Dietary salt regulates uroguanylin expression and signaling activity in the kidney, but not in the intestine

The peptide uroguanylin (Ugn) is expressed at significant levels only in intestine and kidney, and is stored in both tissues primarily (perhaps exclusively) as intact prouroguanylin (proUgn). Intravascular infusion of either Ugn or proUgn evokes well‐characterized natriuretic responses in rodents. Furthermore, Ugn knockout mice display hypertension and salt handling deficits, indicating that the Na(+) excretory mechanisms triggered when the peptides are infused into anesthetized animals are likely to operate under normal physiological conditions, and contribute to electrolyte homeostasis in conscious animals. Here, we provide strong corroborative evidence for this hypothesis, by demonstrating that U(U) (gn)V (the rate of urinary Ugn excretion) approximately doubled in conscious, unrestrained rats consuming a high‐salt diet, and decreased by ~15% after salt restriction. These changes in U(U) (gn)V were not associated with altered plasma proUgn levels (shown here to be an accurate index of intestinal proUgn secretion). Furthermore, enteric Ugn mRNA levels were unaffected by salt intake, whereas renal Ugn mRNA levels increased sharply during periods of increased dietary salt consumption. Together, these data suggest that diet‐evoked Ugn signals originate within the kidney, rather than the intestine, thus strengthening a growing body of evidence against a widely cited hypothesis that Ugn serves as the mediator of an entero‐renal natriuretic signaling axis, while underscoring a likely intrarenal natriuretic role for the peptide. The data further suggest that intrarenal Ugn signaling is preferentially engaged when salt intake is elevated, and plays only a minor role when salt intake is restricted.