YY1-induced upregulation of LncRNA-ARAP1-AS2 and ARAP1 promotes diabetic kidney fibrosis via aberrant glycolysis associated with EGFR/PKM2/HIF-1α pathway
Objectives: Dimeric pyruvate kinase (PK) M2 (PKM2) plays an important role in promoting the accumulation of hypoxia-inducible factor (HIF)-1α, mediating aberrant glycolysis and inducing fibrosis in diabetic kidney disease (DKD). The aim of this work was to dissect a novel regulatory mechanism of Yin and Yang 1 (YY1) on lncRNA-ARAP1-AS2/ARAP1 to regulate EGFR/PKM2/HIF-1α pathway and glycolysis in DKD.Materials and methods: We used adeno-associated virus (AAV)-ARAP1 shRNA to knocked down ARAP1 in diabetic mice and overexpressed or knocked down YY1, ARAP1-AS2 and ARAP1 expression in human glomerular mesangial cells. Gene levels were assessed by Western blotting, RT-qPCR, immunofluorescence staining and immunohistochemistry. Molecular interactions were determined by RNA pull-down, co-immunoprecipitation, ubiquitination assay and dual-luciferase reporter analysis.Results: YY1, ARAP1-AS2, ARAP1, HIF-1α, glycolysis and fibrosis genes expressions were upregulated and ARAP1 knockdown could inhibit dimeric PKM2 expression and partly restore tetrameric PKM2 formation, while downregulate HIF-1α accumulation and aberrant glycolysis and fibrosis in in-vivo and in-vitro DKD models. ARAP1 knockdown attenuates renal injury and renal dysfunction in diabetic mice. ARAP1 maintains EGFR overactivation in-vivo and in-vitro DKD models. Mechanistically, YY1 transcriptionally upregulates ARAP1-AS2 and indirectly regulates ARAP1 and subsequently promotes EGFR activation, HIF-1α accumulation and aberrant glycolysis and fibrosis.Conclusion: Our results first highlight the role of the novel regulatory mechanism of YY1 on ARAP1-AS2 and ARAP1 in promoting aberrant glycolysis and fibrosis by EGFR/PKM2/HIF-1α pathway in DKD and provide potential therapeutic strategies for DKD treatments..
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:14 |
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| Enthalten in: |
Frontiers in Pharmacology - 14(2023) |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Xin Li [VerfasserIn] |
|---|
| Links: |
doi.org [kostenfrei] |
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| Themen: |
ARAP1 |
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| doi: |
10.3389/fphar.2023.1069348 |
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| funding: |
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|---|---|
| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
DOAJ080418139 |
|---|
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| 245 | 1 | 0 | |a YY1-induced upregulation of LncRNA-ARAP1-AS2 and ARAP1 promotes diabetic kidney fibrosis via aberrant glycolysis associated with EGFR/PKM2/HIF-1α pathway |
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| 520 | |a Objectives: Dimeric pyruvate kinase (PK) M2 (PKM2) plays an important role in promoting the accumulation of hypoxia-inducible factor (HIF)-1α, mediating aberrant glycolysis and inducing fibrosis in diabetic kidney disease (DKD). The aim of this work was to dissect a novel regulatory mechanism of Yin and Yang 1 (YY1) on lncRNA-ARAP1-AS2/ARAP1 to regulate EGFR/PKM2/HIF-1α pathway and glycolysis in DKD.Materials and methods: We used adeno-associated virus (AAV)-ARAP1 shRNA to knocked down ARAP1 in diabetic mice and overexpressed or knocked down YY1, ARAP1-AS2 and ARAP1 expression in human glomerular mesangial cells. Gene levels were assessed by Western blotting, RT-qPCR, immunofluorescence staining and immunohistochemistry. Molecular interactions were determined by RNA pull-down, co-immunoprecipitation, ubiquitination assay and dual-luciferase reporter analysis.Results: YY1, ARAP1-AS2, ARAP1, HIF-1α, glycolysis and fibrosis genes expressions were upregulated and ARAP1 knockdown could inhibit dimeric PKM2 expression and partly restore tetrameric PKM2 formation, while downregulate HIF-1α accumulation and aberrant glycolysis and fibrosis in in-vivo and in-vitro DKD models. ARAP1 knockdown attenuates renal injury and renal dysfunction in diabetic mice. ARAP1 maintains EGFR overactivation in-vivo and in-vitro DKD models. Mechanistically, YY1 transcriptionally upregulates ARAP1-AS2 and indirectly regulates ARAP1 and subsequently promotes EGFR activation, HIF-1α accumulation and aberrant glycolysis and fibrosis.Conclusion: Our results first highlight the role of the novel regulatory mechanism of YY1 on ARAP1-AS2 and ARAP1 in promoting aberrant glycolysis and fibrosis by EGFR/PKM2/HIF-1α pathway in DKD and provide potential therapeutic strategies for DKD treatments. | ||
| 650 | 4 | |a LncRNA-ARAP1-AS2 | |
| 650 | 4 | |a ARAP1 | |
| 650 | 4 | |a diabetic kidney disease | |
| 650 | 4 | |a HIF-1α | |
| 650 | 4 | |a glycolysis | |
| 650 | 4 | |a fibrosis | |
| 653 | 0 | |a Therapeutics. Pharmacology | |
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| 700 | 0 | |a Tian-Kui Ma |e verfasserin |4 aut | |
| 700 | 0 | |a Min Wang |e verfasserin |4 aut | |
| 700 | 0 | |a Xiao-Dan Zhang |e verfasserin |4 aut | |
| 700 | 0 | |a Tian-Yan Liu |e verfasserin |4 aut | |
| 700 | 0 | |a Yue Liu |e verfasserin |4 aut | |
| 700 | 0 | |a Zhao-Hui Huang |e verfasserin |4 aut | |
| 700 | 0 | |a Yong-Hong Zhu |e verfasserin |4 aut | |
| 700 | 0 | |a Shuang Zhang |e verfasserin |4 aut | |
| 700 | 0 | |a Li Yin |e verfasserin |4 aut | |
| 700 | 0 | |a Yan-Yan Xu |e verfasserin |4 aut | |
| 700 | 0 | |a Hong Ding |e verfasserin |4 aut | |
| 700 | 0 | |a Cong Liu |e verfasserin |4 aut | |
| 700 | 0 | |a Hang Shi |e verfasserin |4 aut | |
| 700 | 0 | |a Qiu-Ling Fan |e verfasserin |4 aut | |
| 700 | 0 | |a Qiu-Ling Fan |e verfasserin |4 aut | |
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