ERK mediates inhibition of Na⁺/H⁺ exchange and HCO₃^- absorption by nerve growth factor in MTAL

Mitogen-activated protein (MAP) kinases mediate a variety of critical cellular events, but their role in the regulation of epithelial transport is largely undefined. Recently, we demonstrated that nerve growth factor (NGF) inhibits HCO₃^- absorption in the rat medullary thick ascending limb (MTAL) through an unusual mechanism: 1) NGF inhibits basolateral membrane Na⁺/H⁺ exchange activity, an effect opposite to the stimulation of Na⁺/H⁺ exchange by growth factors in other cells; and 2) inhibition of basolateral Na⁺/H⁺ exchange results secondarily in inhibition of apical Na⁺/H⁺ exchange, thereby inhibiting HCO₃^- absorption. In this study, we examined the role of MAP kinases in mediating inhibition by NGF. In tissue strips from the inner stripe of the outer medulla and in microdissected MTALs, NGF increased extracellular signal- regulated kinase (ERK) activity twofold but had no effect on c-Jun NH₂-terminal kinase (JNK) or p38 MAP kinase activity. The selective MAP kinase kinase (MEK1/2) inhibitors U0126 and PD-98059 abolished the NGF-induced ERK activation and largely eliminated (≥60%) the effects of NGF to inhibit basolateral Na⁺/H⁺ exchange activity and transepithelial HCO₃^- absorption in perfused MTALs. The MEK1/2 inhibitors did not affect inhibition of HCO₃^- absorption by bath ethylisopropyl amiloride, indicating that ERK activation is not involved in mediating interaction between the basolateral and apical Na⁺/H⁺ exchangers. These results demonstrate that NGF inhibits basolateral Na⁺/H⁺ exchange activity and HCO₃^- absorption in the MTAL through activation of the ERK signaling pathway. These findings identify a novel action of ERK to inhibit Na⁺/H⁺ exchange activity and establish a role for MAP kinase pathways in the acute regulation of Na⁺/H⁺ exchange activity and transepithelial acid secretion in renal tubules.