Cyclic AMP promotes growth and secretion in human polycystic kidney epithelial cells

Abstract

Background. Progressive cyst enlargement, the hallmark of autosomal-dominant polycystic kidney disease (ADPKD) and autosomal-recessive (ARPKD) polycystic kidney disease, precedes the eventual decline of function in these conditions. The expansion of individual cysts in ADPKD is determined to a major extent by mural epithelial cell proliferation and transepithelial fluid secretion. This study determined if common receptor-mediated agonists and an anonymous lipid stimulate the production of 3′ 5′-cyclic monophosphate (cAMP) in mural epithelial cells from the two major types of human cystic diseases. Methods. cAMP responses to maximally effective concentrations of renal agonists were determined together with measurements of transepithelial anion current and cellular proliferation and extracellular signal-related kinase (ERK 1/2) expression in primary cultures of epithelial cells from human ADPKD and ARPKD cysts. Results. The rank orders of responses to ligands for ADPKD and ARPKD cells were identical: epinephrine > desmopressin (DDAVP) ≈ arginine vasopressin (AVP) > adenosine > prostaglandin E2 (PGE 2) > parathyroid hormone (PTH). cAMP concentrations elevated by epinephrine, DDAVP, adenosine, and PGE2 were diminished by receptor-specific inhibitors. Pools of cyst fluid collected individually from 16 of 19 ADPKD kidneys increased, to varying degrees, cAMP levels in ADPKD and ARPKD cells. PGE2, β-adrenergic and AVP antagonists partially inhibited cAMP accumulation in response to fluids from three kidneys, but a large portion of the endogenous activity was attributed to yet-to-be identified bioactive lipid, designated cyst activating factor (CAF). CAF stimulated cAMP production in ADPKD and ARPKD cells, activated ERK1/2, and increased cellular proliferation in ADPKD cells. CAF increased positive short circuit current (ISC) in polarized ADPKD and T-84 monolayers, indicating stimulation of net anion secretion. Conclusion. Endogenous adenylyl cyclase agonists promote cell proliferation and electrolyte secretion of human ADPKD and ARPKD cells in vitro. We suggest that increased levels of cAMP may accelerate cyst growth and overall renal enlargement in patients with PKD.