Receptor tyrosine kinases mediate epithelial Na+ channel inhibition by epidermal growth factor

Qiusheng Tong, James D Stockand

Research output: Contribution to journalArticle

54 Citations (Scopus)

Abstract

Epidermal growth factor (EGF) decreases Na+ reabsorption across distal nephron epithelia. Activity of the epithelial Na+ channel (ENaC) is limiting for Na+ transport in this portion of the nephron. Abnormal ENaC activity and EGF signaling are both associated with polycystic kidney disease localized to the distal nephron. We tested here whether EGF and other ligands for receptor tyrosine kinases (RTK) decrease ENaC activity. EGF markedly and quickly decreased ENaC activity. The RTK inhibitor erbstatin blocked EGF actions on ENaC and when added alone increased channel activity, uncovering basal suppression by endogenous RTK. The protein tyrosine phosphatase inhibitor vanadate, similar to EGF, decreased ENaC activity. Growth factors and vanadate decreased ENaC activity by decreasing open probability. ENaC was not phosphorylated in response to EGF, indicating that intermediary proteins transduce the inhibitory signal from the EGF receptor (EGFR) to ENaC. We find that neither MAPK 1/2 nor c-Src is signaling intermediaries between EGFR and ENaC. Inhibition of ENaC paralleled decreases in plasma membrane phosphatidylinositol 4,5-bisphosphate levels [PtdIns(4,5)P2] and was abolished by clamping PtdIns(4,5)P2. We conclude that EGF and other ligands for RTK decrease ENaC open probability by decreasing membrane PtdIns(4,5)P 2 levels.

Original languageEnglish (US)
JournalAmerican Journal of Physiology - Renal Physiology
Volume288
Issue number1 57-1
DOIs
StatePublished - Jan 2005

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Epithelial Sodium Channels
Receptor Protein-Tyrosine Kinases
Epidermal Growth Factor
Nephrons
Phosphatidylinositol 4,5-Diphosphate
Vanadates
Epidermal Growth Factor Receptor
Ligands
Polycystic Kidney Diseases
Protein Tyrosine Phosphatases
Phosphatidylinositols
Constriction
Intercellular Signaling Peptides and Proteins

Keywords

  • Distal renal tubule
  • Protein tyrosine phosphatase
  • Sodium reabsorption

ASJC Scopus subject areas

  • Physiology

Cite this

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title = "Receptor tyrosine kinases mediate epithelial Na+ channel inhibition by epidermal growth factor",
abstract = "Epidermal growth factor (EGF) decreases Na+ reabsorption across distal nephron epithelia. Activity of the epithelial Na+ channel (ENaC) is limiting for Na+ transport in this portion of the nephron. Abnormal ENaC activity and EGF signaling are both associated with polycystic kidney disease localized to the distal nephron. We tested here whether EGF and other ligands for receptor tyrosine kinases (RTK) decrease ENaC activity. EGF markedly and quickly decreased ENaC activity. The RTK inhibitor erbstatin blocked EGF actions on ENaC and when added alone increased channel activity, uncovering basal suppression by endogenous RTK. The protein tyrosine phosphatase inhibitor vanadate, similar to EGF, decreased ENaC activity. Growth factors and vanadate decreased ENaC activity by decreasing open probability. ENaC was not phosphorylated in response to EGF, indicating that intermediary proteins transduce the inhibitory signal from the EGF receptor (EGFR) to ENaC. We find that neither MAPK 1/2 nor c-Src is signaling intermediaries between EGFR and ENaC. Inhibition of ENaC paralleled decreases in plasma membrane phosphatidylinositol 4,5-bisphosphate levels [PtdIns(4,5)P2] and was abolished by clamping PtdIns(4,5)P2. We conclude that EGF and other ligands for RTK decrease ENaC open probability by decreasing membrane PtdIns(4,5)P 2 levels.",
keywords = "Distal renal tubule, Protein tyrosine phosphatase, Sodium reabsorption",
author = "Qiusheng Tong and Stockand, {James D}",
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language = "English (US)",
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AU - Tong, Qiusheng

AU - Stockand, James D

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AB - Epidermal growth factor (EGF) decreases Na+ reabsorption across distal nephron epithelia. Activity of the epithelial Na+ channel (ENaC) is limiting for Na+ transport in this portion of the nephron. Abnormal ENaC activity and EGF signaling are both associated with polycystic kidney disease localized to the distal nephron. We tested here whether EGF and other ligands for receptor tyrosine kinases (RTK) decrease ENaC activity. EGF markedly and quickly decreased ENaC activity. The RTK inhibitor erbstatin blocked EGF actions on ENaC and when added alone increased channel activity, uncovering basal suppression by endogenous RTK. The protein tyrosine phosphatase inhibitor vanadate, similar to EGF, decreased ENaC activity. Growth factors and vanadate decreased ENaC activity by decreasing open probability. ENaC was not phosphorylated in response to EGF, indicating that intermediary proteins transduce the inhibitory signal from the EGF receptor (EGFR) to ENaC. We find that neither MAPK 1/2 nor c-Src is signaling intermediaries between EGFR and ENaC. Inhibition of ENaC paralleled decreases in plasma membrane phosphatidylinositol 4,5-bisphosphate levels [PtdIns(4,5)P2] and was abolished by clamping PtdIns(4,5)P2. We conclude that EGF and other ligands for RTK decrease ENaC open probability by decreasing membrane PtdIns(4,5)P 2 levels.

KW - Distal renal tubule

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