Neurotrophin-3 inhibits HCO₃^- absorption via a cAMP-dependent pathway in renal thick ascending limb

-Neurotrophins are expressed in the adult kidney, but their significance is unclear. We showed previously that nerve growth factor (NGF) inhibits HCO₃^- absorption in the rat medullary thick ascending limb (MTAL) via an extracellular signal-regulated kinase (ERK)-dependent pathway. Here we examined whether other neurotrophic factors affect MTAL HCO₃^- absorption. Brain-derived neurotrophic factor and glial cell line-derived neurotrophic factor had no effect. In contrast, neurotrophin-3 (NT-3, 0.7 nM) inhibited HCO₃^- absorption by 40% (half-maximal inhibition at ∼ 0.4 nM). Inhibition by NT-3 was additive to inhibition by NGF. Inhibitors of ERK activation that block inhibition by NGF had no effect on inhibition by NT-3. In contrast, 8-bromo-cAMP or forskolin pretreatment blocked inhibition by NT-3 but not NGF. Inhibition by NT-3 was also blocked by the specific protein kinase A (PKA) inhibitor myristoylated PKI(14-22) amide and by vasopressin, which inhibits HCO₃^- absorption via cAMP. Inhibitors of phosphatidylinositol 3-kinase or protein kinase C did not affect NT3-induced inhibition, but inhibition by NT-3 was eliminated by genistein, consistent with involvement of a receptor tyrosine kinase. These results demonstrate that NT-3 inhibits HCO₃^- absorption via a cAMP- and PKA-dependent pathway. NT-3 and NGF regulate MTAL ion transport through different signal transduction mechanisms. These studies establish a direct role for NT-3 in regulation of renal tubule transport and identify the MTAL as an important target for neurotrophins, which may be involved in the control of renal acid excretion.