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1 Departments of Cellular and Molecular Physiology, and 2 Internal Medicine, Yale University School of Medicine, New Haven, Connecticut 06520-8029; and 3 Department of Molecular Genetics, Biochemistry, and Microbiology, University of Cincinnati College of Medicine, Cincinnati, Ohio 45267-0524
NHE3 is the predominant isoform responsible for apical membrane
Na+/H+
exchange in the proximal tubule. Deletion of NHE3 by gene targeting results in an NHE3
/
mouse with greatly reduced proximal tubule
HCO3 absorption compared with
NHE3+/+ animals (P. J. Schultheis, L. L. Clarke, P. Meneton, M. L. Miller, M. Soleimani,
L. R. Gawenis, T. M. Riddle, J. J. Duffy, T. Doetschman, T. Wang, G. Giebisch, P. S. Aronson, J. N. Lorenz, and G. E. Shull. Nature Genet. 19: 282-285, 1998).
The purpose of the present study was to evaluate the role of other
acidification mechanisms in mediating the remaining component of
proximal tubule HCO3 reabsorption in
NHE3/ mice. Proximal
tubule transport was studied by in situ microperfusion. Net rates of
HCO3 (JHCO3) and fluid
absorption (Jv)
were reduced by 54 and 63%, respectively, in NHE3 null mice compared
with controls. Addition of 100 µM ethylisopropylamiloride (EIPA) to
the luminal perfusate caused significant inhibition of
JHCO3 and
Jv in
NHE3+/+ mice but failed to inhibit
JHCO3 or
Jv in
NHE3/ mice,
indicating lack of activity of NHE2 or other EIPA-sensitive NHE
isoforms in the null mice. Addition of 1 µM bafilomycin
caused a similar absolute decrement in
JHCO3 in
wild-type and NHE3 null mice, indicating equivalent rates of
HCO3 absorption mediated by
H+-ATPase. Addition of 10 µM
Sch-28080 did not reduce
JHCO3 in either wild-type or NHE3 null mice, indicating lack of detectable
H+-K+-ATPase
activity in the proximal tubule. We conclude that, in the absence of
NHE3, neither NHE2 nor any other EIPA-sensitive NHE isoform contributes
to mediating HCO3 reabsorption in the
proximal tubule. A significant component of
HCO3 reabsorption in the proximal
tubule is mediated by bafilomycin-sensitive H+-ATPase, but its activity
is not significantly upregulated in NHE3 null mice.
sodium/proton exchange; proton-adenosinetriphosphatase; proton-potassium-adenosinetriphosphatase; acidification
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