Inhibition of EZH2 ameliorates hyperoxaluria-induced kidney injury through the JNK/FoxO3a pathway
Copyright © 2021. Published by Elsevier Inc..
AIMS: Enhancer of zeste homolog 2 (EZH2), a histone H3 lysine 27 methyltransferase, has been shown to play a role in kidney diseases. However, its role in hyperoxaluria-induced renal tubular epithelial cells (TECs) injury remains unclear.
MATERIALS AND METHODS: A hyperoxaluria rat model was established by providing 0.5% ammonium chloride and drinking water containing 1% ethylene glycol. TECs were exposed to oxalate stress. The 3-DZNeP, a selective EZH2 inhibitor, was administered in vivo and in vitro. Cell viability, ROS production, and apoptosis ratio were evaluated. Crystal deposition was detected by Von Kossa staining and kidney tissue injury was detected by HE staining and TUNEL. EZH2, H3K27me3, cleaved-caspase3, IL-6, and MCP-1 were examined by western blot or immunohistochemistry.
KEY FINDINGS: Inhibition of EZH2 by 3-DZNeP significantly attenuated hyperoxaluria-induced oxidative and inflammatory injury and CaOx crystal deposition in vivo. Similarly, inhibition of EZH2 using 3-DZNeP or shRNA restored cell viability, suppressed LDH release and the production of intracellular ROS in vitro. Furthermore, the MAPK signaling pathway and FoxO3a levels were activated or elevated in TECs exposed to oxalate. EZH2 inhibition using 3-DZNeP blocked these effects. CC90003 (ERK inhibitor) or SB203580 (p38 inhibitor) did not significantly affect the expression of FoxO3a in TECs treated with 3-DZNeP and oxalate; only SP600125 (JNK inhibitor) significantly decreased FoxO3a expression.
SIGNIFICANCE: EZH2 inhibition protects against oxalate-induced TECs injury and reduces CaOx crystal deposition in the kidney may by modulating the JNK/FoxO3a pathway; EZH2 may be a promising therapeutic target in TECs injury.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2022 |
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| Erschienen: |
2022 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:291 |
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| Enthalten in: |
Life sciences - 291(2022) vom: 15. Feb., Seite 120258 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Gao, Xiaomin [VerfasserIn] |
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| Links: |
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| Themen: |
EC 2.1.1.43 |
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| Anmerkungen: |
Date Completed 17.02.2022 Date Revised 17.02.2022 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1016/j.lfs.2021.120258 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM334879418 |
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| 100 | 1 | |a Gao, Xiaomin |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Inhibition of EZH2 ameliorates hyperoxaluria-induced kidney injury through the JNK/FoxO3a pathway |
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| 500 | |a Date Revised 17.02.2022 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Copyright © 2021. Published by Elsevier Inc. | ||
| 520 | |a AIMS: Enhancer of zeste homolog 2 (EZH2), a histone H3 lysine 27 methyltransferase, has been shown to play a role in kidney diseases. However, its role in hyperoxaluria-induced renal tubular epithelial cells (TECs) injury remains unclear | ||
| 520 | |a MATERIALS AND METHODS: A hyperoxaluria rat model was established by providing 0.5% ammonium chloride and drinking water containing 1% ethylene glycol. TECs were exposed to oxalate stress. The 3-DZNeP, a selective EZH2 inhibitor, was administered in vivo and in vitro. Cell viability, ROS production, and apoptosis ratio were evaluated. Crystal deposition was detected by Von Kossa staining and kidney tissue injury was detected by HE staining and TUNEL. EZH2, H3K27me3, cleaved-caspase3, IL-6, and MCP-1 were examined by western blot or immunohistochemistry | ||
| 520 | |a KEY FINDINGS: Inhibition of EZH2 by 3-DZNeP significantly attenuated hyperoxaluria-induced oxidative and inflammatory injury and CaOx crystal deposition in vivo. Similarly, inhibition of EZH2 using 3-DZNeP or shRNA restored cell viability, suppressed LDH release and the production of intracellular ROS in vitro. Furthermore, the MAPK signaling pathway and FoxO3a levels were activated or elevated in TECs exposed to oxalate. EZH2 inhibition using 3-DZNeP blocked these effects. CC90003 (ERK inhibitor) or SB203580 (p38 inhibitor) did not significantly affect the expression of FoxO3a in TECs treated with 3-DZNeP and oxalate; only SP600125 (JNK inhibitor) significantly decreased FoxO3a expression | ||
| 520 | |a SIGNIFICANCE: EZH2 inhibition protects against oxalate-induced TECs injury and reduces CaOx crystal deposition in the kidney may by modulating the JNK/FoxO3a pathway; EZH2 may be a promising therapeutic target in TECs injury | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Enhancer of zeste homolog 2 | |
| 650 | 4 | |a Inflammation | |
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| 700 | 1 | |a Peng, Yonghan |e verfasserin |4 aut | |
| 700 | 1 | |a Fang, Ziyu |e verfasserin |4 aut | |
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| 700 | 1 | |a Ming, Shaoxiong |e verfasserin |4 aut | |
| 700 | 1 | |a Dong, Hao |e verfasserin |4 aut | |
| 700 | 1 | |a Li, Rui |e verfasserin |4 aut | |
| 700 | 1 | |a Zhu, Yasheng |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Wei |e verfasserin |4 aut | |
| 700 | 1 | |a Zhu, Baoyi |e verfasserin |4 aut | |
| 700 | 1 | |a Liao, Junhao |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Zeyu |e verfasserin |4 aut | |
| 700 | 1 | |a Liu, Min |e verfasserin |4 aut | |
| 700 | 1 | |a Li, Weijian |e verfasserin |4 aut | |
| 700 | 1 | |a Zeng, Jianwen |e verfasserin |4 aut | |
| 700 | 1 | |a Gao, Xiaofeng |e verfasserin |4 aut | |
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