Cargando…
Therapeutic Targeting of GSK3β-Regulated Nrf2 and NFκB Signaling Pathways by Salvianolic Acid A Ameliorates Peritoneal Fibrosis
Peritoneal fibrosis is a devastating complication in patients undergoing peritoneal dialysis, with no definite therapy yet available. Salvia miltiorrhiza and its major active component Salvianolic acid A (Sal A) have demonstrated a beneficial effect in myriad diseases. However, their effect on perit...
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/PMC8936188/ https://www.ncbi.nlm.nih.gov/pubmed/35321474 http://dx.doi.org/10.3389/fmed.2022.804899 |
_version_ | 1784672171798298624 |
---|---|
author | Zhou, Fan Yao, Lan Lu, Xiaoqing Li, Yubao Han, Xingmin Wang, Pei |
author_facet | Zhou, Fan Yao, Lan Lu, Xiaoqing Li, Yubao Han, Xingmin Wang, Pei |
author_sort | Zhou, Fan |
collection | PubMed |
description | Peritoneal fibrosis is a devastating complication in patients undergoing peritoneal dialysis, with no definite therapy yet available. Salvia miltiorrhiza and its major active component Salvianolic acid A (Sal A) have demonstrated a beneficial effect in myriad diseases. However, their effect on peritoneal fibrosis is unknown. In murine models of peritoneal dialysis, daily Sal A treatment substantially improved the peritoneal dialysis fluid (PDF) elicited peritoneal fibrosis, marked by thickening of the submesothelial compact zone, accumulation of extracellular matrix and increased expression of vimentin and PAI-1, concomitant with attenuation of GSK3β hyperactivity. This coincided with diminished nitrotyrosine in peritoneal tissues and increased Nrf2 nuclear translocation, entailing a lessened oxidative injury and reinforced Nrf2 antioxidant response. Meanwhile, inflammatory infiltration and maladaptive angiogenesis in peritoneal tissues provoked by PDF injury were also mitigated by Sal A, associated with a suppressed NFκB activation. Mechanistically, ectopic expression of the constitutively active GSK3β blunted the NFκB-suppressing and Nrf2-activating efficacy of Sal A in peritoneal mesothelial cells exposed to hypertonic dextrose, suggesting that GSK3β inhibition mediates the protective effect of Sal A. Collectively, our findings may open the avenue for developing a novel therapy based on Sal A for preventing peritoneal fibrosis in peritoneal dialysis. |
format | Online Article Text |
id | pubmed-8936188 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-89361882022-03-22 Therapeutic Targeting of GSK3β-Regulated Nrf2 and NFκB Signaling Pathways by Salvianolic Acid A Ameliorates Peritoneal Fibrosis Zhou, Fan Yao, Lan Lu, Xiaoqing Li, Yubao Han, Xingmin Wang, Pei Front Med (Lausanne) Medicine Peritoneal fibrosis is a devastating complication in patients undergoing peritoneal dialysis, with no definite therapy yet available. Salvia miltiorrhiza and its major active component Salvianolic acid A (Sal A) have demonstrated a beneficial effect in myriad diseases. However, their effect on peritoneal fibrosis is unknown. In murine models of peritoneal dialysis, daily Sal A treatment substantially improved the peritoneal dialysis fluid (PDF) elicited peritoneal fibrosis, marked by thickening of the submesothelial compact zone, accumulation of extracellular matrix and increased expression of vimentin and PAI-1, concomitant with attenuation of GSK3β hyperactivity. This coincided with diminished nitrotyrosine in peritoneal tissues and increased Nrf2 nuclear translocation, entailing a lessened oxidative injury and reinforced Nrf2 antioxidant response. Meanwhile, inflammatory infiltration and maladaptive angiogenesis in peritoneal tissues provoked by PDF injury were also mitigated by Sal A, associated with a suppressed NFκB activation. Mechanistically, ectopic expression of the constitutively active GSK3β blunted the NFκB-suppressing and Nrf2-activating efficacy of Sal A in peritoneal mesothelial cells exposed to hypertonic dextrose, suggesting that GSK3β inhibition mediates the protective effect of Sal A. Collectively, our findings may open the avenue for developing a novel therapy based on Sal A for preventing peritoneal fibrosis in peritoneal dialysis. Frontiers Media S.A. 2022-03-07 /pmc/articles/PMC8936188/ /pubmed/35321474 http://dx.doi.org/10.3389/fmed.2022.804899 Text en Copyright © 2022 Zhou, Yao, Lu, Li, Han and Wang. 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 | Medicine Zhou, Fan Yao, Lan Lu, Xiaoqing Li, Yubao Han, Xingmin Wang, Pei Therapeutic Targeting of GSK3β-Regulated Nrf2 and NFκB Signaling Pathways by Salvianolic Acid A Ameliorates Peritoneal Fibrosis |
title | Therapeutic Targeting of GSK3β-Regulated Nrf2 and NFκB Signaling Pathways by Salvianolic Acid A Ameliorates Peritoneal Fibrosis |
title_full | Therapeutic Targeting of GSK3β-Regulated Nrf2 and NFκB Signaling Pathways by Salvianolic Acid A Ameliorates Peritoneal Fibrosis |
title_fullStr | Therapeutic Targeting of GSK3β-Regulated Nrf2 and NFκB Signaling Pathways by Salvianolic Acid A Ameliorates Peritoneal Fibrosis |
title_full_unstemmed | Therapeutic Targeting of GSK3β-Regulated Nrf2 and NFκB Signaling Pathways by Salvianolic Acid A Ameliorates Peritoneal Fibrosis |
title_short | Therapeutic Targeting of GSK3β-Regulated Nrf2 and NFκB Signaling Pathways by Salvianolic Acid A Ameliorates Peritoneal Fibrosis |
title_sort | therapeutic targeting of gsk3β-regulated nrf2 and nfκb signaling pathways by salvianolic acid a ameliorates peritoneal fibrosis |
topic | Medicine |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8936188/ https://www.ncbi.nlm.nih.gov/pubmed/35321474 http://dx.doi.org/10.3389/fmed.2022.804899 |
work_keys_str_mv | AT zhoufan therapeutictargetingofgsk3bregulatednrf2andnfkbsignalingpathwaysbysalvianolicacidaamelioratesperitonealfibrosis AT yaolan therapeutictargetingofgsk3bregulatednrf2andnfkbsignalingpathwaysbysalvianolicacidaamelioratesperitonealfibrosis AT luxiaoqing therapeutictargetingofgsk3bregulatednrf2andnfkbsignalingpathwaysbysalvianolicacidaamelioratesperitonealfibrosis AT liyubao therapeutictargetingofgsk3bregulatednrf2andnfkbsignalingpathwaysbysalvianolicacidaamelioratesperitonealfibrosis AT hanxingmin therapeutictargetingofgsk3bregulatednrf2andnfkbsignalingpathwaysbysalvianolicacidaamelioratesperitonealfibrosis AT wangpei therapeutictargetingofgsk3bregulatednrf2andnfkbsignalingpathwaysbysalvianolicacidaamelioratesperitonealfibrosis |