Knockdown of FOXO6 inhibits cell proliferation and ECM accumulation in glomerular mesangial cells cultured under high glucose condition

Wang, Yunqian; Xue, Lijun; Li, Huicong; Shi, Jun; Chen, Baoping

doi:10.1039/c8ra10547b

Cited by 3 publications

(2 citation statements)

References 27 publications

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“…According to literature reports, FOXO6 can activate the phosphoinositide 3-kinase (PI3K)/serine-threonine kinase (AKT) signaling pathway, thereby promoting cell proliferation and inhibiting apoptosis ( Feng and Qiu, 2018 ; Wang et al, 2019 ; Wu et al, 2020 ). Meanwhile, KEGG enrichment analysis suggested that FTO is involved in the pathogenesis of CGN through PI3K/AKT signaling pathway ( Supplementary Figure S3B and Supplementary Table S4 ).…”

Section: Resultsmentioning

confidence: 99%

Overexpression of FTO inhibits excessive proliferation and promotes the apoptosis of human glomerular mesangial cells by alleviating FOXO6 m6A modification via YTHDF3-dependent mechanisms

Zhuang,

Liu,

Wei

et al. 2023

Front. Pharmacol.

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Background: N6-methyladenosine (m6A) is a prevalent post-transcriptional modification presented in messenger RNA (mRNA) of eukaryotic organisms. Chronic glomerulonephritis (CGN) is characterised by excessive proliferation and insufficient apoptosis of human glomerular mesangial cells (HGMCs) but its underlying pathogenesis remains undefined. Moreover, the role of m6A in CGN is poorly understood.Methods: The total level of m6A modification was detected using the m6A quantification assay (Colorimetric). Cell proliferation was assessed by EdU cell proliferation assay, and cell apoptosis was detected by flow cytometry. RNA sequencing was performed to screen the downstream target of fat mass and obesity-associated protein (FTO). MeRIP-qPCR was conducted to detect the m6A level of forkhead box o6 (FOXO6) in HGMCs. RIP assay was utilized to indicate the targeting relationship between YTH domain family 3 (YTHDF3) and FOXO6. Actinomycin D assay was used to investigate the stability of FOXO6 in HGMCs.Results: The study found that the expression of FTO was significantly reduced in lipopolysaccharide (LPS)-induced HGMCs and renal biopsy samples of patients with CGN. Moreover, FTO overexpression and knockdown could regulate the proliferation and apoptosis of HGMCs. Furthermore, RNA sequencing and cellular experiments revealed FOXO6 as a downstream target of FTO in regulating the proliferation and apoptosis of HGMCs. Mechanistically, FTO overexpression decreases the level of FOXO6 m6A modification and reduces the stability of FOXO6 mRNA in a YTHDF3-dependent manner. Additionally, the decreased expression of FOXO6 inhibits the PI3K/AKT signaling pathway, thereby inhibiting the proliferation and promoting apoptosis of HGMCs.Conclusion: This study offers insights into the mechanism through which FTO regulates the proliferation and apoptosis of HGMCs by mediating m6A modification of FOXO6 mRNA. These findings also suggest FTO as a potential diagnostic marker and therapeutic target for CGN.

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Section: Resultsmentioning

confidence: 99%

Overexpression of FTO inhibits excessive proliferation and promotes the apoptosis of human glomerular mesangial cells by alleviating FOXO6 m6A modification via YTHDF3-dependent mechanisms

Zhuang,

Liu,

Wei

et al. 2023

Front. Pharmacol.

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“…According to the evidence collected so far, FOXOs may have both activating and inhibitory effects on fibrogenic processes, and Sirt1, as well as other sirtuins, such as Sirt2 and Sirt3, deacetylate FOXOs, thus favouring their nuclear translocation and FOXO-dependent gene expression. [117][118][119][120][121][122] In particular, in the context of fibrosis, the role of FOXO1 is still controversial, whereas FOXO3a, FOXO4 and FOXO6 have a profibrotic activity. 117-122…”

Section: Pi3k/akt and Mtor Pathwaysmentioning

confidence: 99%

Fibrosis: Sirtuins at the checkpoints of myofibroblast differentiation and profibrotic activity

Zullo

Mancini

Schleip

et al. 2021

Wound Repair Regeneration

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Fibrotic diseases are still a serious concern for public health, due to their high prevalence, complex etiology and lack of successful treatments. Fibrosis consists of excessive accumulation of extracellular matrix components. As a result, the structure and function of tissues are impaired, thus potentially leading to organ failure and death in several chronic diseases. Myofibroblasts represent the principal cellular mediators of fibrosis, due to their extracellular matrix producing activity, and originate from different types of precursor cells, such as mesenchymal cells, epithelial cells and fibroblasts. Profibrotic activation of myofibroblasts can be triggered by a variety of mechanisms, including the transforming growth factor-β signalling pathway, which is a major factor driving fibrosis. Interestingly, preclinical and clinical studies showed that fibrotic degeneration can stop and even reverse by using specific antifibrotic treatments. Increasing scientific evidence is being accumulated about the role of sirtuins in modulating the molecular pathways responsible for the onset and development of fibrotic diseases. Sirtuins are NAD +dependent protein deacetylases that play a crucial role in several molecular pathways within the cells, many of which at the crossroad between health and disease. In this context, we will report the current knowledge supporting the role of sirtuins in the balance between healthy and diseased myofibroblast activity. In particular, we will address the signalling pathways and the molecular targets that trigger the differentiation and profibrotic activation of myofibroblasts and can be modulated by sirtuins.

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FOXP1 inhibits high glucose-induced ECM accumulation and oxidative stress in mesangial cells

Xiang

Xue

et al. 2019

Chemico-Biological Interactions

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Knockdown of FOXO6 inhibits cell proliferation and ECM accumulation in glomerular mesangial cells cultured under high glucose condition

Abstract: Forkhead box O 6 (FOXO6), a FOX transcription factor, has been found to be involved in diabetes mellitus and related complications.

Cited by 3 publications

References 27 publications

Overexpression of FTO inhibits excessive proliferation and promotes the apoptosis of human glomerular mesangial cells by alleviating FOXO6 m6A modification via YTHDF3-dependent mechanisms

Overexpression of FTO inhibits excessive proliferation and promotes the apoptosis of human glomerular mesangial cells by alleviating FOXO6 m6A modification via YTHDF3-dependent mechanisms

Fibrosis: Sirtuins at the checkpoints of myofibroblast differentiation and profibrotic activity

FOXP1 inhibits high glucose-induced ECM accumulation and oxidative stress in mesangial cells

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