<br>YY1诱导的LncRNA-ARAP1-AS2和ARAP1上调通过与EGFR/PKM2/HIF-1α通路相关的异常糖酵解促进糖尿病肾纤维化,Frontiers in Pharmacology

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YY1诱导的LncRNA-ARAP1-AS2和ARAP1上调通过与EGFR/PKM2/HIF-1α通路相关的异常糖酵解促进糖尿病肾纤维化
Frontiers in Pharmacology ( IF 4.4 ) Pub Date : 2023-02-15 , DOI: 10.3389/fphar.2023.1069348
Xin Li _{1,

2} , Tian-Kui Ma ₁ , Min Wang ₁ , Xiao-Dan Zhang ₁ , Tian-Yan Liu ₁ , Yue Liu ₁ , Zhao-Hui Huang ₁ , Yong-Hong Zhu ₁ , Shuang Zhang ₂ , Li Yin ₂ , Yan-Yan Xu ₂ , Hong Ding ₂ , Cong Liu ₃ , Hang Shi ₄ , Qiu-Ling Fan _{1,

5}

Affiliation

目的：二聚丙酮酸激酶 (PK) M2 (PKM2) 在促进缺氧诱导因子 (HIF)-1α 积累、介导异常糖酵解和诱导糖尿病肾病 (DKD) 纤维化方面发挥重要作用。本工作的目的是剖析阴阳 1 (YY1) 对 lncRNA-ARAP1-AS2/ARAP1 的一种新的调节机制，以调节 DKD 中的 EGFR/PKM2/HIF-1α 通路和糖酵解。材料和方法：我们使用腺苷-相关病毒（AAV）-ARAP1 shRNA 可敲低糖尿病小鼠中的 ARAP1，并过表达或敲低人肾小球系膜细胞中的 YY1、ARAP1-AS2 和 ARAP1 表达。通过蛋白质印迹、RT-qPCR、免疫荧光染色和免疫组织化学评估基因水平。通过RNA Pull-down、免疫共沉淀、泛素化实验和双荧光素酶报告基因分析确定分子相互作用。结果：YY1、ARAP1-AS2、ARAP1、HIF-1α、糖酵解和纤维化基因表达上调，并且ARAP1敲低可以抑制二聚体在体内和体外 DKD 模型中，PKM2 表达并部分恢复四聚体 PKM2 形成，同时下调 HIF-1α 积累以及异常糖酵解和纤维化。 ARAP1 敲低可减轻糖尿病小鼠的肾损伤和肾功能障碍。 ARAP1 在体内和体外 DKD 模型中维持 EGFR 过度激活。从机制上讲，YY1 转录上调 ARAP1-AS2 并间接调节 ARAP1，随后促进 EGFR 激活、HIF-1α 积累以及异常糖酵解和纤维化。结论：我们的结果首先强调了 YY1 对 ARAP1-AS2 和 ARAP1 的新型调节机制在通过 EGFR/PKM2/HIF-1α 通路促进 DKD 异常糖酵解和纤维化，为 DKD 治疗提供潜在的治疗策略。

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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.

更新日期：2023-02-15

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