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Scientific article
English

Oncostatin M-induced effects on EMT in human proximal tubular cells: differential role of ERK signaling

Publication date2007
Abstract

Growing evidence suggests that a proportion of interstitial myofibroblasts detected during renal tubulointerstitial fibrosis originates from tubular epithelial cells by a process called epithelial-mesenchymal transition (EMT). The IL-6-type cytokine oncostatin M (OSM) has been recently implicated in the induction of EMT. We investigated OSM effects on the expression of both cell-cell contact proteins and mesenchymal markers and studied OSM-induced intracellular signaling mechanisms associated with these events in human proximal tubular cells. Human recombinant OSM attenuated the expression of N-cadherin, E-cadherin, and claudin-2 in human kidney-2 (HK-2) cells associated with the induction of HK-2 cell scattering in 3D collagen matrices. Conversely, expression of collagen type I, vimentin, and S100A4 was induced by OSM. OSM-stimulated cell scattering was inhibited by antibodies against gp130. Besides inducing phosphorylation of Stat1 and Stat3, OSM led to a strong concentration- and time-dependent phosphorylation of the mitogen-activated protein kinases ERK1, ERK2, and ERK5. MEK1/2 inhibitor U0126 (10 muM) blocked basal and OSM-induced ERK1/2 phosphorylation but not phosphorylation of either ERK5 or Stat1/3. Both synthetic MEK1/2 inhibitors U0126 and Cl-1040, when used at concentrations which inhibit ERK1/2 phosphorylation but not ERK5 phosphorylation, restored N-cadherin expression in the presence of OSM, inhibited basal claudin-2 expression, but did not affect either basal or OSM-inhibited E-cadherin expression or OSM-induced expression of collagen type I and vimentin. These results suggest that in human proximal tubular cells ERK1/2 signaling represents an important component of OSM's inhibitory effect on N-cadherin expression. Furthermore, functional ERK1/2 signaling is necessary for basal claudin-2 expression.

Keywords
  • Animals
  • Cadherins/antagonists & inhibitors
  • Cell Differentiation/drug effects/physiology
  • Cell Line
  • Epithelial Cells/cytology
  • Extracellular Signal-Regulated MAP Kinases/metabolism
  • Humans
  • Kidney Tubules, Proximal/cytology
  • LLC-PK1 Cells
  • MAP Kinase Kinase 1/metabolism
  • MAP Kinase Kinase 2/metabolism
  • MAP Kinase Signaling System/physiology
  • Membrane Proteins/antagonists & inhibitors/metabolism
  • Mesoderm/cytology
  • Oncostatin M/pharmacology
  • Phosphorylation/drug effects
  • Recombinant Proteins/pharmacology
  • Swine
Citation (ISO format)
POLLACK, Verena et al. Oncostatin M-induced effects on EMT in human proximal tubular cells: differential role of ERK signaling. In: American journal of physiology. Renal, fluid and electrolyte physiology, 2007, vol. 293, n° 5, p. F1714–1726. doi: 10.1152/ajprenal.00130.2007
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Article (Accepted version)
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Identifiers
ISSN of the journal0363-6127
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