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.

Parathyroid Hormone-mediated Regulation of Na+-K+-ATPase Requires ERK-dependent Translocation of Protein Kinase Cα

“…Cells-Consistent with previous reports (19,30,31) preliminary studies demonstrated the expression of PKC␣, ␤I, ␤II, and but not of PKC␦, ␥, and ⑀ in OK cells (data not shown). To determine which PKC isoforms were activated by PTH, OK cells were treated with PTH (10 Ϫ7 M) for 15 min.…”

Regulation of Renal A₁ Adenosine Receptors in vivo

“…Conversely, prolonged exposure to antagonists up-regulate and increase the sensitivity of cardiac and brain A 1 ARs [12, 13, 14]. Concomitant regulatory changes in the G i proteins may be associated with changes in the A 1 AR receptor density [15, 16, 17].…”

“…Concomitant regulatory changes in the G i proteins may be associated with changes in the A 1 AR receptor density [15, 16, 17]. In vitro, 48 h treatment with non-selective AR antagonists led to up-regulation of A 1 ARs in LLC-PK1 and OK cells associated with enhanced A 1 AR-mediated responses [14]. However, there are few data available regarding the regulation of the renal A 1 ARs in vivo.…”

Osmotic Diuretics Induce Adenosine A1 Receptor Expression and Protect Renal Proximal Tubular Epithelial Cells against Cisplatin-mediated Apoptosis

“…Specific receptor expression is demonstrated in different nephron segments, such as the glomeruli, the thick ascending limb and collecting duct (16) and the proximal tu-bules (17). In the proximal tubule and the cortical collecting duct, adenosine stimulates the transport of sodium and phosphate via the apical surface (18), that of sodium and bicarbonate via the basolateral symporters (19) and stimulates chloride channel activity (20).…”