The effect of caffeine on renal epithelial cells from patients with autosomal dominant polycystic kidney disease.

Autosomal dominant polycystic kidney disease (AD- PKD) is a hereditary disorder characterized by the progressive enlargement of cysts derived from tubules. Tubule cell prolif- eration and chloride-dependent fluid accumulation, mecha- nisms underlying cyst expansion, are accelerated by adenosine 3':5'-cyclic monophosphate (cAMP). This study examined the extent to which caffeine may stimulate the production of cAMP by cyst epithelial cells, thereby adversely increasing proliferation and fluid secretion. Mural epithelial cells from ADPKD cysts and normal human kidney cortex cells (HKC) were cultured, and cAMP levels were determined in response to caffeine and receptor-mediated agonists linked to adenylyl cyclase. Caffeine, a methylxanthine, slightly increased basal levels of cAMP, as did other nonselective phosphodiesterase (PDE) inhibitors, 1-methyl-3- isobutyl xanthine and theophyl- line and rolipram, a specific PDE IV inhibitor. More impor- tantly, clinically relevant concentrations of caffeine (10 to 50 M) potentiated the effects of desmopressin (DDAVP), pros- taglandin E2 (PGE2), and isoproterenol to increase cAMP levels in both ADPKD and HKC cells. By contrast, at concen- trations that augmented the DDAVP response, caffeine atten- uated cAMP accumulation by adenosine, implicating an action apart from the inhibition of PDE. Caffeine enhanced the effect of DDAVP to stimulate transepithelial short-circuit current of polarized ADPKD monolayers, reflecting an increase in chlo- ride secretion. Caffeine potentiated the effect of DDAVP and PGE2 to increase the levels of phosphorylated extracellular signal-regulated kinase (P-ERK). By contrast, P-ERK levels in HKC cells were not raised by increased intracellular concen- trations of cAMP. It is concluded that PDE inhibition by caffeine increases the accumulation of cAMP, and through this mechanism activates the ERK pathway to cellular proliferation and increases transepithelial fluid secretion in ADPKD cystic epithelium. Caffeine is, therefore, a risk factor for the promo- tion of cyst enlargement in patients with ADPKD.