Nerve growth factor regulates HCO₃/^- absorption in thick ascending limb: Modifying effects of vasopressin

Growth factors stimulate Na⁺/H⁺ exchange activity in many cell types but their effects on acid secretion via this mechanism in renal tubules are poorly understood. We examined the regulation of HCO₃/^- absorption by nerve growth factor (NGF) in the rat medullary thick ascending limb (MTAL), which absorbs HCO₃/^- via apical membrane Na⁺/H⁺ exchange. MTAL were perfused in vitro with 25 mM HCO₃/^- solutions (pH 7.4; 290 mosmol/kgH₂O). Addition of 0.7 nM NGF to the bath decreased HCO₃/^- absorption from 13.1 ± 1.1 to 9.6 ± 0.8 pmol·min^-1·mm^-1 (P < 0.001). In contrast, with 10^-10 M arginine vasopressin (AVP) in the bath, addition of NGF to the bath increased HCO₃/^- absorption from 8.0 ± 1.6 to 12.5 ± 1.3 pmol·min^-1 ·mm^-1 (P < 0.01). Both effects of NGF were blocked by genistein, consistent with the involvement of tyrosine kinase pathways. However, the AVP-dependent stimulation required activation of protein kinase C (PKC), whereas the inhibition was PKC independent, indicating that the NGF-induced signaling pathways leading to inhibition and stimulation of HCO₃/^- absorption are distinct. Hypertonicity blocked the inhibition but not the AVP-dependent stimulation, suggesting that hypertonicity and NGF may inhibit HCO₃/^- absorption via a common mechanism. These data demonstrate that NGF inhibits HCO₃/^absorption in the MTAL under basal conditions but stimulates HCO₃/^- absorption in the presence of AVP, effects that are mediated through distinct signal transduction pathways. They also show that AVP is a critical determinant of the response of the MTAL to growth factor stimulation and suggest that NGF can either inhibit or stimulate apical Na⁺/H⁺ exchange activity depending on its interactions with other regulatory factors. Locally produced growth factors such as NGF may play a role in regulating renal tubule HCO₃/^- absorption.