Multi-omics Integrated Analysis of the Protective Effect of EZH2 inhibition in Mice with Renal Ischemia-Reperfusion Injury
Introduction: Acute kidney injury (AKI) is a common clinical syndrome associated with high morbidity and mortality. Inhibition of the methyltransferase Enhancer of Zeste Homolog 2 (EZH2) by its inhibitor 3-DZNeP (3-Deazaneplanocin A) exerts renal benefits in acute renal ischemia-reperfusion injury (...
| Main Authors: | , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Karger Publishers
2024-02-01
|
| Series: | Kidney & Blood Pressure Research |
| Online Access: | https://beta.karger.com/Article/FullText/537866 |
| _version_ | 1797262592187564032 |
|---|---|
| author | Shanshan Zou Jianing Chen Peihui Zhou Mengzhu Xue Ming Wu Li Wang |
| author_facet | Shanshan Zou Jianing Chen Peihui Zhou Mengzhu Xue Ming Wu Li Wang |
| author_sort | Shanshan Zou |
| collection | DOAJ |
| description | Introduction: Acute kidney injury (AKI) is a common clinical syndrome associated with high morbidity and mortality. Inhibition of the methyltransferase Enhancer of Zeste Homolog 2 (EZH2) by its inhibitor 3-DZNeP (3-Deazaneplanocin A) exerts renal benefits in acute renal ischemia-reperfusion injury (IRI). However, the underlying mechanisms is not completely known. This study aimed to elucidate the pathological mechanism of EZH2 in renal IRI by combination of multi-omics analysis and expression profiling in a public clinical cohort. Methods: In this study, C57BL/6J mice were used to establish acute kidney injury model, which were treated with 3-DZNeP for 24 hours. Kidney samples were collected for RNA-seq analysis, which was combined with publicly available EZH2-ChIP-seq data of mouse embryonic stem cell for a joint analysis to identify differentially expressed genes. Several selected differentially expressed genes were verified by quantitative PCR. Finally, single-nucleus sequencing data and expression profiling in public clinical datasets were used to confirm the negative correlation of the selected genes with EZH2 expression. Results: 3-DZNeP treatment significantly improved renal pathology and function in IRI mice. Through RNA-seq analysis combined with EZH2 ChIP-seq database, 162 differentially expressed genes were found, which might be involved in EZH2-mediated pathology in IRI kidneys. Four differential expressed genes (Scd1, Cidea, Ghr, and Kl) related to lipid metabolism or cell growth were selected based on GO and KEGG enrichment analysis, which were validated by quantitative PCR. Data from snRNA-seq revealed the negative correlation of these four genes with Ezh2 expression in different subpopulations of proximal tubular cells in IRI mice in different pattern. Finally, the negative correlation of these four genes with EZH2 expression was confirmed in patients with acute kidney injury in two clinical datasets. Conclusions: Our study indicates that Scd1, Cidea, Ghr, and Kl are downstream genes regulated by EZH2 in AKI. Upregulation of EZH2 in AKI inhibits the expression of these four genes in different population of proximal tubular cells to minimize normal physiological function, and promote acute or chronic cell injuries following acute kidney injury. |
| first_indexed | 2024-03-07T19:39:33Z |
| format | Article |
| id | doaj.art-a880fb9057d24998b8340a0db37827f1 |
| institution | Directory Open Access Journal |
| issn | 1423-0143 |
| language | English |
| last_indexed | 2024-04-24T23:59:33Z |
| publishDate | 2024-02-01 |
| publisher | Karger Publishers |
| record_format | Article |
| series | Kidney & Blood Pressure Research |
| spelling | doaj.art-a880fb9057d24998b8340a0db37827f12024-03-14T08:00:36ZengKarger PublishersKidney & Blood Pressure Research1423-01432024-02-011110.1159/000537866537866Multi-omics Integrated Analysis of the Protective Effect of EZH2 inhibition in Mice with Renal Ischemia-Reperfusion InjuryShanshan ZouJianing ChenPeihui ZhouMengzhu XueMing WuLi WangIntroduction: Acute kidney injury (AKI) is a common clinical syndrome associated with high morbidity and mortality. Inhibition of the methyltransferase Enhancer of Zeste Homolog 2 (EZH2) by its inhibitor 3-DZNeP (3-Deazaneplanocin A) exerts renal benefits in acute renal ischemia-reperfusion injury (IRI). However, the underlying mechanisms is not completely known. This study aimed to elucidate the pathological mechanism of EZH2 in renal IRI by combination of multi-omics analysis and expression profiling in a public clinical cohort. Methods: In this study, C57BL/6J mice were used to establish acute kidney injury model, which were treated with 3-DZNeP for 24 hours. Kidney samples were collected for RNA-seq analysis, which was combined with publicly available EZH2-ChIP-seq data of mouse embryonic stem cell for a joint analysis to identify differentially expressed genes. Several selected differentially expressed genes were verified by quantitative PCR. Finally, single-nucleus sequencing data and expression profiling in public clinical datasets were used to confirm the negative correlation of the selected genes with EZH2 expression. Results: 3-DZNeP treatment significantly improved renal pathology and function in IRI mice. Through RNA-seq analysis combined with EZH2 ChIP-seq database, 162 differentially expressed genes were found, which might be involved in EZH2-mediated pathology in IRI kidneys. Four differential expressed genes (Scd1, Cidea, Ghr, and Kl) related to lipid metabolism or cell growth were selected based on GO and KEGG enrichment analysis, which were validated by quantitative PCR. Data from snRNA-seq revealed the negative correlation of these four genes with Ezh2 expression in different subpopulations of proximal tubular cells in IRI mice in different pattern. Finally, the negative correlation of these four genes with EZH2 expression was confirmed in patients with acute kidney injury in two clinical datasets. Conclusions: Our study indicates that Scd1, Cidea, Ghr, and Kl are downstream genes regulated by EZH2 in AKI. Upregulation of EZH2 in AKI inhibits the expression of these four genes in different population of proximal tubular cells to minimize normal physiological function, and promote acute or chronic cell injuries following acute kidney injury.https://beta.karger.com/Article/FullText/537866 |
| spellingShingle | Shanshan Zou Jianing Chen Peihui Zhou Mengzhu Xue Ming Wu Li Wang Multi-omics Integrated Analysis of the Protective Effect of EZH2 inhibition in Mice with Renal Ischemia-Reperfusion Injury Kidney & Blood Pressure Research |
| title | Multi-omics Integrated Analysis of the Protective Effect of EZH2 inhibition in Mice with Renal Ischemia-Reperfusion Injury |
| title_full | Multi-omics Integrated Analysis of the Protective Effect of EZH2 inhibition in Mice with Renal Ischemia-Reperfusion Injury |
| title_fullStr | Multi-omics Integrated Analysis of the Protective Effect of EZH2 inhibition in Mice with Renal Ischemia-Reperfusion Injury |
| title_full_unstemmed | Multi-omics Integrated Analysis of the Protective Effect of EZH2 inhibition in Mice with Renal Ischemia-Reperfusion Injury |
| title_short | Multi-omics Integrated Analysis of the Protective Effect of EZH2 inhibition in Mice with Renal Ischemia-Reperfusion Injury |
| title_sort | multi omics integrated analysis of the protective effect of ezh2 inhibition in mice with renal ischemia reperfusion injury |
| url | https://beta.karger.com/Article/FullText/537866 |
| work_keys_str_mv | AT shanshanzou multiomicsintegratedanalysisoftheprotectiveeffectofezh2inhibitioninmicewithrenalischemiareperfusioninjury AT jianingchen multiomicsintegratedanalysisoftheprotectiveeffectofezh2inhibitioninmicewithrenalischemiareperfusioninjury AT peihuizhou multiomicsintegratedanalysisoftheprotectiveeffectofezh2inhibitioninmicewithrenalischemiareperfusioninjury AT mengzhuxue multiomicsintegratedanalysisoftheprotectiveeffectofezh2inhibitioninmicewithrenalischemiareperfusioninjury AT mingwu multiomicsintegratedanalysisoftheprotectiveeffectofezh2inhibitioninmicewithrenalischemiareperfusioninjury AT liwang multiomicsintegratedanalysisoftheprotectiveeffectofezh2inhibitioninmicewithrenalischemiareperfusioninjury |