title: The physiological role of glucagon-like peptide-1 in the regulation of renal function.
abstract: Glucagon like peptide-1 (GLP-1) is an incretin hormone constantly secreted from the intestine at low basal levels in the fasted state; plasma concentrations rise rapidly after nutrient ingestion. Upon release, GLP-1 exerts insulinotropic effects via a G protein-coupled receptor, stimulation of adenylyl cyclase, and cAMP generation. Although primarily involved in glucose homeostasis, GLP-1 can induce diuresis and natriuresis when administered in pharmacological doses in humans and rodents. However, whether endogenous GLP-1 plays a role in regulating renal function remains an open question. This study aimed to test the hypothesis that blockade of GLP-1 receptor (GLP-1R) signaling at baseline influences renal salt and water handling. To this end, the GLP-1R antagonist exendin-9 (100 μg·kg(-1)·min(-1)) or vehicle was administered intravenously to overnight-fasted male Wistar rats for 30 min. This treatment reduced urinary cAMP excretion and renal cortical PKA activity, demonstrating blockade of renal GLP-1R signaling. Exendin-9-infused-rats exhibited reduced glomerular filtration rate, lithium clearance, urinary volume flow, and sodium excretion compared with vehicle-infused controls. Exendin-9 infusion also reduced renal cortical Na(+)/H(+) exchanger isotope 3 (NHE3) phosphorylation at serine 552 (NHE3pS552), a PKA consensus site that correlates with reduced transport activity. Collectively, these results provide novel evidence that GLP-1 is a physiologically relevant natriuretic factor that contributes to sodium balance, in part via tonic modulation of NHE3 activity in the proximal tubule.
authors.affiliation: Heart Institute (InCor), University of São Paulo, São Paulo, Brazil;
authors.forename: Lívia X S
authors.initials: LX
authors.lastname: Farah
authors.affiliation: Heart Institute (InCor), University of São Paulo, São Paulo, Brazil;
authors.forename: Vanessa
authors.initials: V
authors.lastname: Valentini
authors.affiliation: Department of Physiology and Biophysics, University of São Paulo, São Paulo, Brazil; and.
authors.forename: Thaissa D
authors.initials: TD
authors.lastname: Pessoa
authors.affiliation: Department of Physiology and Biophysics, University of São Paulo, São Paulo, Brazil; and.
authors.forename: Gerhard
authors.initials: G
authors.lastname: Malnic
authors.affiliation: Keck School of Medicine, University of Southern California, Los Angeles, California.
authors.forename: Alicia A
authors.initials: AA
authors.lastname: McDonough
authors.affiliation: Heart Institute (InCor), University of São Paulo, São Paulo, Brazil; adriana.girardi@incor.usp.br.
authors.forename: Adriana C C
authors.initials: AC
authors.lastname: Girardi
mesh_terms: D000818:Animals; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D005919:Glomerular Filtration Rate / Q000187:drug effects; D000067757:Glucagon-Like Peptide-1 Receptor / Q000037:antagonists & inhibitors*; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D009318:Natriuresis / Q000187:drug effects*; D045283:Natriuretic Agents / Q000494:pharmacology*; D010446:Peptide Fragments / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects; D017923:Sodium-Hydrogen Exchangers / Q000378:metabolism
chemical_list: D000067757:Glucagon-Like Peptide-1 Receptor; D045283:Natriuretic Agents; D010446:Peptide Fragments; D017923:Sodium-Hydrogen Exchangers; C083773:exendin (9-39); D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases
keywords: GLP-1; NHE3; incretin; proximal tubule