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This Article Full Text Full Text (PDF) All Versions of this Article: 297/6/F1647    most recent 00082.2009v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Carraro-Lacroix, L. R. Articles by Girardi, A. C. C. PubMed PubMed Citation Articles by Carraro-Lacroix, L. R. Articles by Girardi, A. C. C.

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

¹Department of Physiology and Biophysics, Institute of Biomedical Sciences; ; ²Heart Institute (InCor), Medical School, University of São Paulo, and ; ³Department of Physiology, Federal University of São Paulo, São Paulo, Brazil

Submitted February 12, 2009 ; accepted in final form September 17, 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-PK₁ cells. We found that NHE3-mediated Na⁺-dependent intracellular pH (pH_i) 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 pH_i 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.

dipeptidyl peptidase IV; sodium reabsorption; intracellular pH; protein kinase A; exchange protein directly activated by cAMP