PU.1 inhibition attenuates atrial fibrosis and atrial fibrillation vulnerability induced by angiotensin‐II by reducing TGF‐β1/Smads pathway activation

Hu, Juan; Zhang, Jingjing; Li, Li; Wang, Shanling; Huang, Yang; Fan, Xian‐Wei; Zhang, Leiming; Hu, Guang-Ling; Fu, Hai-Xia; Song, Weifeng; Yan, Li; Liu, Jingjing; Wu, Jintao; Kong, Bin

doi:10.1111/jcmm.16678

Cited by 8 publications

(7 citation statements)

References 74 publications

(156 reference statements)

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“…S5 I). Based on the sequencing results, we found significant differences in the expression of transcription factors SPI1/PU.1, which regulates TGFβ1 by enrichment analysis of the sequencing results [30] , [31] . Western blot results also further demonstrated that ANGPTL8 KO could significantly reduce SPI1 expression in the livers of mice treated with HFD for 36 weeks ( Fig.…”

Section: Resultsmentioning

confidence: 97%

ANGPTL8 accelerates liver fibrosis mediated by HFD-induced inflammatory activity via LILRB2/ERK signaling pathways

Zhang

Yuan

et al. 2023

Journal of Advanced Research

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Section: Resultsmentioning

confidence: 97%

ANGPTL8 accelerates liver fibrosis mediated by HFD-induced inflammatory activity via LILRB2/ERK signaling pathways

Zhang

Yuan

et al. 2023

Journal of Advanced Research

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“…Alternatively, there is also evidence to suggest that Rho (56) and Akt(57) may directly stimulate PU.1 activity. PU.1 inhibitor is available and has been tested in different models of tissue fibrosis (40,58). It would be of interest to determine whether PU.1 inhibition could alter renal fibrosis in vivo.…”

Section: Discussionmentioning

confidence: 99%

Brg1 regulates fibroblast-myofibroblast transition to promote renal fibrosis

Wu,

Luo,

Kang

et al. 2023

Preprint

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Excessive fibrogenesis serves to disrupt the anatomical and functional integrity of the kidneys contributing to renal failure. Renal fibroblast is the major precursor to myofibroblast, the effector cell type of renal fibrosis. How fibroblast-myofibroblast transition (FMyT) is regulated in the kidneys remains incompletely understood. In the present study we investigated the role of Brahma related gene 1 (Brg1), a chromatin remodeling protein, in renal fibrosis focusing on mechanistic insights and translational potential. We report that Brg1 was up-regulated during FMyT bothin vitroandin vivo. Brg1 deletion in fibroblasts partially blocked TGF-β induced FMyTin vitroand attenuated renal fibrosis in three different animal models. Importantly, conditional Brg1 knockout inPostn+mature myofibroblasts mitigated renal fibrosis induced by unilateral ureteral obstruction (UUO) or ischemia-reperfusion (IR) in mice. Transcriptomic analysis uncovered Prune2 as a potential target for Brg1. Brg1 interacted with E2F1 to activate Prune2 transcription during FMyT. Concordantly, Prune2 knockdown suppressed TGF-β induced FMyTin vitroand dampened renal fibrosis in mice. Mechanistically, Prune2 likely contributed to FMyT by augmenting phosphorylation and activity of the pro-fibrogenic transcription factor PU.1. Finally, small-molecule Brg1 inhibitor PFI-3 exhibited strong antifibrotic potency in established models of renal fibrosis. In conclusion, our data provide compelling evidence that BRG1 is a pivotal regulator of as well as a promising therapeutic target for renal fibrosis.

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“…For example, Hu et al. concluded that SPI1 suppression reduces angiotensin-II-induced atrial fibrosis, indicating the potential therapeutic value of SPI1 [ 15 ]. Besides, inhibition of SPI1 distinctly reduces inflammation and fibrosis in a dietary mouse model with nonalcoholic steatohepatitis [ 27 ].…”

Section: Discussionmentioning

confidence: 99%

“…The knockdown of SPI1 reduces the expression of pro-inflammatory genes to restrict microglial inflammation [ 14 ]. A previous study suggested that SPI1 repression ameliorates angiotensin-II-induced atrial fibrosis [ 15 ]. Of note, SPI1 is a transcription factor of the E26 transformation specific family, a large family of transcription factors that contains 28 family members and takes part in various cell processes, which was reported to be associated with the co-expression of S100A9 [ 16 , 17 ].…”

Section: Introductionmentioning

confidence: 99%

Salmonella pathogenicity island 1 knockdown confers protection against myocardial fibrosis and inflammation in uremic cardiomyopathy via down-regulation of S100 Calcium Binding Protein A8/A9 transcription

et al. 2022

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Background/Aim Uremic cardiomyopathy (UCM) is a characteristic cardiac pathology that is commonly found in patients with chronic kidney disease. This study dissected the mechanism of SPI1 in myocardial fibrosis and inflammation induced by UCM through S100A8/A9. Methods An UCM rat model was established, followed by qRT-PCR and western blot analyses of SPI1 and S100A8/A9 expression in myocardial tissues. After alterations of SPI1 and S100A8/A9 expression in UCM rats, the blood specimens were harvested from the cardiac apex of rats. The levels of creatine phosphokinase-MB (CK-MB), blood creatinine, blood urea nitrogen (BUN), and inflammatory cytokines (interleukin [IL]-6, IL-1β, and tumor necrosis factor-α [TNF-α]) were examined in the collected blood. Collagen fibrosis was assessed by Masson staining. The expression of fibrosis markers [transforming growth factor (TGF)-β1, α-smooth muscle actin (SMA), Collagen 4a1, and Fibronectin], IL-6, IL-1β, and TNF-α was measured in myocardial tissues. Chromatin immunoprecipitation and dual-luciferase reporter gene assays were conducted to test the binding relationship between SPI1 and S100A8/A9. Results S100A8/A9 and SPI1 were highly expressed in the myocardial tissues of UCM rats. Mechanistically, SPI1 bound to the promoter of S100A8/A9 to facilitate S100A8/A9 transcription. S100A8/A9 or SPI1 knockdown reduced myocardial fibrosis and inflammation and the levels of CK-MB, blood creatinine, and BUN, as well as the expression of TGF-β1, α-SMA, Collagen 4a1, Fibronectin, IL-6, TNF-α, and IL-1β in UCM rats. Conclusion SPI1 knockdown diminished S100A8/A9 transcription, thus suppressing myocardial fibrosis and inflammation caused by UCM.

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PU.1 inhibition attenuates atrial fibrosis and atrial fibrillation vulnerability induced by angiotensin‐II by reducing TGF‐β1/Smads pathway activation

Abstract: This is an open access article under the terms of the Creat ive Commo ns Attri bution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Cited by 8 publications

References 74 publications

ANGPTL8 accelerates liver fibrosis mediated by HFD-induced inflammatory activity via LILRB2/ERK signaling pathways

ANGPTL8 accelerates liver fibrosis mediated by HFD-induced inflammatory activity via LILRB2/ERK signaling pathways

Brg1 regulates fibroblast-myofibroblast transition to promote renal fibrosis

Salmonella pathogenicity island 1 knockdown confers protection against myocardial fibrosis and inflammation in uremic cardiomyopathy via down-regulation of S100 Calcium Binding Protein A8/A9 transcription

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