Evidence for increased renal production of cyclic AMP in mice with hereditary slowly progressive polycystic kidney disease

In vitro studies of epithelial cells from polycystic kidneys strongly support a role for cyclic AMP in the regulation of transepithelial fluid secretion into cysts and the proliferation of epithelial cells lining cyst walls. To evaluate the role of cyclic AMP in vivo, we analyzed kidney tissue, mine and plasma for cyclic AMP in DHA/2FG-pcy/pcy mice with a slowly progressive form of hereditary polycystic kidney disease. In 70 day old non-azotemic animals the total intra-cellular cyclic AMP content of kidneys and the excretion rate of nephrogenous cyclic AMP were elevated more than three-fold above the levels in normal animals of the same age (DBA/2J). The concentration of cyclic AMP in the cyst fluid was lower than in an equivalent volume of kidney tissue, indicating that increased cyclic AMP levels in kidney were due to intracellnlar or tubular fluid accumulation of the nucleotide. Serum urea nitrogen and parathyroid hormone levels were not different in cystic compared to normal animals. Cyst fluid contained a lipophilic secretagogue that stimulated net transepithelial fluid secretion by polarized monolayers of MDCK cells.and stimulated cyclic AMP accumulation and cellular proliferation of MDCK and LLC PK1 cells in vitro. We conclude that renal production and excretion of cyclic AMP is increased in this murine model of polycystic kidney disease and that the production of a lipophilic molecule in cystic kidneys may modulate the rate of fluid secretion and cell proliferation through the intermediacy of cyclic AMP.