Selective EZH2 inhibitor zld1039 alleviates inflammation in cisplatin-induced acute kidney injury partially by enhancing RKIP and suppressing NF-κB p65 pathway

Li, Wen; Tao, Shaohua; Guo, Fan; Li, Ling-Zhi; Yang, Hongliu; Liang, Yan; Zhang, Lidan; Ma, Liang; Fu, Ping

doi:10.1038/s41401-021-00837-8

Cited by 17 publications

(26 citation statements)

References 53 publications

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“…Several latest research results support this argument. ZLD1039 (a selective EZH2 inhibitor) effectively inhibits the expression of EZH2 and H3K27me3, and blocked the upregulation of RKIP and activation of nuclear factor-κB (NF-κB) p65 signaling pathway, thus alleviating inflammation in cisplatin-induced AKI ( Wen et al, 2021 ). This research further demonstrates that H3K27me3 binds to p65 (Rela) and RKIP (PEBP1) promoter regions by CHIP assay, but EZH2 does not directly recruit to these two promoter regions, suggesting that the inhibition of EZH2 on p65 and RKIP expression mainly depends on its methyltransferase activity ( Wen et al, 2021 ).…”

Section: Lysine Methyltransferasementioning

confidence: 99%

“…ZLD1039 (a selective EZH2 inhibitor) effectively inhibits the expression of EZH2 and H3K27me3, and blocked the upregulation of RKIP and activation of nuclear factor-κB (NF-κB) p65 signaling pathway, thus alleviating inflammation in cisplatin-induced AKI ( Wen et al, 2021 ). This research further demonstrates that H3K27me3 binds to p65 (Rela) and RKIP (PEBP1) promoter regions by CHIP assay, but EZH2 does not directly recruit to these two promoter regions, suggesting that the inhibition of EZH2 on p65 and RKIP expression mainly depends on its methyltransferase activity ( Wen et al, 2021 ). Moreover, EZH2-mediated H3K27 methylation attenuates the expression of TIMP-2 and TIMP-3 by inducing promoter DNA methylation in prostate cancer ( Shin and Kim, 2012 ) while the silencing of E-cadherin occurs through H3K27 methylation without DNA methylation in non-small-cell lung carcinoma ( Jia et al, 2021 ).…”

Section: Lysine Methyltransferasementioning

confidence: 99%

“…In conclusion, EZH2 mainly through two action modes to regulate the development of AKI and CKD: 1) By catalyzing H3K27 trimethylation in the nucleus to silence numerous target genes, thereby affecting the expression or phosphorylation of target proteins and the activation of downstream signaling pathways ( Wen et al, 2021 ; Liu et al, 2020 ); 2) EZH2 can also be localized to the cytoplasm and methylate non-histone proteins such as STAT3 ( Zhou et al, 2016 ) and β-catenin ( Wan et al, 2017 ). The role and mechanism of EZH2 in different chronic kidney diseases is summarized in Table 1 .…”

Section: Lysine Methyltransferasementioning

confidence: 99%

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The Role and Mechanism of Lysine Methyltransferase and Arginine Methyltransferase in Kidney Diseases

Zhou

Chen

et al. 2022

Front. Pharmacol.

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Methylation can occur in both histones and non-histones. Key lysine and arginine methyltransferases under investigation for renal disease treatment include enhancer of zeste homolog 2 (EZH2), G9a, disruptor of telomeric silencing 1-like protein (DOT1L), and protein arginine methyltransferases (PRMT) 1 and 5. Recent studies have shown that methyltransferases expression and activity are also increased in several animal models of kidney injury, such as acute kidney injury(AKI), obstructive nephropathy, diabetic nephropathy and lupus nephritis. The inhibition of most methyltransferases can attenuate kidney injury, while the role of methyltransferase in different animal models remains controversial. In this article, we summarize the role and mechanism of lysine methyltransferase and arginine methyltransferase in various kidney diseases and highlight methyltransferase as a potential therapeutic target for kidney diseases.

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Section: Lysine Methyltransferasementioning

confidence: 99%

Section: Lysine Methyltransferasementioning

confidence: 99%

Section: Lysine Methyltransferasementioning

confidence: 99%

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The Role and Mechanism of Lysine Methyltransferase and Arginine Methyltransferase in Kidney Diseases

Zhou

Chen

et al. 2022

Front. Pharmacol.

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“…Animal experimental procedures were licensed and permitted by the Animal Care and Use Ethics Committee of Sichuan University (2020205A). Male C57BL/6J mice were clari ed previously (27). C57BL/6J mice were administered cisplatin (20 mg/kg) with or without BAY 2416964 (20 mg/kg) by intraperitoneal injection.…”

Section: Animal Experimentsmentioning

confidence: 99%

“…Renal tubular damage semi-quantitatively scores were used to assess the pathological injury. The speci c score standards and detailed rules have been shown in previous study (27).…”

Section: Pathological Examinationmentioning

confidence: 99%

Tubular aryl hydrocarbon receptor upregulates EZH2 to promote cell senescence in cisplatin-induced acute kidney injury

Ren

Du³

et al. 2022

Preprint

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Acute kidney injury (AKI) is one of the serious clinical syndromes with high morbidity and mortality. Despite substantial progress in understanding of AKI mechanism, no drug therapy is available for treatment or prevention. In this study, we identified that a ligand-activated transcription factor aryl hydrocarbon receptor (AhR) was highly expressed in the kidneys of cisplatin-induced AKI mice or tubular epithelial TCMK-1 cells. Notably, the AhR inhibition by BAY2416964 and tubular conditional deletion both alleviated cisplatin-induced kidney injury and cellular senescence, which was indicated by senescence-associated β-galactosidase (SA-β-gal) activity, biomarker p53, p21, p16 protein expression, and secretory phenotype IL-1β, IL-6 and TNFα level. Mechanistically, the abnormal AhR expression was positively correlated with the elevated EZH2, a methyltransferase. In addition, AhR inhibition also could suppress the EZH2 expression in the cisplatin-injured kidneys. Furthermore, the ChIP assay displayed that EZH2 may indirectly interact with AhR promoter region by affecting H3K27me3. The direct recruitment between H3K27me3 and AhR promoter is higher in the kidneys of control than that of cisplatin mice, suggesting EZH2 could reversely regulate the AhR expression through weakening H3K27me3 transcriptional inhibition on AhR promoter. Collectively, the present study implicated that AhR and EZH2 have mutual regulation, which further accelerated tubular cellular senescence in cisplatin-induced AKI.

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Epigenetics-mediated pathological alternations and their potential in antiphospholipid syndrome diagnosis and therapy

Tan

Liu

et al. 2022

Autoimmunity Reviews

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Selective EZH2 inhibitor zld1039 alleviates inflammation in cisplatin-induced acute kidney injury partially by enhancing RKIP and suppressing NF-κB p65 pathway

Cited by 17 publications

References 53 publications

The Role and Mechanism of Lysine Methyltransferase and Arginine Methyltransferase in Kidney Diseases

The Role and Mechanism of Lysine Methyltransferase and Arginine Methyltransferase in Kidney Diseases

Tubular aryl hydrocarbon receptor upregulates EZH2 to promote cell senescence in cisplatin-induced acute kidney injury

Epigenetics-mediated pathological alternations and their potential in antiphospholipid syndrome diagnosis and therapy

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