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. 2009 Dec;297(6):F1647-55. doi: 10.1152/ajprenal.00082.2009. Epub 2009 Sep 23.


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 approximately 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cyclic AMP / metabolism
  • Cyclic AMP-Dependent Protein Kinases / antagonists & inhibitors
  • Exenatide
  • Glucagon-Like Peptide-1 Receptor
  • Homeostasis / drug effects
  • Hydrogen-Ion Concentration / drug effects
  • Intracellular Membranes / metabolism
  • Isoquinolines / pharmacology
  • Kidney Tubules, Proximal / cytology
  • Kidney Tubules, Proximal / drug effects*
  • Kidney Tubules, Proximal / metabolism*
  • LLC-PK1 Cells
  • Peptides / pharmacology*
  • Phosphorylation
  • Protein Kinase Inhibitors / pharmacology
  • Rats
  • Receptors, Glucagon / agonists*
  • Signal Transduction / physiology
  • Sodium / metabolism
  • Sodium-Hydrogen Exchanger 3
  • Sodium-Hydrogen Exchangers / metabolism*
  • Sulfonamides / pharmacology
  • Swine
  • Venoms / pharmacology*


  • Glp1r protein, rat
  • Glucagon-Like Peptide-1 Receptor
  • Isoquinolines
  • Peptides
  • Protein Kinase Inhibitors
  • Receptors, Glucagon
  • Slc9a3 protein, rat
  • Sodium-Hydrogen Exchanger 3
  • Sodium-Hydrogen Exchangers
  • Sulfonamides
  • Venoms
  • Sodium
  • Exenatide
  • Cyclic AMP
  • Cyclic AMP-Dependent Protein Kinases
  • N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide