Nerve Growth Factor Inhibits HCO3 − Absorption in Renal Thick Ascending Limb through Inhibition of Basolateral Membrane Na+/H+ Exchange

Nerve growth factor (NGF) inhibits transepithelial HCO 3 − absorption in the rat medullary thick ascending limb (MTAL). To investigate the mechanism of this inhibition, MTALs were perfused in vitro in Na + -free solutions, and apical and basolateral membrane Na + /H + exchange activities were determined from rates of pH i recovery after lumen or bath Na + addition. NGF (0.7 n m in the bath) had no effect on apical Na + /H + exchange activity, but inhibited basolateral Na + /H + exchange activity by 50%. Inhibition of basolateral Na + /H + exchange activity with ethylisopropyl amiloride (EIPA) secondarily reduces apical Na + /H + exchange activity and HCO 3 − absorption in the MTAL (Good, D. W., George, T., and Watts, B. A., III (1995) Proc. Natl. Acad. Sci. U. S. A. 92, 12525–12529). To determine whether a similar mechanism could explain inhibition of HCO 3 − absorption by NGF, apical Na + /H + exchange activity was assessed in physiological solutions (146 m m Na + ) by measurement of the initial rate of cell acidification after lumen EIPA addition. Under these conditions, in which basolateral Na + /H + exchange activity is present, NGF inhibited apical Na + /H + exchange activity. Inhibition of HCO 3 − absorption by NGF was eliminated in the presence of bath EIPA or in the absence of bath Na + . Also, NGF blocked inhibition of HCO 3 − absorption by bath EIPA. We conclude that NGF inhibits basolateral Na + /H + exchange activity in the MTAL, an effect opposite from the stimulation of Na + /H + exchange by growth factors in other systems. NGF inhibits transepithelial HCO 3 − absorption through inhibition of basolateral Na + /H + exchange, most likely as the result of functional coupling in which primary inhibition of basolateral Na + /H + exchange activity results secondarily in inhibition of apical Na + /H + exchange activity. These findings establish a role for basolateral Na + /H + exchange in the regulation of renal tubule HCO 3 − absorption.