on March 16, 2009
Published online before print March 16, 2009, doi: 10.1161/HYPERTENSIONAHA.108.128264
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Submitted on December 19, 2008
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. * To whom correspondence should be addressed. E-mail: mgoy{at}med.unc.edu.
Abstract—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
Revised on January 7, 2009
The Natriuretic Peptide Uroguanylin Elicits Physiologic Actions Through 2 Distinct Topoisomers
Nicholas G. Moss;
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