Department of Veterinary Physiology, College of Veterinary Medicine, Chonnam National University, Gwangju, Korea
Submitted 3 January 2005 ; accepted in final form 6 July 2005
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ABSTRACT |
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adenosine 5'-triphosphate; mitogen-activated protein kinase
Glucose transporters, which incorporate glucose into the cell, can be divided into two groups: the facilitative type of glucose transporter and the SGLT. SGLTs are expressed in apical membranes of the PTCs, where they play a central role in the reabsorption of glucose from the glomerular filtrate (8). SGLT1 and SGLT2 are expressed in rabbit renal PTCs (36). The activation of cAMP by purinoceptors was reported in Madin-Darby canine kidney epithelial cells (38). cAMP is the second messenger in pathways that regulate SGLTs (57). The family of MAPKs includes ERK1/2, JNK, and p38 MAPK (9, 14). In mesangial cells, ERK1/2 and p38 MAPK mediate the ATP-induced cellular response (22, 54). Together, these studies suggest the possibility that these signaling molecules are involved in the effect of ATP on SGLTs in PTCs. However, the subtypes of ATP receptors and the ATP signal transduction mechanism inducing this important physiological effect on SGLTs remain unknown.
When grown in a hormonally defined medium, primary cultured renal PTCs form confluent monolayers of polarized cells, which retain a number of differentiated transport functions typical of renal PTCs (8). Included among these transport functions are a probenecid-sensitive PAH transport system, a Na+-dependent sugar transport system, and a Na+-dependent Pi transport system (8, 58). The results of studies concerning these membrane transport systems in PTCs are directly comparable to results obtained with original renal tissue (56). The PTCs respond to a number of hormones known to affect renal PTCs in vivo, including insulin (which inhibits phosphoenolpyruvate carboxykinase activity at physiological concentrations) (55), and parathyroid hormone (which is stimulatory to adenylate cyclase) (51). The PTCs lack a similar responsiveness to arginine vasopressin and calcitonin, indicating the PTC culture preparation is highly purified (8). More recently, we have reported a dose-dependent, biphasic effect of ANG II on Na+ uptake by the PTCs, consistent with results obtained with intact renal tissue (19). Therefore, PTCs in hormonally defined, serum-free culture conditions would be a powerful tool for studying the effect of ATP on [14C]--methyl-D-glucopyranoside (
-MG) uptake of renal PTCs. Thus we investigated the effect of ATP on
-MG uptake and its related signal cascades in PTCs.
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MATERIALS AND METHODS |
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Isolation of rabbit renal proximal tubules and culture conditions. Primary rabbit renal PTC cultures were prepared according to the method of Chung et al. (8). The PTCs were grown in DMEM-Ham's F-12 medium with 15 mM HEPES and 20 mM sodium bicarbonate (pH 7.4). Immediately before we used the medium, three growth supplements (5 µg/ml insulin, 5 µg/ml transferrin, and 5 x 108 M hydrocortisone) were added. The kidneys of a rabbit were perfused via the renal artery, first with PBS and then with medium containing 0.5% iron oxide. Renal cortical slices were prepared and homogenized. The homogenate was poured first through a 253-µm and then through an 83-µm mesh filter. Tubules and glomeruli on top of the 83-µm filter were transferred into sterile medium. Glomeruli (containing iron oxide) were removed with the stirring bar. The remaining tubules were incubated briefly in medium. The tubules were then washed by centrifugation, resuspended in medium containing the three supplements, and transferred into tissue culture dishes. Medium was changed 1 day after plating and every 2 days thereafter. PTCs were maintained in a 37°C, 5% CO2 humidified environment in serum-free basal medium supplemented with three growth supplements.
Uptake experiments.
To study the effect of ATP on -MG uptake, the confluent monolayers were incubated with ATP before [14C]-
-MG uptake.
-MG uptake experiments were conducted according to the method described previously by Sakhrani et al. (42). To study
-MG uptake, the culture medium was removed by aspiration and the monolayers were gently washed twice with the uptake buffer (in mM: 136 NaCl, 5.4 KC1, 0.41 MgSO4, 1.3 CaCl2, 0.44 Na2HPO4, 0.44 KH2PO4, 5 HEPES, and 2 glutamine, pH 7.4). After the washing procedure, the monolayers were incubated at 37°C for 30 min in an uptake buffer that contained 0.5 mM
-MG and 0.5 µCi/ml [14C]-
-MG. At the end of the incubation period, the monolayers were again washed three times with ice-cold uptake buffer and the cells were solubilized in 0.1% SDS (1 ml). To determine the [14C]-
-MG incorporated intracellularly, 900 µl of each sample were removed and counted in a liquid scintillation counter (LS6500; Beckman Instruments, Fullerton, CA). The remainder of each sample was used for protein determination. The protein content of each sample was determined using the Bradford method (6). The radioactivity counts in each sample were then normalized with respect to protein and were corrected for zero time uptake per milligram of protein. All uptake measurements were performed in triplicate.
RNA isolation and RT-PCR.
Extraction of total RNA from PTCs was performed as described previously (7). PTCs were homogenated with STAT-60, a monophasic solution of phenol, and guanidine isothiocyanate obtained from Tel-Test (Friendswood, TX). Two micrograms of purified RNA were synthesized into cDNA using avian leukemia virus RT with oligo dT18 primers. PCR amplification was performed with 5 µl of RT product, 10 pmol of each primer, 1.25 U of Taq polymerase (Promega, Madison, WI), and 1 mM 2-deoxynucleotide 5'-triphosphate. After an initial incubation at 95°C for 5 min, 28 amplification cycles consisting of 95°C for 40 s, annealing at 55°C for 1 min, and extension at 72°C for 40 s were performed. Rabbit-specific sense and antisense primers used were as follows: P2Y1 sense, 5'-GCATCTCGGTGTACATGTTC-3', and antisense 5'-GCTGTTGAGACTTGCTAGACCT-3'; P2Y2 sense, 5'-TACAGCTCTGTCATGCTGGG-3', and antisense, 5'-GCCAGGAAGTAGAGCACAGG-3'; P2Y4 sense, 5'-CTTTGCAAGTTTGTCCGCTTTC-3', and antisense, 5'-CCGGGCCATGAGTCCATA-3'; and P2Y6 sense, 5'-CTGTGTCATCGCCCAGATATGC-3', and antisense, 5'-GGTTGCCGCCGGAACTTC-3'. This sequence was used to clone the P2Y receptors successfully from the rabbit (29). As a control for the amount of cDNA, RT-PCR was performed using -actin primers. PCR products were visualized using ethidium bromide staining.
Membrane preparation for Western blot analysis. The medium was removed, and the cells were then washed twice with ice-cold PBS, scraped, harvested by microcentrifugation, and resuspended in buffer A (137 mM NaCl, 8.1 mM Na2HPO4, 2.7 mM KCl, 1.5 mM KH2PO4, 2.5 mM EDTA, 1 mM DTT, 0.1 mM PMSF, and 10 µg/ml leupeptin, pH 7.5). The resuspended cells were then mechanically lysed on ice by performing trituration with a 21.1-gauge needle. The lysates were first centrifuged at 1,000 g for 10 min at 4°C. The supernatants were centrifuged at 100,000 g for 1 h at 4°C to prepare cytosolic and total particulate fractions. The particulate fractions, which contained the membrane fraction, were washed twice and resuspended in buffer A containing 1% Triton X-100. The protein in each fraction was quantified using a Bradford procedure (6).
Western blot analysis. Cell homogenates (20 µg of protein) were separated using 10% SDS-PAGE and transferred onto nitrocellulose paper. Blots were then washed with H2O, blocked with 5% skim milk powder in TBST (10 mM Tris·HCl, pH 7.6, 150 mM NaCl, and 0.05% Tween 20) for 2 h and incubated with the primary polyclonal antibody (SGLT1, SGLT2, or MAPK) at dilutions recommended by the supplier. SGLT1 is a rabbit polyclonal antibody that recognizes a synthetic peptide corresponding to amino acids 402420 of the putative extracellular loop of rabbit SGLT1 (a sequence that differs by 1 residue from the complementary region in pig SGLT2). In the present study, we confirmed antibody specificity using control peptides. Subsequently, the membrane was washed and primary antibodies were detected with goat anti-rabbit-IgG conjugated to horseradish peroxidase, and the bands were visualized using ECL (Amersham Pharmacia Biotech, Little Chalfont, UK).
cAMP assay. Samples were prepared for intracellular cAMP determinations by performing homogenization in serum-free medium containing 4 mM EDTA using the Polytron PT 1200, followed by 5-min incubation at 100°C. After centrifugation at 890 g for 5 min, the supernatants was transferred into new tubes and stored at 4°C. These samples were used for cAMP assays using a [3H]cAMP assay system. Values were expressed as picomolar cAMP per milligram of protein.
Statistical analysis. Results were expressed as means ± SE. Statistical analysis was performed using Student's t-test or ANOVA. The difference was considered statistically significant when P < 0.05.
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RESULTS |
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DISCUSSION |
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Previous studies have focused on the roles of purinergic receptors (P2 receptors and adenosine receptors) in glucose transport (15, 18, 49). Adenosine was reported to stimulate SGLT in opossum kidney cells, a PTC line (12). However, in the present study, adenosine did not stimulate -MG uptake, suggesting the role of P2 receptors but not P1 receptors in the regulation of SGLT. In addition, pretreatment with ADA did not block ATP-induced increase of
-MG uptake. Herein we have demonstrated that ATP-induced stimulation of
-MG uptake is mediated by P2Y receptors. These results are in agreement with a recent report that P2Y1 receptors mediate HCO3 reabsorption in the apical membrane of rat PTCs (2). P2Y-dependent GLUT1 activation is deficient in fibroblasts from individuals type 2 diabetes mellitus, suggesting the physiological and clinical role of extracellular ATP in the modulation of glucose transport (46). Our result firstly revealed that activity of SGLT is physiologically upregulated by P2Y receptor activation. However, it is not clear which specific subtypes of P2Y receptors are involved in the effect of ATP on
-MG uptake. Herein we have demonstrated that P2Y1, P2Y2, P2Y4, and P2Y6 receptors are expressed in rabbit PTCs. Some of them may mediate the effect of ATP on
-MG uptake. In the present study, we showed that AMP-CPP (a P2X receptor agonist) did not affect
-MG uptake but UTP (a P2Y receptor agonist) increased it. However, we cannot rule out the possibility that the P2X receptors are involved in the effect of ATP, because MRS-2159 is a partial antagonist against the effect of ATP and UTP and 2-methylthio-ATP are only partially effective. Therefore, molecular identification of P2X and P2Y receptor subtypes remains to be examined in rabbit PTCs.
P2 purinoceptors were previously reported to be coupled to Gi protein in proximal tubule (31). In the present study, ATP-induced stimulation of -MG uptake was blocked by 100 ng/ml PTX, indicating the involvement of a PTX-sensitive G protein. Thus extracellular ATP may suffice to trigger the alterations in G proteins that may activate SGLT. In addition, P2 purinoceptors have been reported to couple to adenylyl cyclase in several systems (11, 39). Several lines of evidence suggested that activation of P2Y receptor inhibits adenylyl cyclase (4, 5). However, in the present study, cAMP/PKA inhibitors blocked the effect of ATP on
-MG uptake, and ATP-induced increase of cAMP formation was prevented by P2Y receptor antagonists. These results suggest that the P2Y purinoceptor is coupled to the adenylyl cyclase-cAMP pathway, which induces stimulation of SGLT in PTCs. Our hypothesis is consistent with the report that the ADP-sensitive P2Y receptor is linked to cAMP accumulation with PKA, one of the activation systems in bovine adrenocortical fasciculata cells (34). Although the reasons why contradictory effects of ATP on the cAMP pathway are observed between astrocytomas and PTCs are not clear, it may be due to the different subtypes of receptors involved in the effect of ATP.
Three principal MAPKs are expressed in whole kidney: ERK1/2, JNK, and p38 MAPK (49). The ATP-induced activation of MAPKs, including ERK1/2, JNK, and p38 MAPK, was shown in mesangial cells and distal tubule cells (23, 24, 35, 51). Our previous report (20) showed that MAPK activation is involved in the regulation of SGLTs in PTCs, in which p44/42 MAPK activation is responsible for the inhibition of SGLTs. Unlike our previous report (20), our present results show that p38 MAPK, but not p44/42 MAPK and JNK, is an important signaling molecule in ATP-induced stimulation of -MG uptake of PTCs. Recently, the cross-talk between cAMP and MAPK activation has been documented in various cells (41, 48). In the present study, ATP-induced activation of p38 MAPK was significantly blocked by PTX (a Gi protein inhibitor) and inhibitors of cAMP-PKA pathways. This result suggests that Gi protein-dependent pathways are molecules that are upstream from the activation of p38 MAPK. This result is consistent with the report of Aimond et al. (1) that ATP-induced activation of p38 MAPK is dependent on the primary activation of the PKA pathway and is prevented by inhibition of adenylyl cyclase and PKA. The regulatory role of PKA in the p38 MAPK signaling cascade is presently unclear. However, it might be involved in the activation of intermediate molecules, such as protein tyrosine phosphatases containing a PKA consensus sequence that shares a common function, as negative regulators of the p38 MAPK pathways (43). In con-clusion, ATP stimulates
-MG uptake via cAMP and p38 MAPK in renal PTCs.
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GRANTS |
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FOOTNOTES |
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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.
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