Oncostatin M-induced effects on EMT in human proximal tubular cells: differential role of ERK signaling.
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.
Pollack
Verena
V
Division of Nephrology, Department of Internal Medicine, Innsbruck Medical University, Anichstrasse 35, A-6020 Innsbruck, Austria.
Sarközi
Rita
R
Banki
Zoltan
Z
Feifel
Elisabeth
E
Wehn
Swantje
S
Gstraunthaler
Gerhard
G
Stoiber
Heribert
H
Mayer
Gert
G
Montesano
Roberto
R
Strutz
Frank
F
Schramek
Herbert
H
D000818:Animals; D015820:Cadherins / Q000037:antagonists & inhibitors; D002454:Cell Differentiation / Q000187:drug effects* / Q000502:physiology; D002460:Cell Line; D057167:Claudins; D004847:Epithelial Cells / Q000166:cytology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D007687:Kidney Tubules, Proximal / Q000166:cytology*; D018374:LLC-PK1 Cells; D048369:MAP Kinase Kinase 1 / Q000378:metabolism; D048370:MAP Kinase Kinase 2 / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000502:physiology*; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D008648:Mesoderm / Q000166:cytology*; D053683:Oncostatin M / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D011994:Recombinant Proteins / Q000494:pharmacology; D013552:Swine
C491875:CLDN2 protein, human; D015820:Cadherins; D057167:Claudins; D008565:Membrane Proteins; D011994:Recombinant Proteins; D053683:Oncostatin M; C482128:MAP2K2 protein, human; D048049:Extracellular Signal-Regulated MAP Kinases; D048369:MAP Kinase Kinase 1; D048370:MAP Kinase Kinase 2; C482125:MAP2K1 protein, human