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1 Department of Internal Medicine, Innsbruck Medical University, Division of Nephrology, Innsbruck, Austria
2 Department of Hygiene, Medical Microbiology and Social Medicine, Innsbruck Medical University, Division of Hygiene and Medical Microbiology, Innsbruck, Austria
3 Department of Physiology and Medical Physics, Division of Physiology, Innsbruck, Austria
4 Georg-August-University Medical Center, Department of Nephrology and Rheumatology, Gottingen, Germany
5 School of Medicine, University of Geneva, Department of Cell Physiology and Metabolism, Geneva, Switzerland
* To whom correspondence should be addressed. E-mail: herbert.schramek{at}i-med.ac.at.
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. 10 µM of the MEK1/2 inhibitor U0126 blocked basal and OSM-induced ERK1/2 phosphorylation but neither phosphorylation of ERK5 nor of 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 neither affect basal nor 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 OSMs inhibitory effect on N-cadherin expression. Furthermore, functional ERK1/2 signaling is necessary for basal claudin-2 expression.
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