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Ameliorative Effects of Osthole on Experimental Renal Fibrosis in vivo and in vitro by Inhibiting IL-11/ERK1/2 Signaling

Objectives: Natural product, osthole, has been proven to have a protective effect on organ fibrosis, including renal fibrosis. All of these studies are mainly focused on the regulation of TGF-β/Smad signaling pathway. However, due to the pleiotropic roles of TGF-β/Smad signaling, direct TGF-β-target...

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Autores principales: Wu, Fan, Zhao, Yan, Shao, Qingqing, Fang, Ke, Dong, Ruolan, Jiang, Shujun, Lu, Fuer, Luo, Jinlong, Chen, Guang
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8155534/
https://www.ncbi.nlm.nih.gov/pubmed/34054526
http://dx.doi.org/10.3389/fphar.2021.646331
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author Wu, Fan
Zhao, Yan
Shao, Qingqing
Fang, Ke
Dong, Ruolan
Jiang, Shujun
Lu, Fuer
Luo, Jinlong
Chen, Guang
author_facet Wu, Fan
Zhao, Yan
Shao, Qingqing
Fang, Ke
Dong, Ruolan
Jiang, Shujun
Lu, Fuer
Luo, Jinlong
Chen, Guang
author_sort Wu, Fan
collection PubMed
description Objectives: Natural product, osthole, has been proven to have a protective effect on organ fibrosis, including renal fibrosis. All of these studies are mainly focused on the regulation of TGF-β/Smad signaling pathway. However, due to the pleiotropic roles of TGF-β/Smad signaling, direct TGF-β-targeted treatments are unlikely to be therapeutically feasible in clinic. Recently, the downstream IL-11/ERK1/2 signaling of TGF-β has become an attractive therapeutic target without upstream disadvantages. Based on that, this study was designed to identify the potential effects of osthole on IL-11/ERK1/2 signaling pathway in renal fibrosis. Methods: The renal fibrosis model was established in vivo and in vitro, we investigated the effects of osthole on unilateral ureteral obstruction (UUO)-induced renal fibrosis and TGF-β-induced HK-2 cells. After preliminarily confirming the antifibrogenic effects of osthole and the link between its antifibrogenic effects and the inhibition of IL-11/ERK1/2 signaling, we applied a direct IL-11-induced HK-2 cells fibrosis model to further explore the inhibitory effects of osthole on IL-11/ERK1/2 signaling pathway. Results: Our results confirmed that osthole can decrease the secretion of fibrosis proteins, such as α-smooth muscle actin (α-SMA), collagen I, and fibronectin, ameliorate experimental renal fibrosis in vivo and in vitro, and the effect was associated with suppressing TGF-β1/Smad signaling. More importantly, we found that IL-11/ERK1/2 signaling in UUO-induced renal fibrosis and TGF-β-induced HK-2 cell model was obviously upregulated, and osthole treatment also significantly inhibited the abnormal IL-11/ERK1/2 signaling activation. Given the direct link between TGF-β/Smad signaling and IL-11/ERK1/2 signaling pathway, we have verified that osthole has a direct inhibitory effect on IL-11/ERK1/2 signaling independent of TGF-β signaling by using an IL-11-induced HK-2 cells fibrosis model. Osthole treatment decreased the protein expression of α-SMA, collagen I and fibronectin without changing their mRNA levels in IL-11-induced HK-2 cells. Moreover, it was observed that the IL-11/ERK1/2 inhibitor, U0126, partly blocked the antifibrogenic effects of osthole. Conclusion: In this study, we found that osthole has a previously unrecognized role in inhibiting IL-11/ERK1/2 signaling pathway. Our work demonstrated that the antifibrogenic effect of osthole is not only mediated by TGF-β/Smad2/3 signaling, but also directly mediated by IL-11/ERK1/2 signaling pathway independent of TGF-β1 signaling.
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spelling pubmed-81555342021-05-28 Ameliorative Effects of Osthole on Experimental Renal Fibrosis in vivo and in vitro by Inhibiting IL-11/ERK1/2 Signaling Wu, Fan Zhao, Yan Shao, Qingqing Fang, Ke Dong, Ruolan Jiang, Shujun Lu, Fuer Luo, Jinlong Chen, Guang Front Pharmacol Pharmacology Objectives: Natural product, osthole, has been proven to have a protective effect on organ fibrosis, including renal fibrosis. All of these studies are mainly focused on the regulation of TGF-β/Smad signaling pathway. However, due to the pleiotropic roles of TGF-β/Smad signaling, direct TGF-β-targeted treatments are unlikely to be therapeutically feasible in clinic. Recently, the downstream IL-11/ERK1/2 signaling of TGF-β has become an attractive therapeutic target without upstream disadvantages. Based on that, this study was designed to identify the potential effects of osthole on IL-11/ERK1/2 signaling pathway in renal fibrosis. Methods: The renal fibrosis model was established in vivo and in vitro, we investigated the effects of osthole on unilateral ureteral obstruction (UUO)-induced renal fibrosis and TGF-β-induced HK-2 cells. After preliminarily confirming the antifibrogenic effects of osthole and the link between its antifibrogenic effects and the inhibition of IL-11/ERK1/2 signaling, we applied a direct IL-11-induced HK-2 cells fibrosis model to further explore the inhibitory effects of osthole on IL-11/ERK1/2 signaling pathway. Results: Our results confirmed that osthole can decrease the secretion of fibrosis proteins, such as α-smooth muscle actin (α-SMA), collagen I, and fibronectin, ameliorate experimental renal fibrosis in vivo and in vitro, and the effect was associated with suppressing TGF-β1/Smad signaling. More importantly, we found that IL-11/ERK1/2 signaling in UUO-induced renal fibrosis and TGF-β-induced HK-2 cell model was obviously upregulated, and osthole treatment also significantly inhibited the abnormal IL-11/ERK1/2 signaling activation. Given the direct link between TGF-β/Smad signaling and IL-11/ERK1/2 signaling pathway, we have verified that osthole has a direct inhibitory effect on IL-11/ERK1/2 signaling independent of TGF-β signaling by using an IL-11-induced HK-2 cells fibrosis model. Osthole treatment decreased the protein expression of α-SMA, collagen I and fibronectin without changing their mRNA levels in IL-11-induced HK-2 cells. Moreover, it was observed that the IL-11/ERK1/2 inhibitor, U0126, partly blocked the antifibrogenic effects of osthole. Conclusion: In this study, we found that osthole has a previously unrecognized role in inhibiting IL-11/ERK1/2 signaling pathway. Our work demonstrated that the antifibrogenic effect of osthole is not only mediated by TGF-β/Smad2/3 signaling, but also directly mediated by IL-11/ERK1/2 signaling pathway independent of TGF-β1 signaling. Frontiers Media S.A. 2021-05-13 /pmc/articles/PMC8155534/ /pubmed/34054526 http://dx.doi.org/10.3389/fphar.2021.646331 Text en Copyright © 2021 Wu, Zhao, Shao, Fang, Dong, Jiang, Lu, Luo and Chen. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Pharmacology
Wu, Fan
Zhao, Yan
Shao, Qingqing
Fang, Ke
Dong, Ruolan
Jiang, Shujun
Lu, Fuer
Luo, Jinlong
Chen, Guang
Ameliorative Effects of Osthole on Experimental Renal Fibrosis in vivo and in vitro by Inhibiting IL-11/ERK1/2 Signaling
title Ameliorative Effects of Osthole on Experimental Renal Fibrosis in vivo and in vitro by Inhibiting IL-11/ERK1/2 Signaling
title_full Ameliorative Effects of Osthole on Experimental Renal Fibrosis in vivo and in vitro by Inhibiting IL-11/ERK1/2 Signaling
title_fullStr Ameliorative Effects of Osthole on Experimental Renal Fibrosis in vivo and in vitro by Inhibiting IL-11/ERK1/2 Signaling
title_full_unstemmed Ameliorative Effects of Osthole on Experimental Renal Fibrosis in vivo and in vitro by Inhibiting IL-11/ERK1/2 Signaling
title_short Ameliorative Effects of Osthole on Experimental Renal Fibrosis in vivo and in vitro by Inhibiting IL-11/ERK1/2 Signaling
title_sort ameliorative effects of osthole on experimental renal fibrosis in vivo and in vitro by inhibiting il-11/erk1/2 signaling
topic Pharmacology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8155534/
https://www.ncbi.nlm.nih.gov/pubmed/34054526
http://dx.doi.org/10.3389/fphar.2021.646331
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