Regulation of Na+/H+ exchanger NHE3 by glucagon-like peptide 1 receptor agonist exendin-4 in renal proximal tubule cells

Autor(es)

Carraro-Lacroix, Luciene R. ^{[1, 2]} ; Malnic, Gerhard ^[1] ; Girardi, Adriana C. C. ^{[1, 3]}

Afiliação do(s) autor(es)

^[1] Univ Sao Paulo, Inst Biomed Sci, Dept Physiol & Biophys, BR-05403900 Sao Paulo - Brazil

^[2] Univ Fed Sao Paulo, Dept Physiol, Sao Paulo - Brazil

^[3] Univ Sao Paulo, Sch Med, Inst Heart, Lab Genet & Mol Cardiol, InCor, BR-05403900 Sao Paulo - Brazil

• Tipo de documento: Artigo Científico
• Fonte: AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY; v. 297, n. 6, p. F1647-F1655, DEC 2009.
• Citações Web of Science: 73

Resumo

Carraro-Lacroix LR, Malnic G, Girardi AC. Regulation of Na(+)/H(+) exchanger NHE3 by glucagon-like peptide 1 receptor agonist exendin-4 in renal proximal tubule cells. Am J Physiol Renal Physiol 297: F1647-F1655, 2009. First published September 23, 2009; doi:10.1152/ajprenal.00082.2009.-The gut incretin hormone glucagon-like peptide 1 (GLP-1) is released in response to ingested nutrients and enhances insulin secretion. In addition to its insulinotropic properties, GLP-1 has been shown to have natriuretic actions paralleled by a diminished proton secretion. We therefore studied the role of the GLP-1 receptor agonist exendin-4 in modulating the activity of Na(+)/H(+) exchanger NHE3 in LLC-PK(1) cells. We found that NHE3-mediated Na(+)-dependent intracellular pH (pH(i)) recovery decreased similar to 50% after 30-min treatment with 1 nM exendin-4. Pharmacological inhibitors and cAMP analogs that selectively activate protein kinase A (PKA) or the exchange protein directly activated by cAMP (EPAC) demonstrated that regulation of NHE3 activity by exendin-4 requires activation of both cAMP downstream effectors. This conclusion was based on the following observations: 1) the PKA antagonist H-89 completely prevented the effect of the PKA activator but only partially blocked the exendin-4-induced NHE3 inhibition; 2) the MEK1/2 inhibitor U-0126 abolished the effect of the EPAC activator but only diminished the exendin-4-induced NHE3 inhibition; 3) combination of H-89 and U-0126 fully prevented the effect of exendin-4 on NHE3; 4) no additive effect in the inhibition of NHE3 activity was observed when exendin-4, PKA, and EPAC activators were used together. Mechanistically, the inhibitory effect of exendin-4 on pHi recovery was associated with an increase of NHE3 phosphorylation. Conversely, this inhibition took place without changes in the surface expression of the transporter. We conclude that GLP-1 receptor agonists modulate sodium homeostasis in the kidney, most likely by affecting NHE3 activity. (AU)

• Processo FAPESP: 07/52945-8 - Importância do peptídeo semelhante ao glucagon 1 (GLP-1) na manutenção do volume extracelular: abordagem funcional, farmacológica e molecular
• Beneficiário: Adriana Castello Costa Girardi
• Modalidade de apoio: Auxílio à Pesquisa - Jovens Pesquisadores
• Processo FAPESP: 04/01683-5 - Estudo molecular e funcional de transportadores de íons em membranas
• Beneficiário: Gerhard Malnic
• Modalidade de apoio: Auxílio à Pesquisa - Temático