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1 Department of Medicine and Physiology & Biophysics, University of Texas Medical Branch, Galveston, TX, USA
2 Department of Molecular Genetics, Biochemistry, and Microbiology, University of Cincinnati College of Medicine, Cincinnati, OH, USA
* To whom correspondence should be addressed. E-mail: dgood{at}utmb.edu.
In the medullary thick ascending limb (MTAL) of rat kidney, inhibiting basolateral Na+/H+ exchange with either amiloride or nerve growth factor (NGF) results secondarily in inhibition of apical Na+/H+ exchange, thereby decreasing transepithelial HCO-3 absorption. To assess the possible role of the Na+/H+ exchanger NHE1 in this regulatory process, MTALs from wild-type and NHE1 knockout (NHE1-/-) mice were studied using in vitro microperfusion. The rate of HCO-3 absorption was decreased 60% in NHE1-/- MTALs (15.4 ± 0.5 pmol/min/mm, wild-type vs 6.0 ± 0.5 pmol/min/mm, NHE1-/-). Transepithelial voltage, an index of the NaCl absorption rate, did not differ in wild-type and NHE1-/- MTALs. Basolateral addition of 10 µM amiloride or 0.7 nM NGF decreased HCO-3 absorption by 45-49% in wild-type MTALs, but had no effect on HCO-3 absorption in NHE1-/- MTALs. Inhibition of HCO-3 absorption by vasopressin and stimulation by hyposmolality, both of which regulate MTAL HCO-3 absorption through primary effects on apical Na+/H+ exchange, were similar in wild-type and NHE1-/- MTALs. Thus, the regulatory defect in NHE1-/- MTALs is specific for factors (bath amiloride and NGF) shown previously to inhibit HCO-3 absorption through primary effects on basolateral Na+/H+ exchange. These findings demonstrate a novel role for NHE1 in transepithelial HCO-3 absorption in the MTAL, in which basolateral NHE1 controls the activity of apical NHE3. Paradoxically, a reduction in NHE1-mediated H+ extrusion across the basolateral membrane leads to a decrease in apical Na+/H+ exchange activity that reduces HCO-3 absorption.
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