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LncRNA ANRIL mediates endothelial dysfunction through BDNF downregulation in chronic kidney disease

Endothelial dysfunction is common in patients with chronic kidney disease (CKD), but the mechanism is unknown. In this study, we found that the circulating ANRIL level was increased and correlated with vascular endothelial dysfunction in patients with CKD, also negatively correlated with plasma brai...

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Autores principales: Su, Hong, Liu, Bing, Chen, Huimin, Zhang, Tingwei, Huang, Tongtong, Liu, Yue, Wang, Cheng, Ma, Qiqi, Wang, Qianhui, Lv, Zhimei, Wang, Rong
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9338026/
https://www.ncbi.nlm.nih.gov/pubmed/35906216
http://dx.doi.org/10.1038/s41419-022-05068-1
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author Su, Hong
Liu, Bing
Chen, Huimin
Zhang, Tingwei
Huang, Tongtong
Liu, Yue
Wang, Cheng
Ma, Qiqi
Wang, Qianhui
Lv, Zhimei
Wang, Rong
author_facet Su, Hong
Liu, Bing
Chen, Huimin
Zhang, Tingwei
Huang, Tongtong
Liu, Yue
Wang, Cheng
Ma, Qiqi
Wang, Qianhui
Lv, Zhimei
Wang, Rong
author_sort Su, Hong
collection PubMed
description Endothelial dysfunction is common in patients with chronic kidney disease (CKD), but the mechanism is unknown. In this study, we found that the circulating ANRIL level was increased and correlated with vascular endothelial dysfunction in patients with CKD, also negatively correlated with plasma brain-derived neurotrophic factor (BDNF) concentration. We constructed the ANRIL knockout mice model, and found that ANRIL deficiency reversed the abnormal expression of BDNF, along with endothelial nitric oxide synthase (eNOS), vascular adhesion molecule 1 (VCAM-1) and Von Willebrand factor (vWF). Meanwhile, mitochondrial dynamics-related proteins, Dynamin-related protein 1 (Drp1) and mitofusins (Mfn2) level were also recovered. In addition, in vitro, serum derived from CKD patients and uremia toxins induced abnormal expression of ANRIL. By making use of the gain- and loss-of-function approaches, we observed that ANRIL mediated endothelial dysfunction through BDNF downregulation. To explore the specific mechanism, RNA pull-down and RNA-binding protein immunoprecipitation (RIP) were used to explore the binding of ANRIL to histone methyltransferase Enhancer of zeste homolog 2 (EZH2). Further experiments found increased EZH2 and histone H3 lysine 27 trimethylation (H3K27me3) levels at the BDNF promoter region. Collectively, we demonstrated that ANRIL mediate BDNF transcriptional suppression through recruitment of EZH2 to the BDNF promoter region, then regulated the proteins expression related to endothelial function and mitochondrial dynamics. This study provides new insights for the study of endothelial dysfunction in CKD.
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spelling pubmed-93380262022-07-31 LncRNA ANRIL mediates endothelial dysfunction through BDNF downregulation in chronic kidney disease Su, Hong Liu, Bing Chen, Huimin Zhang, Tingwei Huang, Tongtong Liu, Yue Wang, Cheng Ma, Qiqi Wang, Qianhui Lv, Zhimei Wang, Rong Cell Death Dis Article Endothelial dysfunction is common in patients with chronic kidney disease (CKD), but the mechanism is unknown. In this study, we found that the circulating ANRIL level was increased and correlated with vascular endothelial dysfunction in patients with CKD, also negatively correlated with plasma brain-derived neurotrophic factor (BDNF) concentration. We constructed the ANRIL knockout mice model, and found that ANRIL deficiency reversed the abnormal expression of BDNF, along with endothelial nitric oxide synthase (eNOS), vascular adhesion molecule 1 (VCAM-1) and Von Willebrand factor (vWF). Meanwhile, mitochondrial dynamics-related proteins, Dynamin-related protein 1 (Drp1) and mitofusins (Mfn2) level were also recovered. In addition, in vitro, serum derived from CKD patients and uremia toxins induced abnormal expression of ANRIL. By making use of the gain- and loss-of-function approaches, we observed that ANRIL mediated endothelial dysfunction through BDNF downregulation. To explore the specific mechanism, RNA pull-down and RNA-binding protein immunoprecipitation (RIP) were used to explore the binding of ANRIL to histone methyltransferase Enhancer of zeste homolog 2 (EZH2). Further experiments found increased EZH2 and histone H3 lysine 27 trimethylation (H3K27me3) levels at the BDNF promoter region. Collectively, we demonstrated that ANRIL mediate BDNF transcriptional suppression through recruitment of EZH2 to the BDNF promoter region, then regulated the proteins expression related to endothelial function and mitochondrial dynamics. This study provides new insights for the study of endothelial dysfunction in CKD. Nature Publishing Group UK 2022-07-29 /pmc/articles/PMC9338026/ /pubmed/35906216 http://dx.doi.org/10.1038/s41419-022-05068-1 Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Su, Hong
Liu, Bing
Chen, Huimin
Zhang, Tingwei
Huang, Tongtong
Liu, Yue
Wang, Cheng
Ma, Qiqi
Wang, Qianhui
Lv, Zhimei
Wang, Rong
LncRNA ANRIL mediates endothelial dysfunction through BDNF downregulation in chronic kidney disease
title LncRNA ANRIL mediates endothelial dysfunction through BDNF downregulation in chronic kidney disease
title_full LncRNA ANRIL mediates endothelial dysfunction through BDNF downregulation in chronic kidney disease
title_fullStr LncRNA ANRIL mediates endothelial dysfunction through BDNF downregulation in chronic kidney disease
title_full_unstemmed LncRNA ANRIL mediates endothelial dysfunction through BDNF downregulation in chronic kidney disease
title_short LncRNA ANRIL mediates endothelial dysfunction through BDNF downregulation in chronic kidney disease
title_sort lncrna anril mediates endothelial dysfunction through bdnf downregulation in chronic kidney disease
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9338026/
https://www.ncbi.nlm.nih.gov/pubmed/35906216
http://dx.doi.org/10.1038/s41419-022-05068-1
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