%0 Journal Article
%T c-Jun-N-Terminal Kinase Signaling Is Involved in Cyclosporine-Induced Epithelial Phenotypic Changes
%A Nicolas Pallet
%A Eric Thervet
%A Dany Anglicheau
%J Journal of Transplantation
%D 2012
%I Hindawi Publishing Corporation
%R 10.1155/2012/348604
%X Tubular epithelial cells play a central role in the pathogenesis of chronic nephropathies. Previous toxicogenomic studies have demonstrated that cyclosporine- (CsA-) induced epithelial phenotypic changes (EPCs) are reminiscent of an incomplete epithelial to mesenchymal transition (EMT) in a TGF-¦Â-independent manner. Furthermore, we identified endoplasmic reticulum (ER) stress as a potential mechanism that may participate in the modulation of tubular cell plasticity during CsA exposure. Because c-jun-N-terminal kinase (JNK), which is activated during ER stress, is implicated in kidney fibrogenesis, we undertook the current study to identify the role of JNK signaling in EPCs induced by CsA. In primary cultures of human renal epithelial cells, CsA activates JNK signaling, and the treatment with a JNK inhibitor reduces the occurrence of cell shape changes, E-cadherin downregulation, cell migration, and Snail-1 expression. Our results suggest that CsA activates JNK signaling, which, in turn, may participate in the morphological alterations through the regulation of Snail-1 expression. 1. Introduction The pathogenesis of cyclosporine (CsA) nephrotoxicity is not fully understood, and many mechanisms have been proposed [1, 2], such as the epithelial to mesenchymal transition (EMT), a phenomenon that has been implicated in the initiation and development of chronic nephropathies [3¨C6]. Under the pressure of numerous facilitating factors, tubular cells can lose their epithelial phenotype, express mesenchymal markers, acquire migratory and invasive potential, and secrete extracellular matrix. EMT promotes the generation of myofibroblasts, and growing evidence has implicated this process in diseased kidneys, leading to renal fibrosis [4, 7¨C9]. A better understanding of the role of tubular cells and EMT in the development of kidney fibrosis may lead to the development of specific biomarkers of early graft damage and to the characterization of novel therapeutic targets. Transcriptomic analysis of tubular cell response to CsA has shown that CsA induces EMT in vitro in a transforming growth factor ¦Â- (TGF-¦Â-) dependent manner [10]. In a previous study, we have shown that CsA promotes TGF-¦Â-independent epithelial phenotypic changes (EPCs). However, we have not observed de novo¦Á-smooth muscle actin (¦Á-SMA) expression, suggesting that CsA induces an incomplete EMT. In addition, we have identified the endoplasmic reticulum (ER) stress as a potential mechanism that may participate in the modulation of tubular cell plasticity in CsA-induced EPCs [11]. However, the precise
%U http://www.hindawi.com/journals/jtrans/2012/348604/