R. Coulson et al., UP-REGULATED RENAL ADENOSINE A(1) RECEPTORS AUGMENT PKC AND GLUCOSE-TRANSPORT BUT INHIBIT PROLIFERATION, American journal of physiology. Renal, fluid and electrolyte physiology, 39(2), 1996, pp. 263-274
Adenosine A(1) receptor densities were increased in cultured LLC-PK1 a
nd OK cells by chronic treatment with the adenosine receptor antagonis
ts 1,3,7-trimethylxanthine (caffeine, 1 mM) and 1,3-dimethyl-8-cyclope
ntylxanthine [cyclopentyltheophylline (CPT), less than or equal to 0.4
mM], respectively. The A(1) receptor number per cell was increased tw
ofold by 10-day treatments with 1 mM caffeine or 0.1 mM CPT, and the s
odium-coupled glucose uptake was augmented twofold by 1 mM caffeine an
d seven-fold by 0.1 mu M CPT (higher doses of CPT were progressively l
ess stimulatory). Glucose uptake was blocked by acute (2-h) treatment
with CPT, adenosine deaminase, or calphostin C. Caffeine (1 mM) or CPT
(greater than or equal to 0.1 mM) inhibited cell proliferation for th
e 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 a
t least twofold during 10 days of 0.1 mM CPT or 1 mM caffeine treatmen
t. 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 A(1) agonist R(-)-N-6-phenylisopropyladenos
ine (R-PIA, 0.1-1 mu M). Moreover, cell proliferation was increased by
adenosine (0.1 mu M R-PIA), whereas Na-K-adenosinetriphosphatase acti
vity was unaltered with chronic antagonist or acute adenosine treatmen
ts. Caffeine treatment may have some non-adenosine A(1) receptor-media
ted actions, because it slightly (30%) augmented protein kinase A acti
vity. It is concluded that chronic exposure of proximal tubule cells t
o caffeine or CPT augments PKC and sodium-glucose transport but retard
s cell proliferation mainly via adenosine A(1) receptor-mediated mecha
nisms.