LIPIDS AND UROLITHIASIS

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DESCRIPTION (Adapted from the Applicant's Abstract): Urinary stone formation is a common human disease accounting for about 1% of hospital admissions in the United States. It is estimated that in the US alone, treatment of the stone related disorders cost at least 2.4 billion dollars/year. Recurrence rate is up to 60% and one third of the patients with recurrent kidney stones may lose the involved kidney. Seventy to eighty percent of the stones contain calcium oxalate (CaOx). Initial event in urinary stone formation is crystal nucleation which is determined to be heterogeneous. Cellular degradation products and membrane bound vesicles are common in mammalian urine and calcific urinary stones. Membrane bound vesicles can induce nucleation which is determined to be phosphate (CaP) and CaOx in vitro. Both CaP and CaOx crystals produced in rat kidneys are almost always formed in association with the membranous vesicles. Based on these observations nucleation of calcific crystals in urine is proposed to be mediated by cellular membranes and their lipids. All vesicles may however not be endowed with the capabilities to nucleate crystals. Apparently there are specific domains on membrane surfaces and only the vesicles with those domains can induce crystal nucleation. What are those domains? How do they become available to the contents of the renal tubular fluid or urine? Goals of this project are to find answers to these and related questions and to develop an understanding of the mechanisms involved in membrane associated crystallization of calcium containing crystals. CaOx crystalluria and nephrolithiasis will be induced in male Sprague-Dawley rats. Lipids associated with the urinary and renal crystal events will be isolated and identified to determine any specificity. CaOx crystal formation will be induced in vitro by incubation of membrane vesicles in a metastable solution of CaOx. Crystal associated vesicles will be separated from the non-crystal associated vesicles by density gradient centrifugation. Lipids of both types of vesicles will be isolated and identified. To investigate actions of various phospholipids, Langmuir monolayers containing specific lipid combinations will be made and their role in nucleation and growth of CaOx crystals will be examined.