Increased protein level of PEPT1 intestinal H+-peptide cotransporter upregulates absorption of glycylsarcosine and ceftibuten in 5/6 nephrectomized rats

In chronic renal failure (CRF), dietary protein is one of the factors that deteriorates residual renal functions. Numerous studies have indicated that the products of protein digestion are mainly absorbed as small peptides. However, how small peptides are absorbed in CRF remains poorly understood. H+-coupled peptide transporter (PEPT1/ SLC15A1) plays an important role in the absorption of small peptides and peptide-like drugs in the small intestine. Because dietary protein intake is one of the risk factors for renal failure, the alteration of intestinal PEPT1 might have implications in the progression of renal disease as well as the pharmacokinetics of peptide-like drugs. In this study, we examined the alteration of intestinal PEPT1 in 5/6 nephrectomized (5/6 NR) rats, extensively used as a model of chronic renal failure. Absorption of [14C]glycylsarcosine and ceftibuten was significantly increased in 5/6 NR rats compared with sham-operated rats, without a change in intestinal protease activity. Western blot analysis indicated that the amount of intestinal PEPT1 protein in 5/6 NR rats was increased mainly at the upper region. On the other hand, the amount of intestinal PEPT1 mRNA was not significantly different from that of sham-operated rats. These findings indicate that the increase in absorption of small peptides and peptide-like drugs, caused by the upregulation of intestinal PEPT1 protein, might contribute to the progression of renal failure as well as the alteration of drug pharmacokinetics.

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Effects of dietary protein on renal function and lipid metabolism in five-sixths nephrectomized rats

British Journal Of Nutrition ◽

10.1079/bjn2002808 ◽

2003 ◽

Vol 89 (4) ◽

pp. 491-497 ◽

Cited By ~ 14

Author(s):

Shu-Tzu Chen ◽

Sheng-Jeng Peng ◽

Jiun-Rong Chen

Keyword(s):

Renal Failure ◽

Renal Function ◽

Lipid Metabolism ◽

Chronic Renal Failure ◽

Renal Disease ◽

Dietary Protein ◽

Casein Diet ◽

Experimental Animals ◽

Rate Of Progression ◽

Progression Of Renal Failure

The objective of the present experiment was to examine the effect of substituting different quantities of soyabean protein for casein on renal function and lipid metabolism in rats with chronic renal failure induced by a five-sixths nephrectomy. Experimental animals were subjected to a nephrectomy and fed either casein or soyabean protein (200 or 100 g/kg diet). The diets were isoenergetic with identical fat, Na, K and P contents. Rats ingesting 200 g casein/kg diet showed a significantly (P<0·05) accelerated course of chronic renal failure, while the soyabean-protein groups showed retarded progression of the experimentally induced renal disease and hypercholesterolaemic effects. Rats in the low-soyabean-protein diet (100 g/kg) also demonstrated increased serum albumin and decreased serum triacylglycerol, total cholesterol concentrations and blood urea-N; however, the low-casein diet significantly (P<0·05) increased serum triacylglycerol. Results of the present study show that the replacement of casein by soyabean protein was related to the rate of progression of renal failure and improvement in lipid profiles in serum of five-sixths nephrectomized rats.

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Upregulation of H+-peptide cotransporter PEPT2 in rat remnant kidney

AJP Renal Physiology ◽

10.1152/ajprenal.0346.2000 ◽

2001 ◽

Vol 281 (6) ◽

pp. F1109-F1116 ◽

Cited By ~ 24

Author(s):

Kazushige Takahashi ◽

Satohiro Masuda ◽

Nobuhiko Nakamura ◽

Hideyuki Saito ◽

Takahiro Futami ◽

...

Keyword(s):

Renal Failure ◽

Chronic Renal Failure ◽

Brush Border ◽

Maximum Velocity ◽

Peptide Transporter ◽

Mrna Levels ◽

Small Peptides ◽

High Affinity ◽

Renal Brush Border Membrane ◽

Remnant Kidney

First published August 21, 2001; 10.1152/ajprenal.0346.2001.—The progression of renal damage resulting from reduced nephron mass has been extensively studied in the 5/6 nephrectomized rat. However, reabsorption of small peptides andd-glucose across the renal proximal tubule in this model remains poorly understood. In this study, we examined the alterations of H+-peptide cotransporters (PEPT1 and PEPT2) and Na+-d-glucose cotransporters (SGLT1 and SGLT2) in chronic renal failure. Two weeks after surgery, H+-dependent [14C]glycylsarcosine uptake by the renal brush-border membrane vesicles isolated from 5/6 nephrectomized rats was significantly increased compared with that from sham-operated controls. Kinetic analysis revealed that the maximum velocity value for [14C]glycylsarcosine uptake by the high-affinity-type of peptide transporter was increased threefold by 5/6 nephrectomy, without significant changes in the apparent Michaelis-Menten constant value. Competitive PCR analyses indicated that the expression of PEPT2 mRNA was markedly increased in the remnant kidney, but PEPT1, SGLT1, and SGLT2 mRNA levels showed no significant changes. These findings indicated that the high-affinity-type H+-peptide cotransport activity is upregulated by 5/6 nephrectomy, accompanied by the increased expression of PEPT2. The upregulation of PEPT2 expression would result in an increase in reabsorption of small peptides and peptide-like drugs across the brush-border membranes in chronic renal failure.

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Spontaneous dietary protein intake during progression of chronic renal failure.

Journal of the American Society of Nephrology ◽

10.1681/asn.v651386 ◽

1995 ◽

Vol 6 (5) ◽

pp. 1386-1391

Author(s):

T A Ikizler ◽

J H Greene ◽

R L Wingard ◽

R A Parker ◽

R M Hakim

Keyword(s):

Renal Failure ◽

Chronic Renal Failure ◽

Dietary Protein ◽

Protein Intake ◽

Mixed Model ◽

Dietary Protein Intake ◽

Nutritional Indices ◽

Igf I ◽

Progression Of Renal Failure ◽

The Mean

Malnutrition at the initiation of dialysis is a strong predictor of subsequent increased mortality on dialysis. Few studies have documented the relationship between the progression of renal failure and spontaneous dietary protein intake (DPI) and other indices of malnutrition. In this prospective study, renal function was sequentially measured by creatinine clearance (CrCl) and DPI by 24-h urine collection; simultaneously, multiple sequential biochemical nutritional indices, including serum albumin, transferrin, prealbumin, and insulin-like growth factor-I (IGF-I) concentrations, were measured. The study involved 90 patients (46 men and 44 women) with chronic renal failure (CRF) of various causes monitored in an outpatient clinic. Dietary interventions were minimal. The mean duration of follow-up was 16.5 +/- 11.8 months. The results show that the mean (+/- SD) DPI was 1.01 +/- 0.21 g/kg per day for patients with CrCl over 50 mL/min and decreased to 0.85 +/- 0.23 g/kg per day for patients with CrCl between 25 and 50 mL/min. The DPI further decreased to a level of 0.70 +/- 0.17 g/kg per day for patients with CrCl between 10 and 25 mL/min and was 0.54 +/- 0.16 g/kg per day for patients with CrCl below 10 mL/min. This trend was statistically significant (P < 0.001). A similar statistically significant trend was observed for serum cholesterol, transferrin, and total creatinine excretion (all P < 0.01). A mixed model analysis indicated that for each 10 mL/min decrease in CrCl, DPI decreased by 0.064 +/- 0.007 g/kg per day, transferrin decreased by 16.7 +/- 4.1 mg/dL, weight decreased by 0.38 +/- 0.13% of initial weight, and IGF-I decreased by 6.2 +/- 1.9 ng/mL. It was concluded that the progression of renal failure is associated with a spontaneous decrease in DPI, especially below a CrCl of 25 mL/min, and that most nutritional indices in CRF patients worsen as CrCl and DPI decrease. Dietary protein restriction should be used cautiously in CRF patients when CrCl falls below 25 mL/min.

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Effects of Dietary Protein on the Progression of Renal Failure in the Fawn-Hooded Rat

Nephron ◽

10.1159/000185953 ◽

1990 ◽

Vol 55 (2) ◽

pp. 203-209 ◽

Cited By ~ 6

Author(s):

M.H. De Keijzer ◽

A.P. Provoost

Keyword(s):

Renal Failure ◽

Dietary Protein ◽

Progression Of Renal Failure

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Dietary Protein Loading and the Oral Adsorbent AST-120 in the Progression of Chronic Renal Failure in the Rat

The International Journal of Artificial Organs ◽

10.1177/039139889201501205 ◽

1992 ◽

Vol 15 (12) ◽

pp. 708-714 ◽

Cited By ~ 3

Author(s):

K. Kumano ◽

T. Sakai ◽

S. Kuwao ◽

M. Ise

Keyword(s):

Renal Failure ◽

Renal Function ◽

Dietary Protein ◽

Diet Group ◽

Normal Diet ◽

High Protein ◽

Renal Infarction ◽

Protein Loading ◽

Progression Of Renal Failure ◽

Oral Adsorbent

Excess protein intake enhances the progression of renal failure. The oral carbonaceous adsorbent, AST-120, was found experimentally and clinically to retard the progression of renal failure. This study was designed to determine whether deterioration of renal function by dietary protein loading can be prevented or mitigated by this oral adsorbent. Rats with uremia induced by partial renal infarction were fed a normal or high-protein diet for 70 days with or without AST-120, in which the inorganic phosphate content was adjusted to the same level. The survival rate deteriorated with the high dietary protein, but was improved from 30% to 100% with AST-120. Dietary protein loading reduced renal function, based on creatinine clearance. AST-120 improved renal function and renal histopathology not only in the normal diet group but in the high-protein group as well. The progression of renal failure induced by protein loading is thus shown to be prevented by oral AST-120. The mechanism for its action remains to be clarified.

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