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Volume 270, Number 17, Issue of April 28, pp. 9883-9889, 1995
©1995 by The American Society for Biochemistry and Molecular Biology, Inc.

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David W. Good , With the technical assistance of Thampi George

In the rat medullary thick ascending limb (MTAL), hyperosmolality inhibits transepithelial HCO absorption (JHCO) by inhibiting apical membrane Na/Hexchange. To examine signaling mechanisms involved in this regulatory response, MTALs were isolated and perfused in vitro with 25 mM HCO solutions (290 mosmol/kg HO). Osmolality was increased in lumen and bath solutions by addition of 300 mM mannitol or 75 mM NaCl. Addition of mannitol reduced JHCO by 60% and addition of NaCl reduced JHCO by 50%. With the protein tyrosine kinase (PTK) inhibitor genistein (7 µM) or herbimycin A (1 µM) in the bath, addition of mannitol reduced JHCO only by 11% and addition of NaCl reduced JHCO only by 15%. Staurosporine (10 M) or forskolin (10 M) in the bath had no effect on inhibition of JHCO by hypertonic NaCl. Genistein had no effect on inhibition of JHCO by vasopressin (a cyclic AMP-dependent process) or stimulation of JHCO by prostaglandin E(a protein kinase C-dependent process). Under isosmotic conditions, addition of genistein or herbimycin A to the bath increased JHCO by 30% through stimulation of apical membrane Na/Hexchange. Addition of the tyrosine phosphatase inhibitor molybdate (50 µM) to the bath reproduced the inhibition of JHCO observed with hyperosmolality. These data indicate that 1) the effect of hyperosmolality to inhibit MTAL HCO absorption through inhibition of apical membrane Na/Hexchange is mediated via a PTK-dependent pathway that functions independent of regulation by cyclic AMP and protein kinase C, and 2) a constitutive PTK activity inhibits apical membrane Na/Hexchange and HCO absorption under isosmotic conditions. Our results suggest that tyrosine phosphorylation is a critical step in inhibition of the apical Na/Hexchanger isoform NHE-3 by hyperosmolality.

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