RENAL ACCUMULATION AND EXCRETION OF CYCLIC ADENOSINE-MONOPHOSPHATE INA MURINE MODEL OF SLOWLY PROGRESSIVE POLYCYSTIC KIDNEY-DISEASE

Evidence from in vitro studies indicates that increased proliferation of epithelial cells and secretion of fluid by these cells may be impor tant factors in the progressive enlargement of renal cysts. The rate o f cellular proliferation and fluid secretion by cyst epithelium in vit ro can be strikingly accelerated by cyclic adenosine 3'5' monophosphat e (cAMP) and agonists that lead to the production of this nucleotide. The extent to which renal cAMP content is increased in polycystic kidn eys is unknown. In the current study, we determined the amount of this nucleotide in intact kidneys, cyst fluid, plasma, and urine in nonazo temic mice (DBA/2FG-pcy/pcy) with a slowly progressive form of inherit ed polycystic kidney disease (PKD). In 45 pcy/pcy mice studied 20, 45, or 70 days after birth, the total kidney cAMP content was 0.22 +/- 0. 01, 0.46 +/- 0.02, and 0.90 +/- 0.05 pmol/mg tissue, respectively. By contrast, in 37 control DBA/2J mice the levels of cAMP at identical ti mes remained relatively constant at 0.22 +/- 0.01, 0.21 +/- 0.01, and 0.29 +/- 0.01 pmol/mg tissue, respectively. In 70-day-old nonazotemic pcy/pcy mice with normal serum levels of parathyroid hormone, cAMP gen erated by the kidneys (nephrogenous cAMP) was 22.9 +/- 2.8 nmol/100 mL creatinine clearance, compared with 6.5 +/- 1.3 in normal animals of the same age (P < 0.001). The cyst fluids of 70-day-old pcy/pcy mice c ontained a lipid that increased transepithelial secretion of fluid by MDCK monolayers from a baseline of 0.012 +/- 0.002 to 0.136 +/- 0.008 mu L/cm(2)/hr (P < 0.05). This lipid also stimulated cellular prolifer ation by monolayers of cultured MDCK and LLC-PK1 cells 2.5- and 7.9-fo ld (P < .05), respectively, and stimulated cAMP accumulation by these cells 1.6- and 2.0-fold (P < .05), respectively. These studies illustr ate that renal cAMP production and excretion increase in concert with the cystic enlargement of the kidneys in DBA/2FG-pcy/pcy mice and iden tify a lipid cAMP agonist in murine renal cystic kidney disease. (C) 1 997 by the National Kidney Foundation, Inc.