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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...

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Autores principales: Zhou, Fan, Yao, Lan, Lu, Xiaoqing, Li, Yubao, Han, Xingmin, Wang, Pei
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
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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.
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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
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