Anti-fibrotic effect of 6-bromo-indirubin-3′-oxime (6-BIO) via regulation of activator protein-1 (AP-1) and specificity protein-1 (SP-1) transcription factors in kidney cells

PAI-1 and CTGF are overexpressed in kidney diseases and cause fibrosis of the lungs, liver, and kidneys. We used a rat model of unilateral ureteral obstruction (UUO) to investigate whether 6-BIO, a glycogen synthase kinase-3β inhibitor, attenuated fibrosis by inhibiting PAI-1 and CTGF in vivo. Addit...

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Autores principales:	Jung Sun Park, In Ae Jung, Hong Sang Choi, Dong-Hyun Kim, Hoon In Choi, Eun Hui Bae, Seong Kwon Ma, Soo Wan Kim
Formato:	article
Lenguaje:	EN
Publicado:	Elsevier 2022
Materias:	6-bromo-indirubin-3’-oxime (6-BIO) Transforming growth factor β (TGFβ) Fibrosis Plasminogen activator inhibitor type-1 (PAI-1) Activator protein-1 (AP-1) Specificity protein 1 (SP-1) Therapeutics. Pharmacology RM1-950
Acceso en línea:	https://doaj.org/article/3d7ac9e4d8db49e491d2041be20a9252
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spelling	oai:doaj.org-article:3d7ac9e4d8db49e491d2041be20a92522021-11-12T04:25:36ZAnti-fibrotic effect of 6-bromo-indirubin-3′-oxime (6-BIO) via regulation of activator protein-1 (AP-1) and specificity protein-1 (SP-1) transcription factors in kidney cells0753-332210.1016/j.biopha.2021.112402https://doaj.org/article/3d7ac9e4d8db49e491d2041be20a92522022-01-01T00:00:00Zhttp://www.sciencedirect.com/science/article/pii/S0753332221011884https://doaj.org/toc/0753-3322PAI-1 and CTGF are overexpressed in kidney diseases and cause fibrosis of the lungs, liver, and kidneys. We used a rat model of unilateral ureteral obstruction (UUO) to investigate whether 6-BIO, a glycogen synthase kinase-3β inhibitor, attenuated fibrosis by inhibiting PAI-1 and CTGF in vivo. Additionally, TGFβ-induced cellular fibrosis was observed in vitro using the human kidney proximal tubular epithelial cells (HK-2), and rat interstitial fibroblasts (NRK49F). Expression of fibrosis-related proteins and signaling molecules such as PAI-1, CTGF, TGFβ, αSMA, SMAD, and MAPK were determined in HK-2 and NRK49F cells using immunoblotting. To identify the transcription factors that regulate the expression of PAI-1 and CTGF the promoter activities of AP-1 and SP-1 were analyzed using luciferase assays. Confocal microscopy was used to observe the co-localization of AP-1 and SP-1 to PAI-1 and CTGF. Expression of PAI-1, CTGF, TGFβ, and α-SMA increased in UUO model as well as in TGFβ-treated HK-2 and NRK49F cells. Furthermore, UUO and TGFβ treatment induced the activation of P-SMAD2/3, SMAD4, P-ERK 1/2, P-P38, and P-JNK MAPK signaling pathways. PAI-1, CTGF, AP-1 and SP-1 promoter activity increased in response to TGFβ treatment. However, treatment with 6-BIO decreased the expression of proteins and signaling pathways associated with fibrosis in UUO model as well as in TGFβ-treated HK-2 and NRK49F cells. Moreover, 6-BIO treatment attenuated the expression of PAI-1 and CTGF as well as the promoter activities of AP-1 and SP-1, thereby regulating the SMAD and MAPK signaling pathways, and subsequently exerting anti-fibrotic effects on kidney cells.Jung Sun ParkIn Ae JungHong Sang ChoiDong-Hyun KimHoon In ChoiEun Hui BaeSeong Kwon MaSoo Wan KimElsevierarticle6-bromo-indirubin-3’-oxime (6-BIO)Transforming growth factor β (TGFβ)FibrosisPlasminogen activator inhibitor type-1 (PAI-1)Activator protein-1 (AP-1)Specificity protein 1 (SP-1)Therapeutics. PharmacologyRM1-950ENBiomedicine & Pharmacotherapy, Vol 145, Iss , Pp 112402- (2022)
institution	DOAJ
collection	DOAJ
language	EN
topic	6-bromo-indirubin-3’-oxime (6-BIO) Transforming growth factor β (TGFβ) Fibrosis Plasminogen activator inhibitor type-1 (PAI-1) Activator protein-1 (AP-1) Specificity protein 1 (SP-1) Therapeutics. Pharmacology RM1-950
spellingShingle	6-bromo-indirubin-3’-oxime (6-BIO) Transforming growth factor β (TGFβ) Fibrosis Plasminogen activator inhibitor type-1 (PAI-1) Activator protein-1 (AP-1) Specificity protein 1 (SP-1) Therapeutics. Pharmacology RM1-950 Jung Sun Park In Ae Jung Hong Sang Choi Dong-Hyun Kim Hoon In Choi Eun Hui Bae Seong Kwon Ma Soo Wan Kim Anti-fibrotic effect of 6-bromo-indirubin-3′-oxime (6-BIO) via regulation of activator protein-1 (AP-1) and specificity protein-1 (SP-1) transcription factors in kidney cells
description	PAI-1 and CTGF are overexpressed in kidney diseases and cause fibrosis of the lungs, liver, and kidneys. We used a rat model of unilateral ureteral obstruction (UUO) to investigate whether 6-BIO, a glycogen synthase kinase-3β inhibitor, attenuated fibrosis by inhibiting PAI-1 and CTGF in vivo. Additionally, TGFβ-induced cellular fibrosis was observed in vitro using the human kidney proximal tubular epithelial cells (HK-2), and rat interstitial fibroblasts (NRK49F). Expression of fibrosis-related proteins and signaling molecules such as PAI-1, CTGF, TGFβ, αSMA, SMAD, and MAPK were determined in HK-2 and NRK49F cells using immunoblotting. To identify the transcription factors that regulate the expression of PAI-1 and CTGF the promoter activities of AP-1 and SP-1 were analyzed using luciferase assays. Confocal microscopy was used to observe the co-localization of AP-1 and SP-1 to PAI-1 and CTGF. Expression of PAI-1, CTGF, TGFβ, and α-SMA increased in UUO model as well as in TGFβ-treated HK-2 and NRK49F cells. Furthermore, UUO and TGFβ treatment induced the activation of P-SMAD2/3, SMAD4, P-ERK 1/2, P-P38, and P-JNK MAPK signaling pathways. PAI-1, CTGF, AP-1 and SP-1 promoter activity increased in response to TGFβ treatment. However, treatment with 6-BIO decreased the expression of proteins and signaling pathways associated with fibrosis in UUO model as well as in TGFβ-treated HK-2 and NRK49F cells. Moreover, 6-BIO treatment attenuated the expression of PAI-1 and CTGF as well as the promoter activities of AP-1 and SP-1, thereby regulating the SMAD and MAPK signaling pathways, and subsequently exerting anti-fibrotic effects on kidney cells.
format	article
author	Jung Sun Park In Ae Jung Hong Sang Choi Dong-Hyun Kim Hoon In Choi Eun Hui Bae Seong Kwon Ma Soo Wan Kim
author_facet	Jung Sun Park In Ae Jung Hong Sang Choi Dong-Hyun Kim Hoon In Choi Eun Hui Bae Seong Kwon Ma Soo Wan Kim
author_sort	Jung Sun Park
title	Anti-fibrotic effect of 6-bromo-indirubin-3′-oxime (6-BIO) via regulation of activator protein-1 (AP-1) and specificity protein-1 (SP-1) transcription factors in kidney cells
title_short	Anti-fibrotic effect of 6-bromo-indirubin-3′-oxime (6-BIO) via regulation of activator protein-1 (AP-1) and specificity protein-1 (SP-1) transcription factors in kidney cells
title_full	Anti-fibrotic effect of 6-bromo-indirubin-3′-oxime (6-BIO) via regulation of activator protein-1 (AP-1) and specificity protein-1 (SP-1) transcription factors in kidney cells
title_fullStr	Anti-fibrotic effect of 6-bromo-indirubin-3′-oxime (6-BIO) via regulation of activator protein-1 (AP-1) and specificity protein-1 (SP-1) transcription factors in kidney cells
title_full_unstemmed	Anti-fibrotic effect of 6-bromo-indirubin-3′-oxime (6-BIO) via regulation of activator protein-1 (AP-1) and specificity protein-1 (SP-1) transcription factors in kidney cells
title_sort	anti-fibrotic effect of 6-bromo-indirubin-3′-oxime (6-bio) via regulation of activator protein-1 (ap-1) and specificity protein-1 (sp-1) transcription factors in kidney cells
publisher	Elsevier
publishDate	2022
url	https://doaj.org/article/3d7ac9e4d8db49e491d2041be20a9252
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Anti-fibrotic effect of 6-bromo-indirubin-3′-oxime (6-BIO) via regulation of activator protein-1 (AP-1) and specificity protein-1 (SP-1) transcription factors in kidney cells

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