Evidence for a potent lipid secretagogue in the cyst fluids of patients with autosomal dominant polycystic kidney disease.

Abstract

Transepithelial fluid secretion appears to be an important factor in the progressive enlargement of cysts in autosomal dominant polycystic kidney disease. Evidence indicates that the fluid within cysts harbors an autocrine, paracrine, or endocrine secretagogue with the capacity to 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 secretagogue. The secretory activity of cyst fluid assayed with polarized monolayers of Madin Darby canine kidney cells could be ascribed to a lipophilic substance of molecular weight < 3,500 d that was not destroyed by freezing, boiling, or proteolytic digestion. This lipid stimulated the production of intracellular cAMP and increased the rate of fluid secretion when added to either surface of cultured renal epithelial cells. Anion exchange chromatography revealed biologic secretory activity to a greater extent in the neutral lipid than in the fatty acid and phospholipid fractions separated from cyst fluid. More extensive chromatographic separation showed preferential appearance of the secretagogue 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 fluid secretion by Madin Darby canine kidney cells; however, their abundance in cyst fluid was insufficient to account for the degree to which secretion was stimulated by cyst fluid. Moreover, the effect of the arachidonic 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 lipid with the capacity to stimulate fluid secretion in renal epithelia. This potent endogenous modulator of fluid transport may have an important role in determining the rate at which cysts expand in autosomal dominant polycystic disease.