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Am J Physiol Renal Physiol 280: F415-F425, 2001;
0363-6127/01 $5.00
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Vol. 280, Issue 3, F415-F425, March 2001

alpha 1-Adrenergic receptors activate NHE1 and NHE3 through distinct signaling pathways in epithelial cells

Fengming Liu and Frank A. Gesek

Department of Pharmacology and Toxicology, Dartmouth Medical School, Hanover, New Hampshire 03755

The Na+/H+ exchanger (NHE) regulates intracellular pH, cell volume, Na+ absorption and H+ secretion in epithelial cells of the renal proximal tubule (PT). alpha 1-Adrenergic receptors (ARs) increase NHE activity in PT cells. The purpose of this study was to determine the mechanism of alpha 1-AR activation of NHE isoforms expressed in PT cells. Northern and Western blotting demonstrate transcripts and protein expression of NHE1 and NHE3 in PT cells. An anti-NHE1 antibody predominately labels protein expressed at basal and lateral membranes. In contrast, NHE3 protein is expressed exclusively at the apical membrane. To determine NHE isoforms regulated by alpha 1-ARs, antisense oligodeoxynucleotides (AS-ODNs) specific for NHE1 and NHE3 isoforms were introduced into cells with streptolysin O permeabilization. Cells incubated with AS-ODNs a total of three times exhibited a reduction in protein expression of ~85%. Na uptake and changes in intracellular pH (pHi) were used as measures of NHE activity in PT cells. alpha 1-AR stimulation increased Na uptake from 8.5 to 13.8 nmol · min-1 · mg protein-1. AS-ODNs to NHE3 significantly reduced alpha 1-AR stimulated Na uptake and increases in pHi; no effect was observed in sense-ODN-treated cells. Inhibition of NHE1 but not NHE3 expression abolishes amiloride-suppressible NHE activity. alpha 1-AR stimulation of NHE1 is inhibited by the protein kinase C (PKC) inhibitor calphostin C whereas NHE3 activity is abolished by the mitogen-activated protein kinase (MAPK) inhibitor PD-98059. In PT cells transfected with MAPK kinase MEKK1COOH, a truncated version of MEKK1 that activates MAPK, NHE3 but not NHE1 activity is stimulated. We conclude that alpha 1-ARs activate distinct signaling pathways to regulate specific NHE isoforms localized on opposite membranes in polarized renal epithelial cells. alpha 1-AR activation of NHE1 is regulated by PKC whereas NHE3 is controlled by MAPK and serves to separately regulate pHi, Na absorption, and proton excretion in PT cells.

antisense oligonucleotide; intracellular pH; mitogen-activated protein kinase; sodium-hydrogen exchanger; protein kinase C; proximal tubule


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