CYST FLUID FROM A MURINE MODEL OF POLYCYSTIC KIDNEY-DISEASE STIMULATES FLUID SECRETION, CYCLIC ADENOSINE-MONOPHOSPHATE ACCUMULATION, AND CELL-PROLIFERATION BY MADIN-DARBY CANINE KIDNEY-CELLS IN-VITRO

Cyst fluids from subjects with autosomal dominant polycystic kidney di sease (ADPKD) cause polarized monolayers of MDCK cells to secrete flui d toward the apical compartment in vitro. To determine the extent to w hich secretagogue accumulation may be a general feature of polycystic diseases, cyst fluid from mice with a slowly progressive form of hered itary PKD (DBA/2FG-pcy/pcy) was added to polarized MDCK monolayers, Ba solateral application of cyst fluids (diluted with culture medium to 1 5% final concentration) from 13 different animals 16 to 35 weeks old i ncreased the fluid secretion rate from a baseline of 0.023 +/- 0.003 t o 0.111 +/- 0.017 mu L/cm(2)/h (P < 0.005), There was a direct relatio n between the concentration of cyst fluid and the rate of net fluid se cretion, The secretory activity of cyst fluid was not altered by prona se treatment or boiling, Cyst fluid (10%) added to the basolateral sur faces of polarized MDCK monolayers for 24 hours increased cell cyclic adenosine monophosphate (AMP) levels from a baseline of 6.3 +/- 0.2 to 17.3 +/- 0.3 pmoles/monolayer (n = 3, P < 0.05), The capacity of cyst fluid to increase cyclic AMP levels was not changed by pronase treatm ent or boiling, There was a direct relation between the level of cellu lar cyclic AMP and the rate of transepithelial fluid secretion caused by cyst fluid, Cyst fluid increased thymidine incorporation by Madin-D arby canine kidney (MDCK) cells to an extent equal to that caused by e pidermal growth factor and caused MDCK cells to form cysts in collagen matricies, The mitogenic activity of cyst fluid was decreased 62% by pronase treatment, suggesting that the substance(s) responsible for th e mitogenic activity may not be the same as that causing fluid secreti on, On the basis of these studies, the authors conclude that, like hum an ADPKD, fluids in the cysts of a slowly progressive murine model of PKD contain material capable of stimulating fluid secretion and mitoge nesis in MDCK cells in vitro, The cyclic AMP signal pathway appears to have an important role in mediating the intracellular actions of endo genous factors that have the capacity to stimulate cyst growth. (C) 19 95 by the National Kidney Foundation, Inc.