analyzed enzymatically in a Hitachi 911 system (Hitachi, Indianapolis, IN) at the Pathology Laboratory, Department of Veterinary Medicine, University of Illinois at Urbana-Champaign. Interassay CV were <5% for SU, <5% for TC and <3.5% for SALB.
Urine analyses.
Urine collections (24-h) were performed daily from dA to d 0 and at d 30, 60, 90, 120, 150 and dF of intervention. Urine was collected in polypropylene vials containing 2 mL of mineral oil to reduce evaporation. Samples were refrigerated promptly after collection. Urine was centrifuged at 413 x g for 5 min at 4°C to remove the mineral oil or any solid debris, and stored at -70°C until analysis. Urine from dA to d 0 was used to measure urinary glucose concentrations. Urine collected at d 0, 30, 60, 90, 120, 150 and dF was analyzed for creatinine (UCREAT) and albumin (UALB) concentrations, and the presence of ketone bodies. UCREAT was analyzed enzymatically in a Hitachi 911 system as described above. The interassay CV was <1.6%. UALB concentration was determined using an ELISA (Albuwell M, Exocell, Philadelphia, PA), with a detection limit of 0.04 mg/L (calculated as 2 SD above blank) (15
). The interassay CV was <7%. Urinary albumin excretion (UAE, in mg albumin/mg creatinine) was determined as the ratio between UALB and UCREAT. The change in UAE from d 0 (
UAE) was also calculated for each time point. The presence of urinary ketone bodies was detected with urine test strips (Chemstrip uGK, Roche Diagnostics, Indianapolis IN).
Tissues analyses.
After cardiac puncture, the mice were killed by cervical dislocation, and kidney tissue was rapidly excised and weighed.
Statistical analysis.
Data are presented as means ± SEM. For outcomes measured at multiple time points of the study (BW, FI, PGLUC, and UAE), they were first analyzed by repeated-measures ANOVA (split-plot approach) with time as a within-subject factor. Between-subject factors included protein type (casein or soy) and quantity (20 or 12%) as main factors and diabetes (DB or CON) as a covariate. Subjects were effects-coded. For UAE, the UAE concentrations at d 0 (referred to as baseline hereafter) were used as an additional covariate. If significant interactions between time and the main factors were detected, a separate analysis was performed for each time point. Otherwise, only dA (for BW) and d 0 were analyzed. At each time point, multiple linear regression for multifactorial experiments (26
) was used to analyze the effects of the between-subject factors above, which were protein type, protein quantity, diabetes and baseline UAE (for UAE only). Effects coding was used to code for the main factors and the covariate diabetes (26
). The covariate "baseline UAE concentrations" was coded as the difference between baseline UAE for each mouse and the mean baseline for all mice (26
). Two- and three-way interactions among the main factors and the covariates were analyzed for all outcome variables. If the interactions were not significant, they were removed as a block and the statistical analysis was rerun with the reduced model. Significance for individual main factors was examined only if the multiple R2 for the model was significant (P < 0.05). All statistical analyses were conducted with an 
level of 0.05, using SAS (version 8.01; SAS Institute, Cary, NC). One-tailed P-values were used to evaluate treatment effects with directional hypotheses (UAE and kidney weight), whereas two-tailed P-values were used for nondirectional hypotheses and all interactions.
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RESULTS |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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Crude protein on a dry-matter basis was 20.3 g/100 g (21.7%), 19.0 g/100 g (20.3%), 12.2 g/100 g (13.0%) and 12.0 g/100 g (12.8%) for 20C, 20S, 12C and 12S, respectively. All diets had the same amount of total phosphorus, whereas the amount of bioavailable phosphorus was different due to the phytic acid content of soy protein (Table 2 ).
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The effect of diabetes and diet on BW varied with time (time x diabetes, P < 0.0001; time x protein type, P = 0.0215; Fig. 1
). DB mice were 40% heavier than CON mice (P < 0.0001) upon arrival (dA). Most DB mice continued to be heavier than CON mice at later time points, but the difference in BW became smaller toward the end of the study, due to considerable weight loss of the DB mice.
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Food intake.
DB mice ate more than CON mice throughout the study (P < 0.0001), and there was no effect of protein type or quantity (data not shown). In DB mice, FI increased from d 0 to 30 (5.9 ± 0.1 to 7.7 ± 0.2 g/d) and stabilized until d 150 (8.3 ± 0.6 g/d). In CON mice, FI was approximately the same throughout the study (2.6 to 2.8 ± 0.2 g/d).
Blood.
All DB mice were diabetic upon arrival, as indicated by urine glucose concentrations (659–1458 mmol/L; data not shown). At d 0, PGLUC concentrations in fed mice were 97% higher in DB than in CON mice (P < 0.0001), and they continued so throughout the study (P < 0.0001). There was no effect of protein type or quantity on PGLUC concentrations in either DB or CON mice that had been fed or deprived of food for 7 h (Fig. 2
).
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49% higher in DB than in CON mice (P = 0.0312). In addition, SU concentrations were higher in the 20C groups (protein quantity, P = 0.0036; protein type, P = 0.0214). TC concentrations (data not shown) were 88% higher in DB than in CON mice (P = 0.0085). No effect of protein type or quantity was found. For SALB concentrations, no effects of diabetes, protein type or quantity were found (data not shown).
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DB mice had 255% higher UAE than CON mice at d 0 (P < 0.0001) (Table 3
). Overall, DB mice also had larger UAE than CON mice (P < 0.0001), but the differences were dependent on dietary treatment (diabetes x protein type P = 0.0200; diabetes x protein quantity, P < 0.0001). The effects of diet on UAE (Fig. 4
) varied with time and were different between DB and CON mice (time x protein quantity, P = 0.0060; time x diabetes x protein quantity, P = 0.0150).
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UAE = -0.14 ± 0.04 at d 30) and was maintained approximately constant thereafter. No effects of diet were seen in CON mice. In DB mice, UAE varied over time and was dependent on diet. Protein quantity began to have an effect at d 30 (P = 0.0155), which became stronger at d 60 (P < 0.0001). It was maintained thereafter, but was reduced somewhat at d 150 (P = 0.0025). Protein type had a detectable effect at d 90 (P = 0.0065), but no effect by d 150. This effect of protein type was attributed mainly to the effect seen at high protein intake. The smaller effect of diet toward the end of the study was caused by a reduction of UAE for the 20C group, whereas the other DB mice maintained approximately the same UAE as in the previous months. Comparing the final time point (dF) to the initial one (d 0), UAE in DB mice was 100% higher for the 20C group, approximately the same for the 20S group, 33% lower for 12C group, and 67% lower for the 12S group (UAE = +0.7 ± 0.38, +0.01 ± 0.38, -0.33 ± 0.23 and -0.47 ± 0.19, respectively). Kidneys.
Kidney weights (Fig. 5
) were 46% higher in DB than in CON mice (P < 0.0001). Protein quantity had a significant effect (P < 0.0013), which was dependent on diabetes (diabetes x protein quantity; P < 0.0358). In DB mice, kidney weights were 19% lower in the 12% protein groups (12C and 12S), but no differences were seen among the CON mice.
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DISCUSSION |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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In the control mice, UAE decreased slightly by 2 mo of age, and leveled off thereafter, independently of dietary treatment. In contrast, UAE of the diabetic mice was already elevated at 35 ± 4 d of age. When a high animal protein diet (20% casein) was fed, UAE of the diabetic mice increased with time to macroalbuminuric concentrations, reaching a maximum at 5 mo of age, and then slightly decreased subsequently. Similar results were reported by Brouhard et al. (28
), who found a maximum UAE at 4.25 mo of age and a decline at 5 mo in diabetic mice fed 27 or 50% protein diets. The later decline in UAE may be related to a reduction in the glomerular filtration rate (GFR) to a level below that of the control mice; this has been shown to occur in male BKS.cg-m +Leprdb/+Leprdb diabetic mice at 5 mo of age as well (29
). In these diabetic mice, lower protein intake (12% protein) led to a decrease in UAE, which indicated an improved macromolecular permselectivity, suggesting a slower progression or even protection from diabetic nephropathy. This UAE reduction with the lower protein diets was seen after 30 d and was maintained for the next 5 mo until the end of the study. This finding agrees with the extensive literature, which shows that low protein diets protect against nephropathy in animal models and in humans [see Maroni and Mitch (3
) for a recent review].
At a high protein intake (20%), our results showed that the increase in UAE that occurred when casein was fed was absent when soy protein was consumed. The diabetic mice consuming the high soy protein diet even had a reduction in UAE after 30 d of intervention, which agreed with the UAE reduction seen when the lower protein diets (with either soy or casein) were consumed. However, when the high soy diet was fed, UAE levels returned to baseline values after 60 d of the dietary intervention and stayed at that microalbuminuric level thereafter, showing only minor fluctuations. This maintenance of UAE at microalbuminuric level suggests that a high soy protein diet may maintain macromolecular permselectivity and slow the progression of diabetic nephropathy. Moreover, we found that the effects of protein type and quantity were independent of glycemic control because no differences were seen in plasma glucose concentrations among the different diabetic groups that had been fed or deprived of food. In summary, our results suggest that soy protein diets may confer some protection against diabetic nephropathy in male BKS.cg-m +Leprdb/+Leprdb diabetic mice.
Other studies in the literature have shown that soy protein has a beneficial effect on nondiabetic nephropathy. In the late 1980s, Williams and Walls showed that in rats subjected to unilateral nephrectomy and partial infarction of the contralateral kidney, replacing casein with soy protein for 3 mo resulted in less proteinuria, less renal hypertrophy, less histological damage and increased survival (10 ). Soy protein was also shown to markedly reduce the progression of nephropathy in the aging rat model Fisher 344, which has a high incidence of old-age nephropathy (30 ). More recently, several studies on animal models of PKD have shown that soy protein is effective in retarding cyst development (31 ), reducing tubular and interstitial pathology (32 ) and ameliorating epithelial and interstitial changes (33 ). The beneficial effect of soy protein on cyst score and kidney weight in the pcy PKD mouse model was shown to be dependent on protein quantity and mouse gender, with the strongest effects seen in females consuming low soy protein diets (6 g/100 g) (34 ). This dependence on protein quantity was noted in the present study, with a stronger effect seen in diabetic mice consuming the low soy protein diet than in those consuming the high soy protein diet. More recently, Maddox and collaborators found that soy protein consumption also prevented an increase in UAE in Zucker rats (35 ).
Several interesting observations from the present study deserve further investigation. First, we found that mice consuming the high soy protein diets or the lower protein diets had lower SU concentrations than those consuming the high casein diet. This difference was likely to be associated with the protein composition of the diet because it was seen in both diabetic and control mice. The lower SU concentrations may be important. As proposed by Bankir et al. (36
), lower SU concentration could affect kidney hemodynamics and reduce hyperfiltration in the diabetic kidney. The second observation concerns the amount of bioavailable phosphorus. All diets in the present study had the same total amount of phosphorus. However, there was less bioavailable phosphorus in the soy protein because the majority of phosphorus in soy (70%) is found in the form of phytic acid (37
). It is thought that low phosphorus intake (independent of protein quantity) slows the progression of renal failure (38
). Thus, the lower amount of bioavailable phosphorus in soy may contribute to the observed effects of the soy protein diet. Third, we found that diabetic mice consuming 12% soy protein had a lower growth rate and a faster weight loss than diabetic mice consuming other diets. However, no such differences were seen among the control mice. This may suggest a differential requirement for certain nutrients between diabetic and control mice. Further research is required to investigate these issues.
In conclusion, the data from this study show that diets rich in soy protein prevent an increase in UAE, which is typically seen in male BKS.cg-m +Leprdb/+Leprdb diabetic mice. This indicates an improvement in glomerular macromolecular permeability and suggests slower development of diabetic nephropathy. The present results offer a promising outlook. The replacement of casein with soy protein, especially at higher protein intake, may offer a new treatment option for the prevention of diabetic nephropathy. We found that at a low protein intake, this replacement did not lead to any significant benefit beyond the effect of protein reduction. However, protein reduction is often not a practical solution due to poor compliance and the risk of malnutrition. Thus, the use of soy protein at higher intake levels may offer a more viable alternative. The present findings are of current interest because type 2 diabetes mellitus is rapidly reaching epidemic proportions in the United States and many other Westernized countries, and end-stage renal disease in type 2 diabetes is increasing progressively worldwide (39 ). The present study provides some encouraging results that may stimulate further investigation to identify the mechanisms by which soy protein may promote renal protection, and to establish quantitatively the optimal combination of animal and soy protein in human subjects.
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FOOTNOTES |
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2 Funded by the Illinois Council on Food and Agriculture Research. S.R.T. was supported by the Fulbright Program, fellowship 15965032 and the Fundação para a Ciência e a Tecnologia (FCT), Portugal.
4 Abbreviations used: 12C, 12% casein; 12S, 12% soy protein; 20C, 20% casein; 20S, 20% soy protein; BW, body weight; CON, control mice; CRF, chronic renal failure; dA, arrival day; DB, diabetic mice; dF, final day; FI, food intake; GFR, glomerular filtration rate; ISP, isolated soy protein; PGLUC, plasma glucose; PKD, polycystic kidney disease; SALB, serum albumin; SU, serum urea; TC, serum total cholesterol; UAE, urinary albumin excretion; UALB, urinary albumin; UCREAT, urinary creatinine; UAE, change in urinary albumin excretion.
Manuscript received 2 July 2002. Initial review completed 24 July 2002. Revision accepted 4 December 2002.
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LITERATURE CITED |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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