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

David Good, Thampi George

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6 Citations (Scopus)

Abstract

-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.

Original languageEnglish (US)
JournalAmerican Journal of Physiology - Cell Physiology
Volume281
Issue number6 50-6
StatePublished - 2001

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Neurotrophin 3
Nerve Growth Factor
Extremities
Kidney
Nerve Growth Factors
Cyclic AMP-Dependent Protein Kinases
Extracellular Signal-Regulated MAP Kinases
Phosphatidylinositol 3-Kinase
8-Bromo Cyclic Adenosine Monophosphate
Glial Cell Line-Derived Neurotrophic Factor
Signal transduction
Genistein
Brain-Derived Neurotrophic Factor
Ion Transport
Receptor Protein-Tyrosine Kinases
Colforsin
Protein Kinase Inhibitors
Vasopressins
Protein Kinase C
Rats

Keywords

  • Kidney
  • Nerve growth factor
  • Neurotrophic factors
  • Trk receptors
  • Vasopressin

ASJC Scopus subject areas

  • Clinical Biochemistry
  • Cell Biology
  • Physiology
  • Physiology (medical)

Cite this

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title = "Neurotrophin-3 inhibits HCO3 - absorption via a cAMP-dependent pathway in renal thick ascending limb",
abstract = "-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.",
keywords = "Kidney, Nerve growth factor, Neurotrophic factors, Trk receptors, Vasopressin",
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year = "2001",
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TY - JOUR

T1 - Neurotrophin-3 inhibits HCO3 - absorption via a cAMP-dependent pathway in renal thick ascending limb

AU - Good, David

AU - George, Thampi

PY - 2001

Y1 - 2001

N2 - -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.

AB - -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.

KW - Kidney

KW - Nerve growth factor

KW - Neurotrophic factors

KW - Trk receptors

KW - Vasopressin

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JO - American Journal of Physiology - Endocrinology and Metabolism

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