1 Department of Pharmacy, Kyoto University Hospital, Faculty of Medicine, Kyoto University, Kyoto 606 - 8507; and 2 Department of Laboratory Medicine, School of Medicine, University of Tokushima, Tokushima 770 - 8503, Japan
![]() |
ABSTRACT |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
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 and
D-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.
5/6 nephrectomy; renal ablation; renal failure; renal tubular reabsorption; peptide-like drug; high-affinity H+-peptide cotransporter
![]() |
INTRODUCTION |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
IN THE KIDNEY, THE PROXIMAL tubule is the primary site of reabsorption of filtered small peptides and D-glucose, both of which are actively transported by specific transporters across the brush-border membranes of renal epithelial cells.
It has been suggested that there are at least two distinct oligopeptide
transporters in the renal brush-border membranes (2, 20).
Two distinct H+-peptide cotransporters, designated as
PEPT1 (low-affinity type) and PEPT2 (high-affinity type), have
been cloned and characterized (5, 21, 22). Both
transporters are expressed in the brush-border membranes of the renal
proximal tubules and recognize peptide-like drugs such as -lactam
antibiotics and angiotensin-converting enzyme (ACE) inhibitors
(11, 12, 17). Recently, we demonstrated that
-lactam
antibiotics interact predominantly with PEPT2 rather than PEPT1 at
therapeutic concentrations (27). Similarly, to the
oligopeptide transporters, two distinct types of
Na+-D-glucose cotransporters (SGLT1 and SGLT2)
have been cloned and characterized (8, 31).
D-Glucose transport across the brush-border membranes of
renal epithelial cells is mediated by SGLT1 and SGLT2 (9).
Although there have been a number of studies of the functional characteristics of these transporters, no information is available about their physiological and pharmacological significance in chronic
renal failure (CRF).
The 5/6 nephrectomized rat has been widely used to study the progression of renal damage resulting from reduction of nephron mass. There have been various reports about the mechanisms of glomerular dysfunction in remnant nephrons (7, 10). Renal ablation results in proteinuria, functional hypertrophy, and progressive kidney disease in the rat (10). Recently, Kwon et al. (14) reported that the levels of expression of aquaporin water channels (AQP1, AQP2, and AQP3) were decreased in CRF. In addition, it was indicated that there were significant decreases in total kidney levels of proximal tubule sodium transporters such as the type 3 Na+/H+ exchanger (NHE-3) in rats with CRF (15). However, mechanisms of tubular transport dysfunction, including the reabsorption of nutrients and the secretion of xenobiotics, have not been reported. Because filtered small peptides and peptide-like drugs are reabsorbed by PEPT1 and PEPT2, both transporters should be responsible for nutritional homeostasis and the effects of drug therapy. Therefore, understanding of the functional and molecular changes in both transporters in CRF would be useful for treatment of patients with progressive renal failure.
In the present study, we examined whether PEPT1 and/or PEPT2 is altered in CRF induced by 5/6 nephrectomy compared with SGLT1 and SGLT2.
![]() |
METHODS |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Animals. For ablation of renal mass, male Wistar albino rats (200-220 g) were anesthetized with pentobarbital sodium (40 mg/kg), and the kidneys were exposed under aseptic conditions via a ventral abdominal incision. The right kidney was removed, and the posterior and anterior apical segmental branches of the left renal artery were individually ligated as described (26). In sham-operated animals used as controls, the peritoneal cavity was exposed, both kidneys were gently manipulated, and the abdominal incision was closed with 4-0 silk sutures. After surgery, all animals were allowed free access to water and standard rat chow. The animal experiments were performed in accordance with the Guidelines for Animal Experiments of Kyoto University.
Renal functional and morphological studies. Samples of aortic blood and bladder urine were obtained for functional data determination. The blood urea nitrogen (BUN) was determined by the urease/indophenol method. The levels of creatinine and glucose in serum and urine were determined by the Jaffé reaction and the o-toluidine/boric acid method, respectively. For measurement, we used assay kits from Wako Pure Chemical Industries (Osaka, Japan). The concentration of urinary albumin was measured using an ELISA kit (Nephrat II, Exocell, Philadelphia, PA).
Kidneys were fixed in ethyl Carnoy's solution and stained with periodic acid-Schiff's reagent (PAS) (26). As samples for morphological studies, viable portions of remnant kidneys were obtained.Preparation of renal brush-border membrane vesicles.
The renal brush-border membranes were isolated from the renal cortex of
sham-operated and 5/6 nephrectomized rats by the Mg2+/EGTA
precipitation method as described previously (27). The brush-border membranes from remnant kidneys were prepared only from the
viable parts of these kidneys. The isolated membranes were suspended in
an experimental buffer to give a final protein concentration of 3.5 mg/ml. The experimental buffer for glycylsarcosine uptake consisted of
100 mM mannitol, 100 mM potassium gluconate, and 10 mM HEPES (pH 7.5),
and the experimental buffer for D-glucose uptake consisted
of 300 mM mannitol and 10 mM HEPES (pH 7.5). The protein content was
determined by the method of Bradford (1), using a protein
assay kit (Bio-Rad, Richmond, CA) with bovine -globulin as the standard.
Uptake studies. [14C]glycylsarcosine (1.78 GBq/mmol) was obtained from Daiichi Pure Chemicals (Ibaraki, Japan). D-[3H]glucose (566.1 GBq/mmol) was purchased from Moravek Biochemicals, (Brea, CA). [14C]glycylsarcosine and D-[3H]glucose uptake by brush-border membrane vesicles were measured by a rapid filtration technique as described (27). The uptake of glycylsarcosine and D-glucose was initiated by the addition of 180 µl of buffer containing 22.2 µM [14C]glycylsarcosine at 37°C and 20 µl of buffer containing 100 µM D-[3H]glucose at 25°C to 20 µl of membrane suspension, respectively. The incubation was stopped by diluting the reaction mixture with an ice-cold stop solution composed of either 150 mM KCl and 20 mM HEPES-Tris (pH 7.5) for glycylsarcosine or 150 mM NaCl, 20 mM HEPES-Tris (pH 7.5), and 0.1 mM phlorizin for D-glucose. The radioactivity of [14C]glycylsarcosine and D-[3H]glucose trapped in membrane vesicles was determined using ACS II (Amersham Pharmacia Biotech, Uppsala, Sweden) by liquid scintillation counting.
Western blotting. The same batch of renal brush-border membranes used for uptake studies was subsequently analyzed for expression of PEPT1 and PEPT2 proteins by immunoblotting as reported previously (27). Rabbit anti-SGLT1 antibody (a gift of Prof. Kasahara) was used according to the method of Takata et al. (28).
Competitive PCR analysis.
The PEPT1, PEPT2, SGLT1, SGLT2, and glyceraldehyde 3-phosphate
dehydrogenase (GAPDH) competitor DNAs were constructed according to the
method of Masuda et al. (19) with some modifications, using a v-erbB retrovirus cDNA fragment (Takara, Shiga,
Japan) as neutral DNA. The PCR-amplified PEPT or SGLT competitor DNA was gel purified using a QIAEX kit (Qiagen, Heidelberg, Germany) and
ligated into PCR-Script SK(+) plasmid vector (Stratagene, La Jolla, CA)
according to the manufacturer's instructions. The orientation and
nucleotide sequences of the subcloned DNAs were confirmed by the
chain-termination method, using a fluorescence 373A DNA sequencer
(Applied Biosystems, Foster, CA). Rat kidney total RNA (1 µg) was
reverse transcribed (the final volume of the reaction was 20 µl) with
random hexamers (100 ng/reaction), using Superscript II RT (GIBCO BRL,
Grand Island, NY), followed by RNase H (GIBCO BRL) digestion. After
10-fold dilution of the reaction with diethylpyrocarbonate-treated
water (final volume of 200 µl), 5-µl aliquots of the diluted
reactions were used for each subsequent 20-µl PCR. After denaturation
of the first-strand DNA at 95°C for 3 min, PCR was performed
according to the following profile: 94°C for 1 min, 65°C for 1 min
(PEPT and SGLT), or 60°C for 1 min (GAPDH), 72°C for 1 min, 35 cycles for PEPT and SGLT, or 32 cycles for GAPDH, with dilutions of
competitor DNAs ranging from 0.1 to 1 amol (1.0 × 1018 mol)/reaction. Primer sets specific for PEPT1,
PEPT2, SGLT1, SGLT2, and GAPDH were used, as shown in Table
1. The expected sizes of amplified
products derived from mRNA (competitor DNA) were as follows: PEPT1, 735 bp (607 bp); PEPT2, 543 bp (604 bp); SGLT1, 499 bp (626 bp); SGLT2, 460 bp (582 bp); and GAPDH, 594 bp (671 bp). The amplified PCR products
were separated by electrophoresis on 1.5% agarose gels and stained
with ethidium bromide. The reactive amounts of bands in each reaction
were determined densitometrically using NIH Image 1.61 (National
Institutes of Health, Bethesda, MD). Quantification was performed
according to the method of Siebert and Larrick (25). To
verify the quality of total cellular RNA extracted, competitive PCR for
GAPDH was performed with the same batch of single-strand DNA to detect
renal PEPT1, PEPT2, SGLT1, and SGLT2 mRNA, and the densitometry data
were normalized for each batch of RNA by determining the amount of
GAPDH as an internal control.
|
![]() |
RESULTS |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Renal functional and morphological studies.
The functional parameters in each group of rats are summarized in Table
2. Two weeks after renal ablation, the
body weight of the nephrectomized rats was lower than that of
sham-operated controls. Serum creatinine and BUN levels were
significantly higher in 5/6 nephrectomized rats compared with those in
sham-operated controls. Urinary creatinine concentration was reduced,
and the urinary albumin-to-creatinine ratio was markedly increased in 5/6 nephrectomized rats. Figure 1 shows
paraffin-embedded sections with PAS staining. Light microscopy revealed
that the tubular diameter was slightly increased in nephrectomized rats
at 2 wk. Simultaneously, glomeruli from nephrectomized rats displayed a wide range of morphological abnormalities. However, sham-operated rats
demonstrated none of these morphological abnormalities.
|
|
Oligopeptide and D-glucose transport studies.
To investigate whether oligopeptide transport activity was altered in
the 5/6 nephrectomized rat kidney, the uptake rate of glycylsarcosine
by renal brush-border membrane vesicles was examined and compared with
the Na+-D-glucose cotransport activity. Figure
2 shows glycylsarcosine and
D-glucose uptake by renal brush-border membrane vesicles
isolated from the nephrectomized and sham-operated rat kidney cortex at 2 wk after surgery. [14C]glycylsarcosine uptake was
examined in the presence of both an inward H+-gradient and
an interior negative membrane potential. The uptake of
[14C]glycylsarcosine was significantly enhanced in the
renal brush-border membrane vesicles from the 5/6 nephrectomized rats
(Fig. 2A). The rate of
D-[3H]glucose uptake in the presence of an
inward Na+ gradient by the renal brush-border membrane
vesicles isolated from the nephrectomized rats was not significantly
altered compared with those from sham-operated controls (Fig.
2B).
|
|
|
Western blotting.
Western blotting was performed to detect the expression of rat PEPT1,
PEPT2, and SGLT1 proteins in the same batch of renal brush-border
membranes as used for transport studies. As shown in Fig.
4, the expression level of PEPT2 protein
in the brush-border membranes isolated from nephrectomized rats was
significantly increased at 2 wk after renal ablation. In contrast, the
expression levels of PEPT1 and SGLT1 in the brush-border membranes
isolated from nephrectomized rats were moderately decreased compared
with those from sham-operated controls (Fig. 4).
|
Competitive PCR analysis.
To obtain quantitative information about the expression levels of
PEPT1, PEPT2, SGLT1, and SGLT2 in the kidney cortex, we carried out
competitive PCR analysis. The data obtained by competitive PCR
amplification using primer sets specific for each transporter (Table 1)
were normalized with the data of competitive PCR for GAPDH in each
tissue (data not shown). As shown in Fig.
5, the expression level of PEPT2 mRNA in
the remnant kidney was markedly increased, compared with that in
sham-operated controls (1.56 ± 0.27 amol/µg total RNA from 5/6
nephrectomized rat kidney vs. 0.67 ± 0.13 amol/µg total RNA
from sham-operated rat kidney, P < 0.05). However,
mRNA expression levels of SGLT1, SGLT2, and PEPT1 in the remnant kidney
were not significantly different from those in the sham-operated
controls.
|
![]() |
DISCUSSION |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
The biochemical abnormalities associated with renal failure may affect pharmacological efficacy due to altered renal excretion, resulting in heightened pharmacodynamic responses (24). Therefore, the dosage of drugs must be adjusted properly in patients with renal dysfunction to avoid adverse reactions and to ensure safety and efficacy. However, the detailed mechanisms of renal excretion of drugs in CRF have not been elucidated. In the present study, we found that the oligopeptide transport activity and the expression of PEPT2 were upregulated in CRF with no morphological changes in tubules (Figs. 2, 4, and 5). However, the Vmax value for the low-affinity-type transport of glycylsarcosine and the expression of PEPT1 were maintained by the 5/6 nephrectomy (Table 3). In addition, the Vmax value of the high-affinity-type peptide transport system was significantly increased in the nephrectomized rats without changing the Vmax value for the low-affinity-type peptide transport system (Fig. 3A and Table 3). Our previous report demonstrated that the Km value of high- or low-affinity uptake of glycylsarcosine in the rat renal brush-border membrane vesicles was comparable with the Km value of PEPT2 or PEPT1 for glycylsarcosine in the stable transfectant, respectively (27). Therefore, the enhanced oligopeptide transport activity in the renal brush-border membrane vesicles isolated from nephrectomized rats would be due to the upregulation of PEPT2. To our knowledge, this is the first report demonstrating the upregulation of renal PEPT2.
Turner and Moran (30) reported that there were two distinct D-glucose transport systems with Km values of 0.35 and 6 mM in the rat renal brush-border membrane vesicles. Lee et al. (16) reported that the Km value for the 3-O-methyl-D-glucose uptake of the rat SGLT1 expressed in oocytes was 397 µM, and You et al. (32) demonstrated that the Km value for the 3-O-methyl-D-glucose uptake of the rat SGLT2 expressed in oocytes was 3 mM. In the present study, we confirmed the involvement of the high- and low-affinity Na+-D-glucose cotransport systems in the rat renal brush-border membrane vesicles isolated from sham-operated and 5/6 nephrectomized rats, corresponding to SGLT1 and SGLT2, respectively (Fig. 3B). Although the Vmax value for the low-affinity-type Na+-D-glucose cotransport activity was significantly decreased in the nephrectomized rats compared with that in sham-operated controls (Table 3), the mRNA expression level of SGLT2 was maintained in the nephrectomized rat kidneys. The discrepancy between the decreased Vmax value for the low-affinity-type D-glucose transport system and the maintained mRNA expression level of SGLT2 in nephrectomized rats should be clarified in the future by determining the expression level of SGLT2 protein using a specific antibody.
There have been some reports concerning upregulation of PEPT1 and SGLT1 in the small intestine. Tanaka et al. (29) reported that the intestinal SGLT1 mRNA levels were markedly reduced in 5-fluorouracil-treated rats, whereas the level of PEPT1 mRNA expression was increased. It has been suggested that the resistance of oligopeptide transport activity to 5-fluorouracil-induced intestinal injury was attributable to increased biosynthesis of PEPT1 (29). In the present study, the mRNA expression level of PEPT2, but not of PEPT1, was significantly increased in the remnant kidney (Fig. 5). These findings indicate that there might be tissue-specific mechanisms for preventing tissue damage by regulating the expression of intestinal PEPT1, and renal PEPT1 or PEPT2.
In regard to substrate-induced regulation, intestinal SGLT1 is upregulated in rats by a high carbohydrate diet (6). It was also reported that a high dietary protein level upregulates oligopeptide transport activity in the rat small intestine (4). In addition, Shiraga et al. (23) reported that upregulation of intestinal dipeptide transport activity by high dietary protein levels is due to transcriptional activation of the PEPT1 gene. In the present study, both urinary albumin/creatinine ratio and the level of PEPT2 mRNA expression were significantly increased in nephrectomized rats 2 wk after renal ablation (Table 2, Fig. 5). These findings and the present results suggest that the enhancement of renal PEPT2 mRNA level might be comparable with the urinary concentration of albumin.
PEPT2 is expressed preferentially in the kidney, but not in the small intestine (22). The present results indicate that the expression of PEPT2 was sensitive to 5/6 nephrectomy (Table 3, Figs. 4 and 5). Therefore, these findings suggest that reabsorption of small peptides and peptide-like drugs across the brush-border membranes was stimulated in CRF. Zhu et al. (33) reported that the oligopeptide transporters PEPT1 and PEPT2 recognize ACE inhibitors (peptide-like drugs). Enalapril, an ACE inhibitor, has been reported to reduce glomerular hypertrophy and protect against the progression of renal lesions after subtotal nephrectomy (3, 13). In addition, meta-analysis of the results of clinical trials indicated that ACE inhibitors reduce renal injury in patients with kidney disease (18). Considering the clinical implications of PEPT2 for treatment of patients with renal injury, the upregulation of PEPT2 at both functional and molecular levels might contribute to prevention of the urinary loss of ACE inhibitors by enhanced reabsorption, preventing progression of renal failure.
In conclusion, we found that the tubular PEPT2 was selectively
upregulated in CRF by 5/6 nephrectomy, but PEPT1, SGLT1, and SGLT2 were
not. These findings would provide useful information for clarification
of the renal handling of peptide-like drugs including -lactam
antibiotics and ACE inhibitors in CRF.
![]() |
ACKNOWLEDGEMENTS |
---|
We thank Dr. M. Kasahara, Laboratory of Biophysics, School of Medicine, Teikyo University, for providing the rabbit anti-SGLT1 antibody.
![]() |
FOOTNOTES |
---|
This work was supported by a Grant-in-Aid for Scientific Research from the Ministry of Education, Science, Sports and Culture of Japan for research on metabolic disorders from the Yamanouchi Foundation.
Address for reprint requests and other correspondence: K. Inui, Dept. of Pharmacy, Kyoto University Hospital, Sakyo-ku, Kyoto 606-8507, Japan (E-mail address: inui{at}kuhp.kyoto-u.ac.jp).
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.
First published August 21, 2001; 10.1152/ajprenal.0346.2001
Received 21 December 2000; accepted in final form 6 August 2001.
![]() |
REFERENCES |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
1.
Bradford, MM.
A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding.
Anal Biochem
72:
248-254,
1976[ISI][Medline].
2.
Daniel, H,
Morse EL,
and
Adibi SA.
The high and low affinity transport systems for dipeptides in kidney brush border membrane respond differently to alterations in pH gradient and membrane potential.
J Biol Chem
266:
19917-19924,
1991
3.
De Lannoy, IAM,
Nespeca R,
and
Pang KS.
Renal handling of enalapril and enalapriat: studies in the isolated red blood cell-perfused rat kidney.
J Pharmacol Exp Ther
251:
1211-1222,
1989[Abstract].
4.
Erickson, RH,
Gum JR, Jr,
Lindstrom MM,
McKean D,
and
Kim YS.
Regional expression and dietary regulation of rat small intestine peptide and amino acid transporter mRNAs.
Biochem Biophys Res Commun
216:
249-257,
1995[ISI][Medline].
5.
Fei, YJ,
Kanai Y,
Nussberger S,
Ganapathy V,
Leibach FH,
Romero MF,
Singh SK,
Boron WF,
and
Hediger MA.
Expression cloning of a mammalian proton-coupled oligopeptide transporter.
Nature
368:
563-566,
1994[ISI][Medline].
6.
Ferraris, RP,
Villenas SA,
Hirayama BA,
and
Diamond J.
Effect of diet on glucose transporter site density along the intestinal crypt-villus axis.
Am J Physiol Gastrointest Liver Physiol
262:
G1060-G1068,
1992
7.
Hayslett, JP.
Functional adaptation to reduction in renal mass.
Physiol Rev
59:
137-164,
1979
8.
Hediger, MA,
Coady MJ,
Ikeda TS,
and
Wright EM.
Expression cloning and cDNA sequencing of the Na+/glucose co-transporter.
Nature
330:
379-381,
1987[ISI][Medline].
9.
Hediger, MA,
and
Rhoads DB.
Molecular physiology of sodium-glucose cotransporters.
Physiol Rev
74:
993-1026,
1994
10.
Hostetter, TH,
Olson JL,
Rennke HG,
Venkatachalam MA,
and
Brenner BM.
Hyperfiltration in remnant nephrons: a potentially adverse response to renal ablation.
Am J Physiol Renal Fluid Electrolyte Physiol
241:
F85-F93,
1981
11.
Inui, K,
and
Terada T.
Dipeptide transporters.
In: Membrane Transporters as Drug Targets, edited by Amidon GL,
and Sadée W.. New York: Kluwer Academic/Plenum, 1999, p. 269-288.
12.
Inui, K,
Masuda S,
and
Saito H.
Cellular and molecular aspects of drug transport in the kidney.
Kidney Int
58:
944-958,
2000[ISI][Medline].
13.
Kaneto, H,
Morrissey J,
McCracken R,
Reyes A,
and
Klahr S.
Enalapril reduces collagen type IV synthesis and expansion of the interstitium in the obstructed rat kidney.
Kidney Int
45:
1637-1647,
1994[ISI][Medline].
14.
Kwon, TH,
Frokiaer J,
Knepper MA,
and
Nielsen S.
Reduced AQP1, -2, and -3 levels in kidneys of rats with CRF induced by surgical reduction in renal mass.
Am J Physiol Renal Physiol
275:
F724-F741,
1998
15.
Kwon, TH,
Frokiaer J,
Fernandez-Llama P,
Maunsbach AB,
Knepper MA,
and
Nielsen S.
Altered expression of Na transporters NHE-3, NaPi-II, Na-K-ATPase, BSC-1, and TSC in CRF rat kidneys.
Am J Physiol Renal Physiol
277:
F257-F270,
1999
16.
Lee, WS,
Kanai Y,
Wells RG,
and
Hediger MA.
The high affinity Na+/glucose cotransporter.
J Biol Chem
269:
12032-12039,
1994
17.
Leibach, FH,
and
Ganapathy V.
Peptide transporters in the intestine and the kidney.
Annu Rev Nutr
16:
99-119,
1996[ISI][Medline].
18.
Maki, DD,
Ma JZ,
Louis TA,
and
Kasiske BL.
Long-term effects of antihypertensive agents on proteinuria and renal function.
Arch Intern Med
155:
1073-1080,
1995[Abstract].
19.
Masuda, S,
Uemoto S,
Hashida T,
Inomata Y,
Tanaka K,
and
Inui K.
Effect of intestinal P-glycoprotein on daily tacrolimus trough level in a living-donor small bowel recipient.
Clin Pharmacol Ther
68:
98-103,
2000[ISI][Medline].
20.
Miyamoto, Y,
Coone JL,
Ganapathy V,
and
Leibach FH.
Distribution and properties of the glycylsarcosine-transport system in rabbit renal proximal tubule.
Biochem J
249:
247-253,
1988[ISI][Medline].
21.
Saito, H,
Okuda M,
Terada T,
Sasaki S,
and
Inui K.
Cloning and characterization of a rat H+/peptide cotransporter mediating absorption of -lactam antibiotics in the intestine and kidney.
J Pharmacol Exp Ther
275:
1631-1637,
1995[Abstract].
22.
Saito, H,
Terada T,
Okuda M,
Sasaki S,
and
Inui K.
Molecular cloning and tissue distribution of rat peptide transporter PEPT2.
Biochim Biophys Acta
1280:
173-177,
1996[ISI][Medline].
23.
Shiraga, T,
Miyamoto K,
Tanaka H,
Yamamoto H,
Taketani Y,
Morita K,
Tamai I,
Tsuji A,
and
Takeda E.
Cellular and molecular mechanisms of dietary regulation on rat intestinal H+/peptide transporter PepT1.
Gastroenterology
116:
354-362,
1999[ISI][Medline].
24.
Shuler, C,
Golper TA,
and
Bennett WM.
Prescribing drugs in renal disease.
In: The Kidney, edited by Brenner BM.. Philadelphia, PA: Saunders, 1996, p. 2653-2702.
25.
Siebert, PD,
and
Larrick JW.
Competitive PCR.
Nature
359:
557-558,
1992[ISI][Medline].
26.
Sunamoto, M,
Kuze K,
Iehara N,
Takeoka H,
Nagata K,
Kita T,
and
Doi T.
Expression of heat shock protein 47 is increased in remnant kidney and correlates with disease progression.
Int J Exp Pathol
79:
133-140,
1998[ISI][Medline].
27.
Takahashi, K,
Nakamura N,
Terada T,
Okano T,
Futami T,
Saito H,
and
Inui K.
Interaction of -lactam antibiotics with H+/peptide cotransporters in rat renal brush-border membranes.
J Pharmacol Exp Ther
286:
1037-1042,
1998
28.
Takata, K,
Kasahara T,
Kasahara M,
Ezaki O,
and
Hirano H.
Localization of Na+-dependent active type and erythrocyte/HepG2-type glucose transporters in rat kidney: immunofluorescence and immunogold study.
J Histochem Cytochem
39:
287-298,
1991[Abstract].
29.
Tanaka, H,
Miyamoto K,
Morita K,
Haga H,
Segawa H,
Shiraga T,
Fujioka A,
Kouda T,
Taketani Y,
Hisano S,
Fukui Y,
Kitagawa K,
and
Takeda E.
Regulation of the PepT1 peptide transporter in the rat small intestine in response to 5-fluorouracil-induced injury.
Gastroenterology
114:
714-723,
1998[ISI][Medline].
30.
Turner, RJ,
and
Moran A.
Heterogeneity of sodium-dependent D-glucose transport sites along the proximal tubule: evidence from vesicle studies.
Am J Physiol Renal Fluid Electrolyte Physiol
242:
F406-F414,
1982[ISI][Medline].
31.
Wells, RG,
Pajor AM,
Kanai Y,
Turk E,
Wright EM,
and
Hediger MA.
Cloning of a human cDNA with similarity to the sodium-glucose cotransporter.
Am J Physiol Renal Fluid Electrolyte Physiol
263:
F459-F465,
1992
32.
You, G,
Lee WS,
Barros EJG,
Kanai Y,
Huo TL,
Khawaja S,
Wells RG,
Nigam SK,
and
Hediger MA.
Molecular characteristics of Na+-coupled glucose transporters in adult and embryonic rat kidney.
J Biol Chem
270:
29365-29371,
1995
33.
Zhu, T,
Chen XZ,
Steel A,
Hediger MA,
and
Smith DE.
Differential recognition of ACE inhibitors in Xenopus laevis oocytes expressing rat PEPT1 and PEPT2.
Pharm Res
17:
526-532,
2000[ISI][Medline].