Mechanisms of action of uroguanylin and guanylin and their role in salt handling

Guanylin (GN) peptides belong to the growing family of natriuretic peptides. While atrial natriuretic peptide (ANP) is predominantly produced in the heart and causes natriuresis in the kidney [1], it was suggested that GN peptides are intestinal peptides that have effects on the kidney. GN peptides are small peptides with 15–19 amino acids. To this family belongs GN, originally isolated from rat intestine [2]. A second member of this family was isolated from opossum urine and is called uroguanylin (UGN) [3]. Two new members, renoguanylin [4] and lymphoguanylin [5], were recently discovered; however, their physiological role is still unknown. The mechanism of the action of GN and UGN in the intestine is well-known. It is assumed that they act similarly in several other organs that express these peptides, like airways, pancreas, testis, salivary gland and sweat glands. In the kidney, however, the signalling mechanisms and their actions are diverse. Enterochromaffin cells along the intestine secrete GN and UGN into the intestinal lumen [6,7]. Both hormones activate the membrane-bound guanylate cyclase C (GC-C) and increase the intracellular concentration of cGMP [2,3], which inhibits Naþ absorption mediated via apical Naþ/Hþ exchange (NHE) and activates the protein kinase G II. In addition, cGMP increases cAMP in the cell via inhibition of phosphodiesterase III, which activates protein kinase A. Protein kinase G II and protein kinase A increase the secretion of Cl , HCO 3 and water via activation of the cystic fibrosis transmembrane conductance regulator (CFTR) (for a review see [8]). The digestive system communicates with other organs in response to food via the secretion of hormones into the circulation, e.g. via gastric inhibitory polypeptide and glucagon-like peptide-1, which leads to increased insulin levels even before the glucose reaches the blood, preventing hyperglycaemia after a meal. The same mechanism seems to work in the case of salt intake. Salt taken orally leads to a more pronounced natriuresis than salt injected intravenously [9]. With the first description of GN peptides it was hypothesized that they act as intestinal natriuretic peptides. It is still not completely resolved whether GN peptides work in such an endocrine manner and/or whether their action is paracrine in those organs that express and secrete these peptides, such as the kidney.