LncRNA ANRIL mediates endothelial dysfunction through BDNF downregulation in chronic kidney disease
Abstract 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 pl...
| Main Authors: | , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Publishing Group
2022-07-01
|
| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-022-05068-1 |
| _version_ | 1818017896165539840 |
|---|---|
| author | Hong Su Bing Liu Huimin Chen Tingwei Zhang Tongtong Huang Yue Liu Cheng Wang Qiqi Ma Qianhui Wang Zhimei Lv Rong Wang |
| author_facet | Hong Su Bing Liu Huimin Chen Tingwei Zhang Tongtong Huang Yue Liu Cheng Wang Qiqi Ma Qianhui Wang Zhimei Lv Rong Wang |
| author_sort | Hong Su |
| collection | DOAJ |
| description | Abstract 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. |
| first_indexed | 2024-04-14T07:32:37Z |
| format | Article |
| id | doaj.art-1337fc2822ef454580edac31071e3ad0 |
| institution | Directory Open Access Journal |
| issn | 2041-4889 |
| language | English |
| last_indexed | 2024-04-14T07:32:37Z |
| publishDate | 2022-07-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj.art-1337fc2822ef454580edac31071e3ad02022-12-22T02:05:47ZengNature Publishing GroupCell Death and Disease2041-48892022-07-0113711410.1038/s41419-022-05068-1LncRNA ANRIL mediates endothelial dysfunction through BDNF downregulation in chronic kidney diseaseHong Su0Bing Liu1Huimin Chen2Tingwei Zhang3Tongtong Huang4Yue Liu5Cheng Wang6Qiqi Ma7Qianhui Wang8Zhimei Lv9Rong Wang10Department of Nephrology, Shandong Provincial Hospital Affiliated to Shandong First Medical UniversityDepartment of Nephrology, Shandong Provincial Hospital Affiliated to Shandong First Medical UniversityDepartment of Nephrology, Shandong Provincial Hospital Affiliated to Shandong First Medical UniversityDepartment of Nephrology, Shandong Provincial Hospital Affiliated to Shandong First Medical UniversityDepartment of Nephrology, Shandong Provincial Hospital Affiliated to Shandong First Medical UniversityDepartment of Nephrology, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong UniversityDepartment of Nephrology, Shandong Provincial Hospital Affiliated to Shandong First Medical UniversityDepartment of Nephrology, Shandong Provincial Hospital Affiliated to Shandong First Medical UniversityDepartment of Nephrology, Shandong Provincial Hospital Affiliated to Shandong First Medical UniversityDepartment of Nephrology, Shandong Provincial Hospital Affiliated to Shandong First Medical UniversityDepartment of Nephrology, Shandong Provincial Hospital Affiliated to Shandong First Medical UniversityAbstract 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.https://doi.org/10.1038/s41419-022-05068-1 |
| spellingShingle | Hong Su Bing Liu Huimin Chen Tingwei Zhang Tongtong Huang Yue Liu Cheng Wang Qiqi Ma Qianhui Wang Zhimei Lv Rong Wang LncRNA ANRIL mediates endothelial dysfunction through BDNF downregulation in chronic kidney disease Cell Death and 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 |
| url | https://doi.org/10.1038/s41419-022-05068-1 |
| work_keys_str_mv | AT hongsu lncrnaanrilmediatesendothelialdysfunctionthroughbdnfdownregulationinchronickidneydisease AT bingliu lncrnaanrilmediatesendothelialdysfunctionthroughbdnfdownregulationinchronickidneydisease AT huiminchen lncrnaanrilmediatesendothelialdysfunctionthroughbdnfdownregulationinchronickidneydisease AT tingweizhang lncrnaanrilmediatesendothelialdysfunctionthroughbdnfdownregulationinchronickidneydisease AT tongtonghuang lncrnaanrilmediatesendothelialdysfunctionthroughbdnfdownregulationinchronickidneydisease AT yueliu lncrnaanrilmediatesendothelialdysfunctionthroughbdnfdownregulationinchronickidneydisease AT chengwang lncrnaanrilmediatesendothelialdysfunctionthroughbdnfdownregulationinchronickidneydisease AT qiqima lncrnaanrilmediatesendothelialdysfunctionthroughbdnfdownregulationinchronickidneydisease AT qianhuiwang lncrnaanrilmediatesendothelialdysfunctionthroughbdnfdownregulationinchronickidneydisease AT zhimeilv lncrnaanrilmediatesendothelialdysfunctionthroughbdnfdownregulationinchronickidneydisease AT rongwang lncrnaanrilmediatesendothelialdysfunctionthroughbdnfdownregulationinchronickidneydisease |