ANGIOTENSIN II REGULATION OF ENTERIC OXALATE ELIMINATION

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Approximately one million cases of stone diseases are diagnosed in the United States every year. Most kidney stones (80%) are comprised of calcium oxalate and a major risk factor in this disease is elevated urinary oxalate excretion. The broad aims are to investigate and enhance elimination of oxalate into the large intestine where it can be innocuously degraded by the substrate-specific bacteria (Oxalobacter sp.) which reside exclusively in this segment of the alimentary tract. The specific aims of this proposal focus on the signals involved in shifting the balance from renal to enteric oxalate elimination and on the modulation of this colonic oxalate secretion and excretion. Three key pieces of information have emerged from our recent studies of colonic oxalate transport in rats with chronic renal failure (CRF). 1). The large intestine is the primary site for the CRF-induced adaptation where basal oxalate absorption is reversed to a secretory flux inhibitable by angiotensin II (ANG II, subtype AT1) receptor antagonists. 2). In CRF rat intestine, AT1 receptors are up-regulated exclusively in the large intestinal segment. 3). The effects of AT1 receptor agonism and antagonism on oxalate transport in the CRF rat can be simulated in vitro in a control rat which normally supports a basal absorptive flux of oxalate. Together, these observations imply that ANG II plays a role in local modulation of colonic oxalate secretion. The working hypothesis to be tested is that the balance between renal and enteric oxalate elimination is modulated by an up- regulation in colonic AT1 receptors. The research plan is divided into two interrelated parts and involves using a cultured cell model along with a variety of animal models created in an effort to simulate human hyperoxaluric/hyperoxalemic conditions. Pr I is aimed at examining the signals involve din initiating the local up-regulation of colonic T1 receptors in oxalate secreting colonic tissues. In Part II, the signaling transduction pathways involved in coupling AT1 receptor agonism to the transport systems initiating oxalate secretion will be addressed. The outcome of the propose studies will provide a significant advance in our fundamental understanding of adaptations in oxalate handling in kidney disease. The potential for oxalate excretion into the lumen of the large intestine, where it can be degraded by Oxalobacter enzymes, provides for a "sump" mechanism which, is exploited, could have significant impact on reducing hyperoxalemia, hyperoxaluria, oxalosis, and the resulting various pathophysiological and debilitating conditions.