Aldosterone inhibits apical NHE3 and HCO3- absorption via a nongenomic ERK-dependent pathway in medullary thick ascending limb

Am J Physiol Renal Physiol. 2006 Nov;291(5):F1005-13. doi: 10.1152/ajprenal.00507.2005. Epub 2006 Jun 6.


Although aldosterone influences a variety of cellular processes through nongenomic mechanisms, the significance of nongenomic pathways for aldosterone-induced regulation of epithelial function is not understood. Recently, we demonstrated that aldosterone inhibits transepithelial HCO(3)(-) absorption in the medullary thick ascending limb (MTAL) through a nongenomic pathway. This inhibition is mediated through a direct cellular action of aldosterone to inhibit the apical membrane NHE3 Na(+)/H(+) exchanger. The present study was designed to identify the intracellular signaling pathway(s) responsible for this aldosterone-induced transport regulation. In rat MTALs perfused in vitro, addition of 1 nM aldosterone to the bath decreased HCO(3)(-) absorption by 30%. This inhibition was not mediated by cAMP/PKA and was not prevented by inhibitors of PKC or PI3-K, pertussis toxin, or rapamycin. The inhibition of HCO(3)(-) absorption by aldosterone was largely eliminated by the MEK/ERK inhibitors U-0126 and PD-98059. Aldosterone increased ERK activity 1.8-fold in microdissected MTALs. This ERK activation is rapid (</=5 min) and is blocked by U-0126 or PD-98059 but is unaffected by spironolactone or actinomycin D. Pretreatment with U-0126 to block ERK activation prevented the effect of aldosterone to inhibit apical NHE3. These data demonstrate that aldosterone inhibits NHE3 and HCO(3)(-) absorption in the MTAL through rapid activation of the ERK signaling pathway. The results identify NHE3 as a target for nongenomic regulation by aldosterone and establish a role for ERK in the acute regulation of NHE3 and its epithelial absorptive functions.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Aldosterone / metabolism*
  • Aldosterone / pharmacology
  • Animals
  • Bicarbonates / metabolism*
  • Cell Polarity
  • Cyclic AMP / metabolism
  • Enzyme Activation / drug effects
  • Enzyme Activation / physiology
  • Epithelial Cells / drug effects
  • Epithelial Cells / metabolism
  • GTP-Binding Proteins / metabolism
  • In Vitro Techniques
  • Kidney Medulla / metabolism
  • Loop of Henle / metabolism*
  • MAP Kinase Signaling System / drug effects
  • MAP Kinase Signaling System / physiology*
  • Male
  • Mitogen-Activated Protein Kinase 1 / metabolism
  • Mitogen-Activated Protein Kinase 3 / metabolism
  • Pertussis Toxin / pharmacology
  • Phosphatidylinositol 3-Kinases / metabolism
  • Protein Kinase C / metabolism
  • Protons
  • Rats
  • Rats, Sprague-Dawley
  • Ribosomal Protein S6 Kinases, 70-kDa / metabolism
  • Sodium / metabolism
  • Sodium-Hydrogen Exchanger 3
  • Sodium-Hydrogen Exchangers / metabolism*


  • Bicarbonates
  • Protons
  • Slc9a3 protein, rat
  • Sodium-Hydrogen Exchanger 3
  • Sodium-Hydrogen Exchangers
  • Aldosterone
  • Sodium
  • Cyclic AMP
  • Pertussis Toxin
  • Phosphatidylinositol 3-Kinases
  • Ribosomal Protein S6 Kinases, 70-kDa
  • Protein Kinase C
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3
  • GTP-Binding Proteins