Pharmacologic Inhibition of Histone Deacetylase 6 Prevents the Progression of Chlorhexidine Gluconate-Induced Peritoneal Fibrosis by Blockade of M2 Macrophage Polarization
Peritoneal fibrosis contributes to ultrafiltration failure in peritoneal dialysis (PD) patients and thus restricts the wide application of PD in clinic. Recently we have demonstrated that histone deacetylase 6 (HDAC6) is critically implicated in high glucose peritoneal dialysis fluid (HG-PDF) induce...
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Frontiers Media S.A.
2022-06-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2022.899140/full |
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| author | Yingfeng Shi Jinqing Li Hui Chen Yan Hu Lunxian Tang Xun Zhou Min Tao Zexin Lv Si Chen Andong Qiu Na Liu |
| author_facet | Yingfeng Shi Jinqing Li Hui Chen Yan Hu Lunxian Tang Xun Zhou Min Tao Zexin Lv Si Chen Andong Qiu Na Liu |
| author_sort | Yingfeng Shi |
| collection | DOAJ |
| description | Peritoneal fibrosis contributes to ultrafiltration failure in peritoneal dialysis (PD) patients and thus restricts the wide application of PD in clinic. Recently we have demonstrated that histone deacetylase 6 (HDAC6) is critically implicated in high glucose peritoneal dialysis fluid (HG-PDF) induced peritoneal fibrosis, however, the precise mechanisms of HDAC6 in peritoneal fibrosis have not been elucidated. Here, we focused on the role and mechanisms of HDAC6 in chlorhexidine gluconate (CG) induced peritoneal fibrosis and discussed the mechanisms involved. We found Tubastatin A (TA), a selective inhibitor of HDAC6, significantly prevented the progression of peritoneal fibrosis, as characterized by reduction of epithelial-mesenchymal transition (EMT) and extracellular matrix (ECM) protein deposition. Inhibition of HDAC6 remarkably suppressed the expression of matrix metalloproteinases-2 (MMP2) and MMP-9. Administration of TA also increased the expression of acetylation Histone H3 and acetylation α-tubulin. Moreover, our results revealed that blockade of HDAC6 inhibited alternatively M2 macrophages polarization by suppressing the activation of TGF-β/Smad3, PI3K/AKT, and STAT3, STAT6 pathways. To give a better understanding of the mechanisms, we further established two cell injured models in Raw264.7 cells by using IL-4 and HG-PDF. Our in vitro experiments illustrated that both IL-4 and HG-PDF could induce M2 macrophage polarization, as demonstrated by upregulation of CD163 and Arginase-1. Inhibition of HDAC6 by TA significantly abrogated M2 macrophage polarization dose-dependently by suppressing TGF-β/Smad, IL4/STAT6, and PI3K/AKT signaling pathways. Collectively, our study revealed that blockade of HDAC6 by TA could suppress the progression of CG-induced peritoneal fibrosis by blockade of M2 macrophage polarization. Thus, HDAC6 may be a promising target in peritoneal fibrosis treatment. |
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| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-04-12T14:06:20Z |
| publishDate | 2022-06-01 |
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| series | Frontiers in Immunology |
| spelling | doaj.art-5470ce2ce4914dcd9df836068fc8b4f02022-12-22T03:30:03ZengFrontiers Media S.A.Frontiers in Immunology1664-32242022-06-011310.3389/fimmu.2022.899140899140Pharmacologic Inhibition of Histone Deacetylase 6 Prevents the Progression of Chlorhexidine Gluconate-Induced Peritoneal Fibrosis by Blockade of M2 Macrophage PolarizationYingfeng Shi0Jinqing Li1Hui Chen2Yan Hu3Lunxian Tang4Xun Zhou5Min Tao6Zexin Lv7Si Chen8Andong Qiu9Na Liu10Department of Nephrology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, ChinaDepartment of Nephrology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, ChinaDepartment of Nephrology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, ChinaDepartment of Nephrology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, ChinaEmergency Department of Critical Care Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, ChinaDepartment of Nephrology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, ChinaDepartment of Nephrology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, ChinaDepartment of Nephrology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, ChinaDepartment of Nephrology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, ChinaSchool of Life Science and Technology, Advanced Institute of Translational Medicine, Tongji University, Shanghai, ChinaDepartment of Nephrology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, ChinaPeritoneal fibrosis contributes to ultrafiltration failure in peritoneal dialysis (PD) patients and thus restricts the wide application of PD in clinic. Recently we have demonstrated that histone deacetylase 6 (HDAC6) is critically implicated in high glucose peritoneal dialysis fluid (HG-PDF) induced peritoneal fibrosis, however, the precise mechanisms of HDAC6 in peritoneal fibrosis have not been elucidated. Here, we focused on the role and mechanisms of HDAC6 in chlorhexidine gluconate (CG) induced peritoneal fibrosis and discussed the mechanisms involved. We found Tubastatin A (TA), a selective inhibitor of HDAC6, significantly prevented the progression of peritoneal fibrosis, as characterized by reduction of epithelial-mesenchymal transition (EMT) and extracellular matrix (ECM) protein deposition. Inhibition of HDAC6 remarkably suppressed the expression of matrix metalloproteinases-2 (MMP2) and MMP-9. Administration of TA also increased the expression of acetylation Histone H3 and acetylation α-tubulin. Moreover, our results revealed that blockade of HDAC6 inhibited alternatively M2 macrophages polarization by suppressing the activation of TGF-β/Smad3, PI3K/AKT, and STAT3, STAT6 pathways. To give a better understanding of the mechanisms, we further established two cell injured models in Raw264.7 cells by using IL-4 and HG-PDF. Our in vitro experiments illustrated that both IL-4 and HG-PDF could induce M2 macrophage polarization, as demonstrated by upregulation of CD163 and Arginase-1. Inhibition of HDAC6 by TA significantly abrogated M2 macrophage polarization dose-dependently by suppressing TGF-β/Smad, IL4/STAT6, and PI3K/AKT signaling pathways. Collectively, our study revealed that blockade of HDAC6 by TA could suppress the progression of CG-induced peritoneal fibrosis by blockade of M2 macrophage polarization. Thus, HDAC6 may be a promising target in peritoneal fibrosis treatment.https://www.frontiersin.org/articles/10.3389/fimmu.2022.899140/fullperitoneal dialysisperitoneal fibrosishistone deacetylase 6macrophage polarizationtubastatin A |
| spellingShingle | Yingfeng Shi Jinqing Li Hui Chen Yan Hu Lunxian Tang Xun Zhou Min Tao Zexin Lv Si Chen Andong Qiu Na Liu Pharmacologic Inhibition of Histone Deacetylase 6 Prevents the Progression of Chlorhexidine Gluconate-Induced Peritoneal Fibrosis by Blockade of M2 Macrophage Polarization Frontiers in Immunology peritoneal dialysis peritoneal fibrosis histone deacetylase 6 macrophage polarization tubastatin A |
| title | Pharmacologic Inhibition of Histone Deacetylase 6 Prevents the Progression of Chlorhexidine Gluconate-Induced Peritoneal Fibrosis by Blockade of M2 Macrophage Polarization |
| title_full | Pharmacologic Inhibition of Histone Deacetylase 6 Prevents the Progression of Chlorhexidine Gluconate-Induced Peritoneal Fibrosis by Blockade of M2 Macrophage Polarization |
| title_fullStr | Pharmacologic Inhibition of Histone Deacetylase 6 Prevents the Progression of Chlorhexidine Gluconate-Induced Peritoneal Fibrosis by Blockade of M2 Macrophage Polarization |
| title_full_unstemmed | Pharmacologic Inhibition of Histone Deacetylase 6 Prevents the Progression of Chlorhexidine Gluconate-Induced Peritoneal Fibrosis by Blockade of M2 Macrophage Polarization |
| title_short | Pharmacologic Inhibition of Histone Deacetylase 6 Prevents the Progression of Chlorhexidine Gluconate-Induced Peritoneal Fibrosis by Blockade of M2 Macrophage Polarization |
| title_sort | pharmacologic inhibition of histone deacetylase 6 prevents the progression of chlorhexidine gluconate induced peritoneal fibrosis by blockade of m2 macrophage polarization |
| topic | peritoneal dialysis peritoneal fibrosis histone deacetylase 6 macrophage polarization tubastatin A |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2022.899140/full |
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