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

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Abstract

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.

Original languageEnglish (US)
JournalAmerican Journal of Physiology - Renal Physiology
Volume282
Issue number6 51-6
StatePublished - 2002

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Extracellular Signal-Regulated MAP Kinases
Nerve Growth Factor
Extremities
Mitogen-Activated Protein Kinases
MAP Kinase Kinase 2
Sodium-Hydrogen Antiporter
JNK Mitogen-Activated Protein Kinases
Amiloride
p38 Mitogen-Activated Protein Kinases
Baths
Intercellular Signaling Peptides and Proteins
Kidney
Acids
Membranes

Keywords

  • Epithelial transport
  • Extracellular signal-regulated kinase
  • Kidney
  • Medullary thick ascending limb
  • Mitogen-activated protein kinase

ASJC Scopus subject areas

  • Physiology

Cite this

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title = "ERK mediates inhibition of Na+/H+ exchange and HCO3 - absorption by nerve growth factor in MTAL",
abstract = "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.",
keywords = "Epithelial transport, Extracellular signal-regulated kinase, Kidney, Medullary thick ascending limb, Mitogen-activated protein kinase",
author = "Bruns Watts and David Good",
year = "2002",
language = "English (US)",
volume = "282",
journal = "American Journal of Physiology - Endocrinology and Metabolism",
issn = "0193-1849",
publisher = "American Physiological Society",
number = "6 51-6",

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TY - JOUR

T1 - ERK mediates inhibition of Na+/H+ exchange and HCO3 - absorption by nerve growth factor in MTAL

AU - Watts, Bruns

AU - Good, David

PY - 2002

Y1 - 2002

N2 - 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.

AB - 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.

KW - Epithelial transport

KW - Extracellular signal-regulated kinase

KW - Kidney

KW - Medullary thick ascending limb

KW - Mitogen-activated protein kinase

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M3 - Article

VL - 282

JO - American Journal of Physiology - Endocrinology and Metabolism

JF - American Journal of Physiology - Endocrinology and Metabolism

SN - 0193-1849

IS - 6 51-6

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