Formononetin ameliorates ferroptosis-associated fibrosis in renal tubular epithelial cells and in mice with chronic kidney disease by suppressing the Smad3/ATF3/SLC7A11 signaling

Zhu, Bingwen; Ni, Yufang; Gong, Yi; Kang, Xiaoshuang; Guo, Huaiying; Liu, Xiaoheng; Li, Jianchun; Wang, Li

doi:10.1016/j.lfs.2022.121331

Cited by 39 publications

(21 citation statements)

References 31 publications

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“…qRT-PCR was performed using Eastep qPCR Master Mix (Cat# Q711-02, Vazyme, China), and the LightCycler® 480 II Real-time PCR System (Roche, Germany). The primers used for qRT-PCR are listed in Table 1 , and the sequences of other primers are consistent with those used in previously published articles [ 17 ]. The expression level of the target gene was detected with pre-designed primers, and the relative expression level was calculated by the 2^(-ΔCt) method and normalized to GAPDH as an internal reference gene.…”

Section: Methodsmentioning

confidence: 89%

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RfxCas13d-mediated inhibition of Circ1647 alleviates renal fibrosis via PI3K/AKT signaling pathway

Ni,

Zhang,

Xian

et al. 2024

Renal Failure

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Background Circular RNAs ( CircRNAs ) have been shown to be involved in the development of chronic kidney disease (CKD). This study aimed to investigate the role of Circ1647 in renal fibrosis, which is a hallmark of CKD. Methods In this study, we established a unilateral ureteral obstruction (UUO) model and delivered Circ1647 RfxCas13d knockdown plasmid into renal parenchymal cells via retrograde injection through the ureter followed by electroporation. After that, the pathological changes were determined by Hematoxylin and Eosin. Meanwhile, Immunohistochemistry, qRT-PCR and Western blot were conducted to assess the degree of fibrosis. In addition, overexpressing of Circ1647 in renal tubular epithelial cells (TCMK1) was performed to investigate the underlying mechanisms of Circ1647 . Results Our results displayed that electroporation-mediated knockdown of Circ1647 by RfxCas13d knockdown plasmid significantly inhibited renal fibrosis in UUO mice as evidenced by reduced expression of fibronectin and α-SMA (alpha-smooth muscle actin). Conversely, overexpression of Circ1647 in TCMK1 cells promoted the fibrosis. In terms of mechanism, Circ1647 may mediate the PI3K/AKT Signaling Pathway as demonstrated by the balance of the phosphorylation of PI3K and AKT in vivo and the aggravated phosphorylation of PI3K and AKT in vitro . These observations were corroborated by the effects of the PI3K inhibitor LY294002, which mitigated fibrosis post Circ1647 overexpression. Conclusion Our study suggests that Circ1647 plays a significant role in renal fibrosis by mediating the PI3K/AKT signaling pathway. RfxCas13d-mediated inhibition of Circ1647 may serve as a therapeutic target for renal fibrosis in CKD.

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Section: Methodsmentioning

confidence: 89%

“…The unilateral ureteral obstruction (UUO) model was established in male C57BL/6 mice as described previously [ 16 , 17 ]. Briefly, the mice were anesthetized with 1% pentobarbital, and the left ureter was exposed through a midline incision on the lower back.…”

Section: Methodsmentioning

confidence: 99%

RfxCas13d-mediated inhibition of Circ1647 alleviates renal fibrosis via PI3K/AKT signaling pathway

Ni,

Zhang,

Xian

et al. 2024

Renal Failure

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“…Histological analyses were performed essentially as described before 37 – 39 . Pictures were taken using an Olympus IX-70 microscope.…”

Section: Methodsmentioning

confidence: 99%

An MRTF-A–ZEB1–IRF9 axis contributes to fibroblast–myofibroblast transition and renal fibrosis

et al. 2023

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Myofibroblasts, characterized by the expression of the matricellular protein periostin (Postn), mediate the profibrogenic response during tissue repair and remodeling. Previous studies have demonstrated that systemic deficiency in myocardin-related transcription factor A (MRTF-A) attenuates renal fibrosis in mice. In the present study, we investigated the myofibroblast-specific role of MRTF-A in renal fibrosis and the underlying mechanism. We report that myofibroblast-specific deletion of MRTF-A, achieved through crossbreeding Mrtfa-flox mice with Postn-CreERT2 mice, led to amelioration of renal fibrosis. RNA-seq identified zinc finger E-Box binding homeobox 1 (Zeb1) as a downstream target of MRTF-A in renal fibroblasts. MRTF-A interacts with TEA domain transcription factor 1 (TEAD1) to bind to the Zeb1 promoter and activate Zeb1 transcription. Zeb1 knockdown retarded the fibroblast–myofibroblast transition (FMyT) in vitro and dampened renal fibrosis in mice. Transcriptomic assays showed that Zeb1 might contribute to FMyT by repressing the transcription of interferon regulatory factor 9 (IRF9). IRF9 knockdown overcame the effect of Zeb1 depletion and promoted FMyT, whereas IRF9 overexpression antagonized TGF-β-induced FMyT. In conclusion, our data unveil a novel MRTF-A–Zeb1–IRF9 axis that can potentially contribute to fibroblast–myofibroblast transition and renal fibrosis. Screening for small-molecule compounds that target this axis may yield therapeutic options for the mollification of renal fibrosis.

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“…[ 48 ] Our studies confirmed that ACSL4-mediated ferroptosis was involved in UUO and adenine diet-induced kidney fibrosis. [ 6 , 26 ] Other reported signaling pathways include Smad3/ATF3/SLC7A11 signaling, [ 49 ] Akt/GSK-3p/Nrf2 signaling, [ 50 ] XBP1-Hrd1-Nrf2 signaling, [ 51 ] AKT/ mTOR/Nrf2 signaling, [ 52 ] TLR4/Nox4 signaling [ 53 ] and so on ( Figure 3A ).…”

Section: Kidney Fibrosismentioning

confidence: 99%

“…With the deepening of research, the therapeutic potential of targeting ferroptosis in fibrotic kidneys has been increasingly recognized ( Figure 4A ). In recent years, there has been an increased number of natural active ingredients found to possess anti-renal fibrotic effects, including vitexin, [ 59 ] rhein, [ 60 ] fisetin, [ 6 ] puerarin, [ 53 ] salidroside, [ 61 ] formononetin, [ 49 ] nobiletin, [ 62 ] and tectorigenin. [ 63 ] Furthermore, the marketed drug for renal anemia (roxadustat) was also found to exert its anti-fibrotic effects through targeting ferroptosis.…”

Section: Kidney Fibrosismentioning

confidence: 99%

Ferroptosis in organ fibrosis: From mechanisms to therapeutic medicines

Lai,

Wang,

Huang

et al. 2024

Journal of Translational Internal Medicine

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Fibrosis occurs in many organs, and its sustained progress can lead to organ destruction and malfunction. Although numerous studies on organ fibrosis have been carried out, its underlying mechanism is largely unknown, and no ideal treatment is currently available. Ferroptosis is an iron-dependent process of programmed cell death that is characterized by lipid peroxidation. In the past decade, a growing body of evidence demonstrated the association between ferroptosis and fibrotic diseases, while targeting ferroptosis may serve as a potential therapeutic strategy. This review highlights recent advances in the crosstalk between ferroptosis and organ fibrosis, and discusses ferroptosis-targeted therapeutic approaches against fibrosis that are currently being explored.

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Formononetin ameliorates ferroptosis-associated fibrosis in renal tubular epithelial cells and in mice with chronic kidney disease by suppressing the Smad3/ATF3/SLC7A11 signaling

Cited by 39 publications

References 31 publications

RfxCas13d-mediated inhibition of Circ1647 alleviates renal fibrosis via PI3K/AKT signaling pathway

RfxCas13d-mediated inhibition of Circ1647 alleviates renal fibrosis via PI3K/AKT signaling pathway

An MRTF-A–ZEB1–IRF9 axis contributes to fibroblast–myofibroblast transition and renal fibrosis

Ferroptosis in organ fibrosis: From mechanisms to therapeutic medicines

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