Cargando…
GSK3β-dependent lysosome biogenesis: An effective pathway to mitigate renal fibrosis with LM49
Renal fibrosis is an incurable disorder characterised by an imbalance of the extracellular matrix (ECM) favouring excess production over degradation. The identification of actionable pathways and agents that promote ECM degradation to restore ECM homeostasis may help mitigate renal fibrosis. In this...
Autores principales: | , , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2022
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9550195/ https://www.ncbi.nlm.nih.gov/pubmed/36225562 http://dx.doi.org/10.3389/fphar.2022.925489 |
_version_ | 1784805826196668416 |
---|---|
author | Ren, Jinhong Wei, Huizhi Sun, Jian Feng, Xiue Zhang, Yuanlin Yuan, Hongxia Miao, Junqiu Qi, Xiaoming Qiao, Yuanbiao Xiao, Baoguo Li, Qingshan |
author_facet | Ren, Jinhong Wei, Huizhi Sun, Jian Feng, Xiue Zhang, Yuanlin Yuan, Hongxia Miao, Junqiu Qi, Xiaoming Qiao, Yuanbiao Xiao, Baoguo Li, Qingshan |
author_sort | Ren, Jinhong |
collection | PubMed |
description | Renal fibrosis is an incurable disorder characterised by an imbalance of the extracellular matrix (ECM) favouring excess production over degradation. The identification of actionable pathways and agents that promote ECM degradation to restore ECM homeostasis may help mitigate renal fibrosis. In this study, we identified 5,2′-dibromo-2,4′,5′-trihydroxydiphenylmethanone (LM49), a compound we previously synthesised, as a small-molecule inducer of ECM degradation. LM49 administration efficiently reduced ECM deposition in renal tissue of diabetic nephropathy rats and in transforming growth factor β-treated renal fibroblast cells. LM49 promoted the cytosol-to-nucleus translocation of transcription factor EB (TFEB) to increase lysosome biogenesis, leading to lysosome-based degradation of the ECM. TFEB-mediated lysosome biogenesis was induced by LM49 directly inhibiting the activity of glycogen synthase kinase 3β (GSK3β) rather than mammalian target of rapamycin complex 1. LM49 inhibited GSK3β kinase activity concentration-dependently via competing with ATP. Direct binding between LM49 and GSK3β was confirmed by the bio-layer interferometry assay, cellular thermal shift assay, and drug affinity responsive target stability. A molecular docking and molecular dynamic simulation revealed that LM49 occupied the ATP pocket of GSK3β, which was consistent with the kinase activity assay. In summary, LM49 enhances TFEB-mediated lysosome biogenesis by directly inhibiting GSK3β, leading to the degradation of the ECM by lysosomes. The enhancement of GSK3β-dependent lysosome biogenesis to rebalance the ECM may be a novel strategy to counteract renal fibrosis, and LM49 may be a viable clinical candidate for treating this disorder. |
format | Online Article Text |
id | pubmed-9550195 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-95501952022-10-11 GSK3β-dependent lysosome biogenesis: An effective pathway to mitigate renal fibrosis with LM49 Ren, Jinhong Wei, Huizhi Sun, Jian Feng, Xiue Zhang, Yuanlin Yuan, Hongxia Miao, Junqiu Qi, Xiaoming Qiao, Yuanbiao Xiao, Baoguo Li, Qingshan Front Pharmacol Pharmacology Renal fibrosis is an incurable disorder characterised by an imbalance of the extracellular matrix (ECM) favouring excess production over degradation. The identification of actionable pathways and agents that promote ECM degradation to restore ECM homeostasis may help mitigate renal fibrosis. In this study, we identified 5,2′-dibromo-2,4′,5′-trihydroxydiphenylmethanone (LM49), a compound we previously synthesised, as a small-molecule inducer of ECM degradation. LM49 administration efficiently reduced ECM deposition in renal tissue of diabetic nephropathy rats and in transforming growth factor β-treated renal fibroblast cells. LM49 promoted the cytosol-to-nucleus translocation of transcription factor EB (TFEB) to increase lysosome biogenesis, leading to lysosome-based degradation of the ECM. TFEB-mediated lysosome biogenesis was induced by LM49 directly inhibiting the activity of glycogen synthase kinase 3β (GSK3β) rather than mammalian target of rapamycin complex 1. LM49 inhibited GSK3β kinase activity concentration-dependently via competing with ATP. Direct binding between LM49 and GSK3β was confirmed by the bio-layer interferometry assay, cellular thermal shift assay, and drug affinity responsive target stability. A molecular docking and molecular dynamic simulation revealed that LM49 occupied the ATP pocket of GSK3β, which was consistent with the kinase activity assay. In summary, LM49 enhances TFEB-mediated lysosome biogenesis by directly inhibiting GSK3β, leading to the degradation of the ECM by lysosomes. The enhancement of GSK3β-dependent lysosome biogenesis to rebalance the ECM may be a novel strategy to counteract renal fibrosis, and LM49 may be a viable clinical candidate for treating this disorder. Frontiers Media S.A. 2022-09-26 /pmc/articles/PMC9550195/ /pubmed/36225562 http://dx.doi.org/10.3389/fphar.2022.925489 Text en Copyright © 2022 Ren, Wei, Sun, Feng, Zhang, Yuan, Miao, Qi, Qiao, Xiao and Li. 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 Ren, Jinhong Wei, Huizhi Sun, Jian Feng, Xiue Zhang, Yuanlin Yuan, Hongxia Miao, Junqiu Qi, Xiaoming Qiao, Yuanbiao Xiao, Baoguo Li, Qingshan GSK3β-dependent lysosome biogenesis: An effective pathway to mitigate renal fibrosis with LM49 |
title | GSK3β-dependent lysosome biogenesis: An effective pathway to mitigate renal fibrosis with LM49 |
title_full | GSK3β-dependent lysosome biogenesis: An effective pathway to mitigate renal fibrosis with LM49 |
title_fullStr | GSK3β-dependent lysosome biogenesis: An effective pathway to mitigate renal fibrosis with LM49 |
title_full_unstemmed | GSK3β-dependent lysosome biogenesis: An effective pathway to mitigate renal fibrosis with LM49 |
title_short | GSK3β-dependent lysosome biogenesis: An effective pathway to mitigate renal fibrosis with LM49 |
title_sort | gsk3β-dependent lysosome biogenesis: an effective pathway to mitigate renal fibrosis with lm49 |
topic | Pharmacology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9550195/ https://www.ncbi.nlm.nih.gov/pubmed/36225562 http://dx.doi.org/10.3389/fphar.2022.925489 |
work_keys_str_mv | AT renjinhong gsk3bdependentlysosomebiogenesisaneffectivepathwaytomitigaterenalfibrosiswithlm49 AT weihuizhi gsk3bdependentlysosomebiogenesisaneffectivepathwaytomitigaterenalfibrosiswithlm49 AT sunjian gsk3bdependentlysosomebiogenesisaneffectivepathwaytomitigaterenalfibrosiswithlm49 AT fengxiue gsk3bdependentlysosomebiogenesisaneffectivepathwaytomitigaterenalfibrosiswithlm49 AT zhangyuanlin gsk3bdependentlysosomebiogenesisaneffectivepathwaytomitigaterenalfibrosiswithlm49 AT yuanhongxia gsk3bdependentlysosomebiogenesisaneffectivepathwaytomitigaterenalfibrosiswithlm49 AT miaojunqiu gsk3bdependentlysosomebiogenesisaneffectivepathwaytomitigaterenalfibrosiswithlm49 AT qixiaoming gsk3bdependentlysosomebiogenesisaneffectivepathwaytomitigaterenalfibrosiswithlm49 AT qiaoyuanbiao gsk3bdependentlysosomebiogenesisaneffectivepathwaytomitigaterenalfibrosiswithlm49 AT xiaobaoguo gsk3bdependentlysosomebiogenesisaneffectivepathwaytomitigaterenalfibrosiswithlm49 AT liqingshan gsk3bdependentlysosomebiogenesisaneffectivepathwaytomitigaterenalfibrosiswithlm49 |