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      Interleukin-1β-Induced Transdifferentiation of Renal Proximal Tubular Cells Is Mediated by Activation of JNK and p38 MAPK

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          Interleukin (IL)-1β induces renal tubular epithelial cells to transdifferentiate to myofibroblasts, which express α-smooth muscle actin (α-SMA). To understand the signal transduction mechanisms involved in transdifferentiation, we examined the roles of mitogen-activated protein kinases (MAPKs) in IL-1β-stimulated α-SMA expression and cell migration in the HK-2 human renal proximal tubular cell line. IL-1β induced the transdifferentiation of renal proximal tubular cells, which was characterized by upregulated expression of α-SMA and increased cell migration. In addition, IL-1β increased the activity of the three members of the MAPK family, ERK, JNK and p38 MAPK, in these cells. Both SP600125, a specific inhibitor of JNK, and SB203580, a specific inhibitor of p38 MAPK, suppressed the IL-1β-induced expression of α-SMA and cell migration, but these effects were not observed with PD98059, a specific inhibitor of ERK. These results suggest that IL-1β-induced HK-2 cell transdifferentiation is mediated, at least in part, through the activation of the JNK and p38 MAPK signaling pathways.

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          Most cited references 21

          • Record: found
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          Leaving the neighborhood: molecular mechanisms involved during epithelial-mesenchymal transition.

           P Savagner (2001)
          Several molecular mechanisms contribute directly and mechanically to the loss of epithelial phenotype. During epithelial-mesenchymal transition (EMT), adherens junctions and desmosomes are at least partially dissociated. At the same time, a massive cytoskeleton reorganization takes place, involving the rho family and the remodeling of the actin microfilament mesh. Numerous pathways have been described in vitro that control phenotype transition in specific cell models. In vivo developmental studies suggest that transcriptional control, activated by a specific pathway involving Ras, Src and potentially the Wnt pathway, is an essential step. Recent functional and localization experiments indicate that the slug/snail family of transcription factors functions overall as an epithelial phenotype repressor and could represent a key EMT contributor. Copyright 2001 John Wiley & Sons, Inc.
            • Record: found
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            • Article: not found

            Tubular epithelial-myofibroblast transdifferentiation in progressive tubulointerstitial fibrosis in 5/6 nephrectomized rats.

             Hui Yang,  David Huang,  W Mu (1998)
            Tubulointerstitial fibrosis is the final common pathway to end-stage renal failure. The present study investigated the potential role of tubular epithelial cells (TEC) in progressive fibrosis in the rat remnant kidney model. Rats underwent 5/6 nephrectomy or a sham operation (control), and groups of six animals were killed at weeks 1, 3, 5, 9, 13, 17 and 21. Immunohistochemistry staining and in situ hybridization at week 3 after nephrectomy demonstrated de novo expression of alpha-smooth muscle actin (alpha-SMA)--a marker of smooth muscle cells and myofibroblasts--by TEC that was invariably associated with disruption of the tubular basement membrane (TBM). This phenotypic evidence of tubular epithelial-myofibroblast transdifferentiation was supported by ultrastructural studies identifying the presence of characteristic actin microfilaments and dense bodies within TEC with a transformed morphology. In the late stage of this apparent tubular epithelial-myofibroblast transdifferentiation, TEC lost apical-basal polarity and tight junctions, became elongated, detached from the TBM, separated from neighboring cells and appeared to migrate into the peritubular interstitium through the damaged basement membrane. Indeed, focal peritubular accumulation of alpha-SMA+ myofibroblasts and local tubulointerstitial fibrosis was closely associated with alpha-SMA+ tubules, suggesting a tubular epithelial origin for some of these cells. Quantitative analysis found a significant correlation between the number of alpha-SMA+ TEC and the accumulation of interstitial alpha-SMA+ myofibroblasts and the severity of tubulointerstitial fibrosis (both P < 0.001). This study provides phenotypic and morphological evidence to support the hypothesis that TEC are pro-fibrogenitor cells capable of tubular epithelial-myofibroblast transdifferentiation in progressive renal fibrosis. In addition, we postulate that disruption of the TBM, which facilitates epithelial cell contact with the interstitial matrix, promotes this process of transdifferentiation.
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              A role for p38(MAPK)/HSP27 pathway in smooth muscle cell migration.

              Smooth muscle cells are exposed to growth factors and cytokines that contribute to pathological states including airway hyperresponsiveness, atherosclerosis, angiogenesis, smooth muscle hypertrophy, and hyperplasia. A common feature of several of these conditions is migration of smooth muscle beyond the initial boundary of the organ. Signal transduction pathways activated by extracellular signals that instigate migration are mostly undefined in smooth muscles. We measured migration of cultured tracheal myocytes in response to platelet-derived growth factor, interleukin-1beta, and transforming growth factor-beta. Cellular migration was blocked by SB203580, an inhibitor of p38(MAPK). Time course experiments demonstrated increased phosphorylation of p38(MAPK). Activation of p38(MAPK) resulted in the phosphorylation of HSP27 (heat shock protein 27), which may modulate F-actin polymerization. Inhibition of p38(MAPK) activity inhibited phosphorylation of HSP27. Adenovirus-mediated expression of activated mutant MAPK kinase 6b(E), an upstream activator for p38(MAPK), increased cell migration, whereas overexpression of p38alpha MAPK dominant negative mutant and an HSP27 phosphorylation mutant blocked cell migration completely. The results indicate that activation of the p38(MAPK) pathway by growth factors and proinflammatory cytokines regulates smooth muscle cell migration and may contribute to pathological states involving smooth muscle dysfunction.

                Author and article information

                Nephron Exp Nephrol
                Cardiorenal Medicine
                S. Karger AG
                March 2005
                20 January 2005
                : 99
                : 3
                : e68-e76
                Renal Division, Department of Medicine, First Hospital, and Institute of Nephrology, Peking University, Beijing, People’s Republic of China
                83414 Nephron Exp Nephrol 2005;99:e68–e76
                © 2005 S. Karger AG, Basel

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                Figures: 4, Tables: 1, References: 42, Pages: 1
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