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

Abstract

A previous study demonstrated that proximal tubule cells regulate HCO3−reabsorption by sensing acute changes in basolateral CO2concentration, suggesting that there is some sort of CO2sensor 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 CO2signal-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 CO2sensitivity of HCO3−absorption rate ( J[Formula: see text]). 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[Formula: see text]. 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 CO2sensitivity. In conclusion, the transduction of the CO2signal requires activation of a tyrosine kinase, perhaps an erbB. The possibilities include the following: 1) a TK is simply permissive for the effect of CO2on J[Formula: see text]; 2) a CO2receptor activates an sTK, which would then raise J[Formula: see text]; 3) a CO2receptor transactivates an RTK; and 4) the CO2receptor could itself be an RTK.