The formation and enlargement of renal cysts depends on the abnormal accumulation of fluid by transepithelial secretion. Fluid secretion in human autosomal dominant polycystic kidney disease (ADPKD) cysts can be stimulated by the production of cyclic AMP within the epithelial cells. Thus, the rate of cyst filling with fluid may be increased by the stimulation of cyclic AMP formation by endocrine, paracrine, and autocrine substances that activate adenylate cyclase or inhibit cyclic AMP phosphodiesterase. A potent endogenous secretagogue has recently been identified within polycystic kidneys. Fluid within the cysts of individuals with ADPKD contains a novel neutral lipid that causes increased secretion of NaCl and fluid by human ADPKD cyst epithelium in vitro. This apparently unique lipid stimulates cellular cyclic AMP accumulation and increases transepithelial short circuit current, giving net chloride secretion, in renal epithelial cells. The cyst fluid lipid also stimulates the proliferation of cyst epithelial cells and is a potent monocyte chemoattractant. In view of these features this lipid or family of lipids has been named cyst activating factor (CAF). It is hypothesized that CAF is a potent lipid product of renal cyst formation in ADPKD and functions as a progression factor that accelerates pathogenesis by increasing cellular proliferation, stimulating transepithelial fluid secretion, and promoting interstitial inflammation and fibrosis. This proposal aims to: 1) Purify to homogeneity CAF from ADPKD cyst fluid and determine its molecular structure by appropriate analytical, biochemical, and biophysical techniques; and 2) to characterize the metabolism of CAF in cultured renal tubule epithelial cells. The achievement of these aims requires the application of techniques in cell biology, cell physiology, analytical biochemistry, and biochemistry. The applicant believes that the successful completion of these aims will shed light upon the chemical nature and potential roles of a newly recognized renal lipid that is specifically relevant to the pathogenesis of polycystic kidney disease, and may provide information relevant to other disorders that culminate in progressive renal destruction.
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