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Fisetin reduces the senescent tubular epithelial cell burden and also inhibits proliferative fibroblasts in murine lupus nephritis

Systemic lupus erythematosus (SLE) is a chronic autoimmune inflammatory disease characterized by the involvement of multiple organs. Lupus nephritis (LN) is a major risk factor for overall morbidity and mortality in SLE patients. Hence, designing effective drugs is pivotal for treating individuals w...

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Autores principales: Ijima, Shogo, Saito, Yuki, Nagaoka, Kentaro, Yamamoto, Sena, Sato, Tsukasa, Miura, Norihiro, Iwamoto, Taiki, Miyajima, Maki, Chikenji, Takako S.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9714549/
https://www.ncbi.nlm.nih.gov/pubmed/36466895
http://dx.doi.org/10.3389/fimmu.2022.960601
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author Ijima, Shogo
Saito, Yuki
Nagaoka, Kentaro
Yamamoto, Sena
Sato, Tsukasa
Miura, Norihiro
Iwamoto, Taiki
Miyajima, Maki
Chikenji, Takako S.
author_facet Ijima, Shogo
Saito, Yuki
Nagaoka, Kentaro
Yamamoto, Sena
Sato, Tsukasa
Miura, Norihiro
Iwamoto, Taiki
Miyajima, Maki
Chikenji, Takako S.
author_sort Ijima, Shogo
collection PubMed
description Systemic lupus erythematosus (SLE) is a chronic autoimmune inflammatory disease characterized by the involvement of multiple organs. Lupus nephritis (LN) is a major risk factor for overall morbidity and mortality in SLE patients. Hence, designing effective drugs is pivotal for treating individuals with LN. Fisetin plays a senolytic role by specifically eliminating senescent cells, inhibiting cell proliferation, and exerting anti-inflammatory, anti-oxidant, and anti-tumorigenic effects. However, limited research has been conducted on the utility and therapeutic mechanisms of fisetin in chronic inflammation. Similarly, whether the effects of fisetin depend on cell type remains unclear. In this study, we found that LN-prone MRL/lpr mice demonstrated accumulation of Ki-67-positive myofibroblasts and p15(INK4B)-positive senescent tubular epithelial cells (TECs) that highly expressed transforming growth factor β (TGF-β). TGF-β stimulation induced senescence of NRK-52E renal TECs and proliferation of NRK-49F renal fibroblasts, suggesting that TGF-β promotes senescence and proliferation in a cell type-dependent manner, which is inhibited by fisetin treatment in vitro. Furthermore, fisetin treatment in vivo reduced the number of senescent TECs and myofibroblasts, which attenuated kidney fibrosis, reduced senescence-associated secretory phenotype (SASP) expression, and increased TEC proliferation. These data suggest that the effects of fisetin vary depending on the cell type and may have therapeutic effects in complex and diverse LN pathologies.
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spelling pubmed-97145492022-12-02 Fisetin reduces the senescent tubular epithelial cell burden and also inhibits proliferative fibroblasts in murine lupus nephritis Ijima, Shogo Saito, Yuki Nagaoka, Kentaro Yamamoto, Sena Sato, Tsukasa Miura, Norihiro Iwamoto, Taiki Miyajima, Maki Chikenji, Takako S. Front Immunol Immunology Systemic lupus erythematosus (SLE) is a chronic autoimmune inflammatory disease characterized by the involvement of multiple organs. Lupus nephritis (LN) is a major risk factor for overall morbidity and mortality in SLE patients. Hence, designing effective drugs is pivotal for treating individuals with LN. Fisetin plays a senolytic role by specifically eliminating senescent cells, inhibiting cell proliferation, and exerting anti-inflammatory, anti-oxidant, and anti-tumorigenic effects. However, limited research has been conducted on the utility and therapeutic mechanisms of fisetin in chronic inflammation. Similarly, whether the effects of fisetin depend on cell type remains unclear. In this study, we found that LN-prone MRL/lpr mice demonstrated accumulation of Ki-67-positive myofibroblasts and p15(INK4B)-positive senescent tubular epithelial cells (TECs) that highly expressed transforming growth factor β (TGF-β). TGF-β stimulation induced senescence of NRK-52E renal TECs and proliferation of NRK-49F renal fibroblasts, suggesting that TGF-β promotes senescence and proliferation in a cell type-dependent manner, which is inhibited by fisetin treatment in vitro. Furthermore, fisetin treatment in vivo reduced the number of senescent TECs and myofibroblasts, which attenuated kidney fibrosis, reduced senescence-associated secretory phenotype (SASP) expression, and increased TEC proliferation. These data suggest that the effects of fisetin vary depending on the cell type and may have therapeutic effects in complex and diverse LN pathologies. Frontiers Media S.A. 2022-11-17 /pmc/articles/PMC9714549/ /pubmed/36466895 http://dx.doi.org/10.3389/fimmu.2022.960601 Text en Copyright © 2022 Ijima, Saito, Nagaoka, Yamamoto, Sato, Miura, Iwamoto, Miyajima and Chikenji 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 Immunology
Ijima, Shogo
Saito, Yuki
Nagaoka, Kentaro
Yamamoto, Sena
Sato, Tsukasa
Miura, Norihiro
Iwamoto, Taiki
Miyajima, Maki
Chikenji, Takako S.
Fisetin reduces the senescent tubular epithelial cell burden and also inhibits proliferative fibroblasts in murine lupus nephritis
title Fisetin reduces the senescent tubular epithelial cell burden and also inhibits proliferative fibroblasts in murine lupus nephritis
title_full Fisetin reduces the senescent tubular epithelial cell burden and also inhibits proliferative fibroblasts in murine lupus nephritis
title_fullStr Fisetin reduces the senescent tubular epithelial cell burden and also inhibits proliferative fibroblasts in murine lupus nephritis
title_full_unstemmed Fisetin reduces the senescent tubular epithelial cell burden and also inhibits proliferative fibroblasts in murine lupus nephritis
title_short Fisetin reduces the senescent tubular epithelial cell burden and also inhibits proliferative fibroblasts in murine lupus nephritis
title_sort fisetin reduces the senescent tubular epithelial cell burden and also inhibits proliferative fibroblasts in murine lupus nephritis
topic Immunology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9714549/
https://www.ncbi.nlm.nih.gov/pubmed/36466895
http://dx.doi.org/10.3389/fimmu.2022.960601
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