Role of glucagon-like peptide-1 as a mediator of the interaction between NHE3 and dipeptidyl peptidase IV in renal proximal tubule

Abstract

The proximal tubule plays a central role in the regulation of extracellular volume since it is responsible for roughly two-thirds of the reabsorption of the sodium filtered in the glomeruli. In the proximal tubule, the principal apical membrane pathway for reabsorption of Na+ and secretion of H+ is Na+-H+ exchange mediated by the isoform 3 of the exchanger Na+/H+ (NHE3). The activity of NHE3 is modified by a series of molecular mechanisms, among which are associated with other proteins. It has been previously shown that dipeptidyl peptidase IV (DPPIV) physically associates with NHE3 in the apical membrane of the renal proximal tubule. Previous studies in vitro and in vivo revealed a connection between inhibition of the catalytic activity of DPPIV and the NHE3 activity, demonstrating the existence of physical and functional interaction between these two proteins. A large number of peptide hormones are cleaved by DPPIV in vitro; however, much fewer peptides were identified as physiological substrates for DPPIV in vivo. Among them, is the glucagon-like peptide-1 (GLP-1). GLP-1 and its analogs exert natriuretic effects in humans and in experimental models, and it is believed that this mechanism is related, at least in part, to the reduction of proximal tubular function. Corroborating with the natriuretic actions of GLP-1 in the proximal tubule, our group demonstrated that both GLP-1 and the GLP-1 receptor agonist, exendin-4, inhibit the activity of NHE3 in this nephron segment. Based on these data, we point out the peptide GLP-1 as a potential candidate to mediate the functional interaction between NHE3 and DPPIV. In light of these facts, this study aims to evaluate the possible role of GLP-1 as a mediator of the interaction between NHE3 and DPPIV in the renal proximal tubule. The hypothesis that the GLP-1R receptor physically interacts with NHE3 and DPPIV forming a protein complex in the apical membrane of the proximal tubule will also be tested.(AU)