title: Upregulated renal adenosine A1 receptors augment PKC and glucose transport but inhibit proliferation.
abstract: Adenosine A1 receptor densities were increased in cultured LLC-PK1 and OK cells by chronic treatment with the adenosine receptor antagonists 1,3,7-trimethylxanthine (caffeine, 1 mM) and 1,3-dimethyl-8-cyclopentylxanthine [cyclopentyltheophylline (CPT), < or = 0.4 mM], respectively. The A1 receptor number per cell was increased twofold by 10-day treatments with 1 mM caffeine or 0.1 mM CPT, and the sodium-coupled glucose uptake was augmented twofold by 1 mM caffeine and sevenfold by 0.1 microM CPT (higher doses of CPT were progressively less stimulatory). Glucose uptake was blocked by acute (2-h) treatment with CPT, adenosine deaminase, or calphostin C. Caffeine (1 mM) or CPT (> or = 0.1 mM) inhibited cell proliferation for the first 10 days, then cell growth assumed a normal proliferative rate despite continued presence of antagonist. Cytosolic protein kinase C (PKC) beta-isoform immunoactivity and PKC-beta II mRNA were elevated at least twofold during 10 days of 0.1 mM CPT or 1 mM caffeine treatment. The sustained elevation in sodium-glucose symport and PKC activity observed with adenosine receptor antagonists was similar to acute (2-h) effects of the adenosine A1 agonist R(-)-N6-phenylisopropyladenosine (R-PIA, 0.1-1 microM). Moreover, cell proliferation was increased by adenosine (0.1 microM R-PIA), whereas Na-K-adenosinetriphosphatase activity was unaltered with chronic antagonist or acute adenosine treatments. Caffeine treatment may have some non-adenosine A1 receptor-mediated actions, because it slightly (30%) augmented protein kinase A activity. It is concluded that chronic exposure of proximal tubule cells to caffeine or CPT augments PKC and sodium-glucose transport but retards cell proliferation mainly via adenosine A1 receptor-mediated mechanisms.
authors.affiliation: Department of Veterans Affairs, James A. Haley Veterans Hospital, Tampa, Florida 33612, USA.
authors.forename: R
authors.initials: R
authors.lastname: Coulson
authors.forename: P S
authors.initials: PS
authors.lastname: Proch
authors.forename: R A
authors.initials: RA
authors.lastname: Olsson
authors.forename: C E
authors.initials: CE
authors.lastname: Chalfant
authors.forename: D R
authors.initials: DR
authors.lastname: Cooper
mesh_terms: D000243:Adenosine Deaminase / Q000494:pharmacology; D000818:Animals; D001692:Biological Transport / Q000502:physiology; D002110:Caffeine / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D002460:Cell Line; D005947:Glucose / Q000378:metabolism*; D007668:Kidney / Q000166:cytology / Q000378:metabolism*; D018374:LLC-PK1 Cells; D010660:Phenylisopropyladenosine / Q000494:pharmacology; D011493:Protein Kinase C / Q000378:metabolism*; D058906:Purinergic P1 Receptor Agonists; D058915:Purinergic P1 Receptor Antagonists; D018047:Receptors, Purinergic P1 / Q000378:metabolism*; D013552:Swine; D013806:Theophylline / Q000031:analogs & derivatives / Q000494:pharmacology; D015854:Up-Regulation
chemical_list: D058906:Purinergic P1 Receptor Agonists; D058915:Purinergic P1 Receptor Antagonists; D018047:Receptors, Purinergic P1; D010660:Phenylisopropyladenosine; C053907:8-cyclopentyl-1,3-dimethylxanthine; D002110:Caffeine; D013806:Theophylline; D011493:Protein Kinase C; D000243:Adenosine Deaminase; D005947:Glucose