The Natriuretic Peptide Uroguanylin Elicits Physiologic Actions Through 2 Distinct Topoisomers

The peptide uroguanylin regulates electrolyte transport in the intestine and kidney. Human uroguanylin has two conformations that can be stably isolated, owing to 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 saliuretic responses, but the activity profiles for the two peptides differ markedly. The uroguanylin B dose-response curve is sigmoidal with a threshold dose near 10 nmol/kg body weight, whereas uroguanylin A has a comparable threshold, but a bell-shaped dose-response curve. Additionally, 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 whose 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