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Transepithelial HCO₃^– absorption is defective in renal thick ascending limbs from Na⁺/H⁺ exchanger NHE1 null mutant mice

¹Departments of Medicine and ²Physiology and Biophysics, University of Texas Medical Branch, Galveston, Texas 77555; and ³Department of Molecular Genetics, Biochemistry, and Microbiology, University of Cincinnati College of Medicine, Cincinnati, Ohio 45267

Submitted 14 May 2004 ; accepted in final form 29 July 2004

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 HCO₃^– 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 HCO₃^– absorption was decreased 60% in NHE1^–/– MTALs (15.4 ± 0.5 pmol·min^–1·mm^–1 wild-type vs. 6.0 ± 0.5 pmol·min^–1·mm^–1 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 HCO₃^– absorption by 45–49% in wild-type MTALs but had no effect on HCO₃^– absorption in NHE1^–/– MTALs. Inhibition of HCO₃^– absorption by vasopressin and stimulation by hyposmolality, both of which regulate MTAL HCO₃^– 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 HCO₃^– absorption through primary effects on basolateral Na⁺/H⁺ exchange. These findings demonstrate a novel role for NHE1 in transepithelial HCO₃^– 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 HCO₃^– absorption.

growth factors; sodium hydrogen exchanger type 3

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