SALT AND WATER HOMEOSTASIS - UROGUANYLIN IS A CIRCULATING PEPTIDE-HORMONE WITH NATRIURETIC ACTIVITY

Guanylin and uroguanylin are small, heat-stable peptides that were ini tially isolated from rat jejunum and opossum urine, respectively, Both peptides bind to and activate a common set of apical membrane recepto rs that contain a guanylate cyclase catalytic domain within the recept or molecule. The guanylin/uroguanylin receptors are found on the lumin al surface of epithelial cells lining the intestinal tract and renal p roximal tubules as well as in other organs, Activation of receptor-gua nylate cyclase signaling molecules by uroguanylin or guanylin elicits large increases in guanosine cyclic 3'-5' monophosphate (cGMP) product ion, Intracellular accumulation of this second messenger in target cel ls leads to the stimulation of intestinal chloride secretion, culminat ing in the enhancement of salt and water secretion into the intestinal lumen as well as increases in urinary sodium, potassium, and water ex cretion by actions of cGMP in the renal tubules. Uroguanylin and guany lin are produced throughout the intestinal mucosa and, surprisingly, u roguanylin messenger RNA (mRNA) is also expressed in both atria and ve ntricles of the heart, Both proguanylin and prouroguanylin are inactiv e polypeptides, and activation is accomplished by cleavage and release of the COOH-terminal peptides, guanylin and uroguanylin, Uroguanylin is postulated to function as an intestinal natriuretic hormone because : (1) prouroguanylin and uroguanylin both circulate in the plasma of n ormal animals; (2) uroguanylin is the predominant peptide agonist appe aring in the filtrate and, thus, in urine; (3) the receptors for urogu anylin are localized to the apical membranes of renal tubular cells; ( 4) uroguanylin is substantially more potent than guanylin in eliciting a natriuresis; and (5) uroguanylin is expressed in the duodenum and m yocardium, which are appropriate sites in the body for the production and release of a hormone that acts as a natriuretic agonist in vivo, T he hypothesis that uroguanylin links the intestine with the kidney in an endocrine axis also predicts that the secretion of uroguanylin from the intestinal mucosa will be influenced by dietary levels of salt, A ccordingly, plasma levels of uroguanylin or prouroguanylin should be i nfluenced by oral salt loads. Future investigations will focus on the basic endocrinology of uroguanylin to provide answers to this intrigui ng question, In conclusion, uroguanylin is a candidate for a physiolog ical role as an intestinal natriuretic hormone, Key features of the bi ology of uroguanylin provide a putative explanation for the substantia l natriuresis that occurs in human subjects and experimental animals a fter an oral salt load. Moreover, uroguanylin and guanylin participate cooperatively in an intrinsic pathway for regulation of intestinal sa lt and water transport, thus providing another means of influencing sa lt and water homeostasis in addition to the renal actions of uroguanyl in. (C) 1996 by the National Kidney Foundation, Inc.