EVIDENCE FOR A POTENT LIPID SECRETAGOGUE IN THE CYST FLUIDS OF PATIENTS WITH AUTOSOMAL-DOMINANT POLYCYSTIC KIDNEY-DISEASE

Transepithelial fluid secretion appears to be an important factor in t he progressive enlargement of cysts in autosomal dominant polycystic k idney disease. Evidence indicates that the fluid within cysts harbors an autocrine, paracrine, or endocrine secretagogue with the capacity t o modulate the rate of cyst expansion. Fluids from five patients with autosomal dominant polycystic kidney disease were studied to determine the chemical nature and the physiologic function of the putative secr etagogue. The secretory activity of cyst fluid assayed with polarized monolayers of Madin Darby canine kidney cells could be ascribed to a l ipophilic substance of molecular weight <3,500 d that was not destroye d by freezing, boiling, or proteolytic digestion. This lipid stimulate d the production of intracellular cAMP and increased the rate of fluid secretion when added to either surface of cultured renal epithelial c ells. Anion exchange chromatography revealed biologic secretory activi ty to a greater extent in the neutral lipid than in the fatty acid and phospholipid fractions separated from cyst fluid. More extensive chro matographic separation showed preferential appearance of the secretago gue in a fraction of neutral lipids enriched in monoglycerides. Among several candidate lipids, 1-mono-arachidonyl glyceride and arachidonic acid were found to mimic the effect of the cyst fluid to stimulate fl uid secretion by Madin Darby canine kidney cells; however, their abund ance in cyst fluid was insufficient to account for the degree to which secretion was stimulated by cyst fluid. Moreover, the effect of the a rachidonic acid species to stimulate fluid secretion was inhibited by treatment with indomethacin, whereas the effect of the cyst fluid was not, On the basis of this study, it was concluded that human autosomal dominant polycystic kidney disease cyst fluid contains an anonymous l ipid with the capacity to stimulate fluid secretion in renal epithelia , This potent endogenous modulator of fluid transport may have an impo rtant role in determining the rate at which cysts expand in autosomal dominant polycystic disease.