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      Norcantharidin Inhibits Renal Interstitial Fibrosis by Blocking the Tubular Epithelial-Mesenchymal Transition

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          Abstract

          Epithelial–mesenchymal transition (EMT) is thought to contribute to the progression of renal tubulointerstitial fibrosis. Norcantharidin (NCTD) is a promising agent for inhibiting renal interstitial fibrosis. However, the molecular mechanisms of NCTD are unclear. In this study, a unilateral ureteral obstruction (UUO) rat model was established and treated with intraperitoneal NCTD (0.1 mg/kg/day). The UUO rats treated with NCTD showed a reduction in obstruction-induced upregulation of α-SMA and downregulation of E-cadherin in the rat kidney (P<0.05). Human renal proximal tubule cell lines (HK-2) stimulated with TGF-β 1 were treated with different concentrations of NCTD. HK-2 cells stimulated by TGF-β 1 in vitro led to downregulation of E-cadherin and increased de novo expression of α-SMA; co-treatment with NCTD attenuated all of these changes (P<0.05). NCTD reduced TGF-β 1-induced expression and phosphorylation of Smad2/3 and downregulated the expression of Snail1 (P<0.05). These results suggest that NCTD antagonizes tubular EMT by inhibiting the Smad pathway. NCTD may play a critical role in preserving the normal epithelial phenotype and modulating tubular EMT.

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          Evidence that fibroblasts derive from epithelium during tissue fibrosis.

          Theodore M Danoff, Masayuki Iwano, David Plieth … (2002)
          Interstitial fibroblasts are principal effector cells of organ fibrosis in kidneys, lungs, and liver. While some view fibroblasts in adult tissues as nothing more than primitive mesenchymal cells surviving embryologic development, they differ from mesenchymal cells in their unique expression of fibroblast-specific protein-1 (FSP1). This difference raises questions about their origin. Using bone marrow chimeras and transgenic reporter mice, we show here that interstitial kidney fibroblasts derive from two sources. A small number of FSP1(+), CD34(-) fibroblasts migrate to normal interstitial spaces from bone marrow. More surprisingly, however, FSP1(+) fibroblasts also arise in large numbers by local epithelial-mesenchymal transition (EMT) during renal fibrogenesis. Both populations of fibroblasts express collagen type I and expand by cell division during tissue fibrosis. Our findings suggest that a substantial number of organ fibroblasts appear through a novel reversal in the direction of epithelial cell fate. As a general mechanism, this change in fate highlights the potential plasticity of differentiated cells in adult tissues under pathologic conditions.
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            Phospho-control of TGF-beta superfamily signaling.

            Katharine H Wrighton, Xia Lin, Xin-Hua Feng (2009)
            Members of the transforming growth factor-beta (TGF-beta) family control a broad range of cellular responses in metazoan organisms via autocrine, paracrine, and endocrine modes. Thus, aberrant TGF-beta signaling can play a key role in the pathogenesis of several diseases, including cancer. TGF-beta signaling pathways are activated by a short phospho-cascade, from receptor phosphorylation to the subsequent phosphorylation and activation of downstream signal transducers called R-Smads. R-Smad phosphorylation state determines Smad complex assembly/disassembly, nuclear import/export, transcriptional activity and stability, and is thus the most critical event in TGF-beta signaling. Dephosphorylation of R-Smads by specific phosphatases prevents or terminates TGF-beta signaling, highlighting the need to consider Smad (de)phosphorylation as a tightly controlled and dynamic event. This article illustrates the essential roles of reversible phosphorylation in controlling the strength and duration of TGF-beta signaling and the ensuing physiological responses.
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              Snail is required for TGFbeta-induced endothelial-mesenchymal transition of embryonic stem cell-derived endothelial cells.

              Yasuhiro Yoshimatsu, Kohei Miyazono, Tomoko Yamazaki … (2008)
              Epithelial-mesenchymal transition (EMT) plays important roles in various physiological and pathological processes, and is regulated by signaling pathways mediated by cytokines, including transforming growth factor beta (TGFbeta). Embryonic endothelial cells also undergo differentiation into mesenchymal cells during heart valve formation and aortic maturation. However, the molecular mechanisms that regulate such endothelial-mesenchymal transition (EndMT) remain to be elucidated. Here we show that TGFbeta plays important roles during mural differentiation of mouse embryonic stem cell-derived endothelial cells (MESECs). TGFbeta2 induced the differentiation of MESECs into mural cells, with a decrease in the expression of the endothelial marker claudin 5, and an increase in expression of the mural markers smooth muscle alpha-actin, SM22alpha and calponin, whereas a TGFbeta type I receptor kinase inhibitor inhibited EndMT. Among the transcription factors involved in EMT, Snail was induced by TGFbeta2 in MESECs. Tetracycline-regulated expression of Snail induced the differentiation of MESECs into mural cells, whereas knockdown of Snail expression abrogated TGFbeta2-induced mural differentiation of MESECs. These results indicate that Snail mediates the actions of endogenous TGFbeta signals that induce EndMT.
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                Author and article information

                Contributors
                Emmanuel A. Burdmann: Role: Editor
                Journal
                Journal ID (nlm-ta): PLoS One
                Journal ID (iso-abbrev): PLoS ONE
                Journal ID (publisher-id): plos
                Journal ID (pmc): plosone
                Title: PLoS ONE
                Publisher: Public Library of Science (San Francisco, USA )
                ISSN (Electronic): 1932-6203
                Publication date Collection: 2013
                Publication date (Electronic): 25 June 2013
                Volume: 8
                Issue: 6
                Electronic Location Identifier: e66356
                Affiliations
                [1 ]Division of Nephrology, Second Xiangya Hospital, Central South University, Changsha, P.R. China
                [2 ]Division of Nephrology, The first affiliated hospital, XinJiang Medical University,Uramuq, P.R. China
                [3 ]Department of Clinical Laboratory, Second Xiangya Hospital, Central South University, P.R. China
                University of Sao Paulo Medical School, Brazil
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Conceived and designed the experiments: YL FY-L LS YM-P. Performed the experiments: YL YS LX YP-L YY-X YH-Y. Analyzed the data: JL SB-D HL. Contributed reagents/materials/analysis tools: LS LX MW. Wrote the paper: YL SW TH. Revised the manuscript: YL FY-L.

                Article
                Publisher ID: PONE-D-12-30368
                DOI: 10.1371/journal.pone.0066356
                PMC ID: 3692527
                PubMed ID: 23825538
                SO-VID: 84bc03fd-218a-4515-add9-b8de43ba99e3
                Copyright statement: Copyright @ 2013
                License:

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                Date received : 4 October 2012
                Date accepted : 5 May 2013
                Page count
                Pages: 10
                Funding
                This study was supported by the National Natural Science Foundation of China (Grant No.81100486), the Natural Science Foundation of Hunan Province of China (Grant No.10JJ2011), and the scientific project of the Research Center of Metabolic Syndrome in Central South University of China (Grant No.DY-2008-02-03). The corresponding author and all the above grand funders played a role in designing and doing the experiment and writing the manuscript.
                Categories
                Subject: Research Article
                Subject: Biology
                Subject: Anatomy and Physiology
                Subject: Renal System
                Subject: Model Organisms
                Subject: Animal Models
                Subject: Rat
                Subject: Molecular Cell Biology
                Subject: Cell Adhesion
                Subject: Cadherins
                Subject: Signal Transduction
                Subject: Signaling in Cellular Processes
                Subject: Smad Signaling
                Subject: Signaling Pathways
                Subject: Medicine
                Subject: Drugs and Devices
                Subject: Drug Research and Development

                ScienceOpen disciplines: Uncategorized
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                ScienceOpen disciplines: Uncategorized

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