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

Abstracts from the 8th International Conference on cGMP Generators, Effectors and Therapeutic Implications

This work was supported by a restricted research grant of Bayer AG

CD4(+) T cells and CXC chemokines modulate the pathogenesis of Staphylococcus aureus wound infections

T cells are critical for the formation of intraabdominal abscesses by Staphylococcus aureus. We hypothesized that T cells modulate the development of experimental staphylococcal infections by controlling polymorphonuclear leukocyte (PMN) trafficking. In models of staphylococcal s.c. abscess formation, hindpaw infection, and surgical wound infection, S. aureus multiplied in the tissues of WT C57BL/6J mice and elicited a marked inflammatory response. CD4(+) αβ T cells homed to the surgical wound infection site of WT animals. In contrast, significantly fewer S. aureus were recovered from the tissues of mice deficient in αβ T cells, and the inflammatory response was considerably diminished compared with that of WT animals. αβ T cell receptor (−/−) mice had significantly lower concentrations of PMN-specific CXC chemokines in wound tissue than did WT mice. The severity of the wound infection was enhanced by administration of a CXC chemokine and abrogated by antibodies that blocked the CXC receptor. An acapsular mutant was less virulent than the parental S. aureus strain in both the s.c. abscess and the surgical wound infection models in WT mice. These data reveal an important and underappreciated role for CD4(+) αβ T cells in S. aureus infections in controlling local CXC chemokine production, neutrophil recruitment to the site of infection, and subsequent bacterial replication