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      Ruxolitinib Alleviates Renal Interstitial Fibrosis in UUO Mice

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          Abstract

          Ruxolitinib is a selective inhibitor of Jak1/2. Downstream signaling pathways of Jak, such as Stat3 and Akt/mTOR, are overactivated and contribute to renal interstitial fibrosis. Therefore, we explored the effect of Ruxolitinib on this pathological process. Unilateral ureteral obstruction (UUO) models and TGF-β1-treated fibroblasts and renal tubular epithelial cells were adopted in this study. Ruxolitinib was administered to UUO mice and TGF-β1-treated cells. Kidneys from UUO mice with Ruxolitinib treatment displayed less tubular injuries compared with those without Ruxolitinib treatment. Ruxolitinib treatment suppressed fibroblast activation and extracellular matrix (ECM) production in UUO kidneys and TGF-β1-treated fibroblasts. Ruxolitinib treatment also blocked epithelial-mesenchymal transition (EMT) in UUO kidneys and TGF-β 1-treated renal tubular epithelial cells. Moreover, Ruxolitinib treatment alleviated UUO-induced inflammation, oxidative stress and apoptosis. Mechanistically, Ruxolitinib treatment attenuated activation of both Stat3 and Akt/mTOR/Yap pathways. In conclusion, Ruxolitinib treatment can ameliorate UUO-induced renal interstitial fibrosis, suggesting that Ruxolitinib may be potentially used to treat fibrotic kidney disease.

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          Origin and function of myofibroblasts in kidney fibrosis.

          Valerie LeBleu, Gangadhar Taduri, Joyce O'Connell … (2013)
          Myofibroblasts are associated with organ fibrosis, but their precise origin and functional role remain unknown. We used multiple genetically engineered mice to track, fate map and ablate cells to determine the source and function of myofibroblasts in kidney fibrosis. Through this comprehensive analysis, we identified that the total pool of myofibroblasts is split, with 50% arising from local resident fibroblasts through proliferation. The nonproliferating myofibroblasts derive through differentiation from bone marrow (35%), the endothelial-to-mesenchymal transition program (10%) and the epithelial-to-mesenchymal transition program (5%). Specific deletion of Tgfbr2 in α-smooth muscle actin (αSMA)(+) cells revealed the importance of this pathway in the recruitment of myofibroblasts through differentiation. Using genetic mouse models and a fate-mapping strategy, we determined that vascular pericytes probably do not contribute to the emergence of myofibroblasts or fibrosis. Our data suggest that targeting diverse pathways is required to substantially inhibit the composite accumulation of myofibroblasts in kidney fibrosis.
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            YAP/TAZ Are Mechanoregulators of TGF-β-Smad Signaling and Renal Fibrogenesis.

            Stephen Szeto, Masahiro Narimatsu, Mingliang Lu … (2016)
            Like many organs, the kidney stiffens after injury, a process that is increasingly recognized as an important driver of fibrogenesis. Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) are related mechanosensory proteins that bind to Smad transcription factors, the canonical mediators of profibrotic TGF-β responses. Here, we investigated the role of YAP/TAZ in the matrix stiffness dependence of fibroblast responses to TGF-β. In contrast to growth on a stiff surface, fibroblast growth on a soft matrix led to YAP/TAZ sequestration in the cytosol and impaired TGF-β-induced Smad2/3 nuclear accumulation and transcriptional activity. YAP knockdown or treatment with verteporfin, a drug that was recently identified as a potent YAP inhibitor, elicited similar changes. Furthermore, verteporfin reduced YAP/TAZ levels and decreased the total cellular levels of Smad2/3 after TGF-β stimulation. Verteporfin treatment of mice subjected to unilateral ureteral obstruction similarly reduced YAP/TAZ levels and nuclear Smad accumulation in the kidney, and attenuated renal fibrosis. Our data suggest that organ stiffening cooperates with TGF-β to induce fibrosis in a YAP/TAZ- and Smad2/3-dependent manner. Interference with this YAP/TAZ and TGF-β/Smad crosstalk likely underlies the antifibrotic activity of verteporfin. Finally, through repurposing of a clinically used drug, we illustrate the therapeutic potential of a novel mechanointerference strategy that blocks TGF-β signaling and renal fibrogenesis.
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              Breast cancer stem cells transition between epithelial and mesenchymal states reflective of their normal counterparts.

              Suling Liu, Yang Cong, Dong Wang … (2014)
              Previous studies have suggested that breast cancer stem cells (BCSCs) mediate metastasis, are resistant to radiation and chemotherapy, and contribute to relapse. Although several BCSC markers have been described, it is unclear whether these markers identify the same or independent BCSCs. Here, we show that BCSCs exist in distinct mesenchymal-like (epithelial-mesenchymal transition [EMT]) and epithelial-like (mesenchymal-epithelial transition [MET]) states. Mesenchymal-like BCSCs characterized as CD24(-)CD44(+) are primarily quiescent and localized at the tumor invasive front, whereas epithelial-like BCSCs express aldehyde dehydrogenase (ALDH), are proliferative, and are located more centrally. The gene-expression profiles of mesenchymal-like and epithelial-like BCSCs are remarkably similar across different molecular subtypes of breast cancer, and resemble those of distinct basal and luminal stem cells found in the normal breast. We propose that the plasticity of BCSCs that allows them to transition between EMT- and MET-like states endows these cells with the capacity for tissue invasion, dissemination, and growth at metastatic sites.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Int J Biol Sci
                Journal ID (iso-abbrev): Int. J. Biol. Sci
                Journal ID (publisher-id): ijbs
                Title: International Journal of Biological Sciences
                Publisher: Ivyspring International Publisher (Sydney )
                ISSN (Electronic): 1449-2288
                Publication date Collection: 2020
                Publication date (Electronic): 1 January 2020
                Volume: 16
                Issue: 2
                Pages: 194-203
                Affiliations
                [1 ]Department of Pathophysiology, College of Basic Medical Science, China Medical University, Shenyang, China.
                [2 ]Department of Nephrology, Shengjing Hospital, China Medical University, Shenyang, China.
                [3 ]Center of Laboratory Technology and Experimental Medicine, China Medical University, Shenyang, China.
                Author notes

                ✉ Corresponding author: Chenghai Zhao (E-mail: chzhao@cmu.edu.cn), Department of Pathophysiology, College of Basic Medical Science, China Medical University, Shenyang, China. Tel 86+24+31939318.

                Competing Interests: The authors have declared that no competing interest exists.

                Article
                Publisher ID: ijbsv16p0194
                DOI: 10.7150/ijbs.39024
                PMC ID: 6949153
                PubMed ID: 31929748
                SO-VID: 6231617e-b395-4d45-b9d2-1b9ca8b6a471
                Copyright © © The author(s)
                License:

                This is an open access article distributed under the terms of the Creative Commons Attribution License ( https://creativecommons.org/licenses/by/4.0/). See http://ivyspring.com/terms for full terms and conditions.

                History
                Date received : 9 August 2019
                Date accepted : 15 October 2019
                Categories
                Subject: Research Paper

                ScienceOpen disciplines: Life sciences
                Keywords: ruxolitinib,jak,stat3,mtor,tgf-β1
                Data availability:
                ScienceOpen disciplines: Life sciences
                Keywords: ruxolitinib, jak, stat3, mtor, tgf-β1

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