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Role of a tyrosine kinase in the CO₂-induced stimulation of HCO₃^– reabsorption by rabbit S2 proximal tubules

Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, Connecticut

Submitted 29 December 2005 ; accepted in final form 6 March 2006

A previous study demonstrated that proximal tubule cells regulate HCO₃^– reabsorption by sensing acute changes in basolateral CO₂ concentration, suggesting that there is some sort of CO₂ sensor at or near the basolateral membrane (Zhou Y, Zhao J, Bouyer P, and Boron WF Proc Natl Acad Sci USA 102: 3875–3880, 2005). Here, we hypothesized that an early element in the CO₂ signal-transduction cascade might be either a receptor tyrosine kinase (RTK) or a receptor-associated (or soluble) tyrosine kinase (sTK). In our experiments, we found, first, that basolateral 17.5 µM genistein, a broad-spectrum tyrosine kinase inhibitor, virtually eliminates the CO₂ sensitivity of HCO₃^– absorption rate (J). Second, we found that neither basolateral 250 nM nor basolateral 2 µM PP2, a high-affinity inhibitor for the Src family that also inhibits the Bcr-Abl sTK as well as the Kit RTK, reduces the CO₂-stimulated increase in J. Third, we found that either basolateral 35 nM PD168393, a high-affinity inhibitor of RTKs in the erbB (i.e., EGF receptor) family, or basolateral 10 nM BPIQ-I, which blocks erbB RTKs by competing with ATP, eliminates the CO₂ sensitivity. In conclusion, the transduction of the CO₂ signal requires activation of a tyrosine kinase, perhaps an erbB. The possibilities include the following: 1) a TK is simply permissive for the effect of CO₂ on J; 2) a CO₂ receptor activates an sTK, which would then raise J; 3) a CO₂ receptor transactivates an RTK; and 4) the CO₂ receptor could itself be an RTK.

kidney; out-of-equilibrium solutions; acid-base; volume reabsorption; signal transduction

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