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(Hypertension. 2009;53:867.)
© 2009 American Heart Association, Inc.

Original Articles

The Natriuretic Peptide Uroguanylin Elicits Physiologic Actions Through 2 Distinct Topoisomers

Nicholas G. Moss; Dorothy A. Riguera; Robert M. Solinga; Marco M. Kessler; Daniel P. Zimmer; William J. Arendshorst; Mark G. Currie; Michael F. Goy

From the Department of Cell and Molecular Physiology (N.G.M., D.A.R., W.J.A., M.F.G.), University of North Carolina, Chapel Hill; and Ironwood Pharmaceuticals (R.M.S., M.M.K., D.P.Z., M.G.C.), Cambridge, Mass.

Correspondence to Michael F. Goy, University of North Carolina at Chapel Hill, Department of Cell and Molecular Physiology, 5309B Medical Biomolecular Research Building, CB#7545, 111 Mason Farm Rd, Chapel Hill, NC 27599. E-mail mgoy{at}med.unc.edu

The peptide uroguanylin regulates electrolyte transport in the intestine and kidney. Human uroguanylin has 2 conformations that can be stably isolated because of their slow interconversion rate. The A isomer potently activates the guanylate cyclase C receptor found primarily in the intestine. The B isomer, by contrast, is a very weak agonist of this receptor, leading to a widely held assumption that it is physiologically irrelevant. We show here, however, that human uroguanylin B has potent natriuretic activity in the kidney. Interestingly, uroguanylin A and B both induce saluretic responses, but the activity profiles for the 2 peptides differ markedly. The uroguanylin B dose-response curve is sigmoidal with a threshold dose of 10 nmol/kg of body weight, whereas uroguanylin A has a comparable threshold but a bell-shaped dose-response curve. In addition, our study indicates a unique interplay between the A and B isoforms, such that the A form at high concentrations antagonizes the natriuretic action of the B form. These data show that the kidney contains a uroguanylin receptor of which the pharmacological profile does not match that of the well-defined intestinal uroguanylin receptor (guanylate cyclase C), an observation consistent with previous studies showing that the kidney of the guanylate cyclase C knockout mouse remains responsive to uroguanylin. The results presented here also support the unconventional notion that distinct conformations of a single endocrine peptide can elicit different responses in different tissues.

Key Words: sodium excretion • natriuretic peptide • hypertension • electrolyte homeostasis • uroguanylin • peptide isomerization