Regulation of Na+/H+ exchanger NHE3 by glucagon-like peptide 1 receptor agonist exendin-4 in renal proximal tubule cells
| Autor: | Adriana C. C. Girardi, Luciene Regina Carraro-Lacroix, G Malnic |
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| Rok vydání: | 2009 |
| Předmět: |
Agonist
endocrine system medicine.medical_specialty Sodium-Hydrogen Exchangers Physiology medicine.drug_class Swine Intracellular pH Glucagon-Like Peptide-1 Receptor Kidney Tubules Proximal Internal medicine medicine Cyclic AMP Receptors Glucagon Animals Homeostasis Phosphorylation Protein kinase A Receptor Protein Kinase Inhibitors Glucagon-like peptide 1 receptor Sulfonamides urogenital system Activator (genetics) Chemistry Sodium-Hydrogen Exchanger 3 Venoms digestive oral and skin physiology Sodium Intracellular Membranes Hydrogen-Ion Concentration Isoquinolines Cyclic AMP-Dependent Protein Kinases Rats Sodium–hydrogen antiporter Endocrinology Exenatide LLC-PK1 Cells Peptides Signal Transduction |
| Zdroj: | American journal of physiology. Renal physiology. 297(6) |
| ISSN: | 1522-1466 |
| Popis: | 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-PK1cells. We found that NHE3-mediated Na+-dependent intracellular pH (pHi) recovery decreased ∼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 pHirecovery 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. |
| Databáze: | OpenAIRE |
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