EVIDENCE FOR INFLAMMATORY AND SECRETAGOGUE LIPIDS IN CYST FLUIDS FROMPATIENTS WITH AUTOSOMAL-DOMINANT POLYCYSTIC KIDNEY-DISEASE

Advanced autosomal dominant polycystic kidney disease (ADPKD) is chara cterized morphologically by massive cyst enlargement, moderate interst itial infiltration with mononuclear cells, and extensive fibrosis. In patients affected by a common genotype (PKD1), it has been suggested t hat the progressive decline in renal function that transpires over a h ighly variable time course may be due to endogenous or exogenous epige netic factors. We have postulated that a neutral lipid, discovered in human cyst fluid and stimulating the rates of transepithelial fluid se cretion and cellular proliferation of renal epithelial cells in vitro may have a potential role in cyst growth and the progressive decline o f kidney function. In this study, we used thin-layer chromatography (T LC) and high-performance TLC (HPTLC) to determine whether lipid extrac ts of human cyst fluid stimulated monocyte chemotaxis in vitro. Monocy te chemotactic activity, determined by the transmembrane migration of murine RAW 264.7 cells, was stimulated (Delta 26.0 +/- 1.5 optical den sity units) by a lipid fraction less polar than sphingosine but more p olar by TLC and HPTLC than I-monooleoylglycerol. A high level of secre tagogue activity was detected in this fraction (Delta 0.336 +/- 0.022 mu l/cm(2) 1 hr) and to a lesser extent (Delta 0.253 +/- 0.022 mu l/cm (2)/hr) in a neighboring fraction that encompassed the l-monooleoylgly cerol standard. Cyst fluid with undetectable secretagonue activity had a monocyte chemotactic activity level only 18% as great as fluids wit h high levels of secretagogue activity. The secretagogue and chemotact ic activities in TLC-HPTLC fractions were resistant to treatment with KOH, but both were diminished by HCl, borohydride, or periodate. Rat p roximal tubule cultures incubated with oleate complexed with albumin e laborated secretagogue and chemotactic activities in the conditioned m edium, with TLC-HPTLC mobility characteristics similar to the biologic ally active cyst fluid lipids. On the basis of these studies, we concl ude that human cyst fluids harbor potent secretagogue and chemotactic lipids that may have a role in determining the functional course of AD PKD. On the basis of preliminary chemical characterizations, we sugges t that the secretatogue and monocyte chemotactic activities of cyst fl uid may reflect the action of lipid molecules of similar structure, th e source of which may be renal epithelial cells.