Pathologic HDAC1/c-Myc signaling axis is responsible for angiotensinogen transcription and hypertension induced by high-fat diet
High-fat diet (HFD)-induced obesity is a cause of resistant hypertension. We have shown a possible link between histone deacetylases (HDACs) and renal angiotensinogen (Agt) upregulation in the HFD-induced hypertension, whereas the underlying mechanisms remain to be elucidated. Here, using a HDAC1/2...
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| Format: | Article |
| Language: | English |
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Elsevier
2023-08-01
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| Series: | Biomedicine & Pharmacotherapy |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S0753332223007163 |
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| author | Eui Kyung Youn Hyun Min Cho Jin Ki Jung Ga-Eun Yoon Masumi Eto Jee In Kim |
| author_facet | Eui Kyung Youn Hyun Min Cho Jin Ki Jung Ga-Eun Yoon Masumi Eto Jee In Kim |
| author_sort | Eui Kyung Youn |
| collection | DOAJ |
| description | High-fat diet (HFD)-induced obesity is a cause of resistant hypertension. We have shown a possible link between histone deacetylases (HDACs) and renal angiotensinogen (Agt) upregulation in the HFD-induced hypertension, whereas the underlying mechanisms remain to be elucidated. Here, using a HDAC1/2 inhibitor romidepsin (FK228) and siRNAs, we determined roles of HDAC1 and HDAC2 in HFD-induced hypertension and found the pathologic signaling axis between HDAC1 and Agt transcription. Treatment with FK228 canceled the increased blood pressure of male C57BL/6 mice induced by HFD. FK228 also blocked upregulation of renal Agt mRNA, protein, angiotensin II (Ang II) or serum Ang II. Activation and nuclear accumulation of both HDAC1 and HDAC2 occurred in the HFD group. The HFD-induced HDAC activation was associated with an increase in deacetylated c-Myc transcription factor. Silencing of HDAC1, HDAC2 or c-Myc in HRPTEpi cells decreased Agt expression. However, only HDAC1 knockdown, but not HDAC2, increased c-Myc acetylation, suggesting selective roles in two enzymes. Chromatin immunoprecipitation assay revealed that HFD induced the binding of HDAC1 and deacetylated c-Myc at the Agt gene promoter. A putative c-Myc binding sequence in the promotor region was necessary for Agt transcription. Inhibition of c-Myc downregulated Agt and Ang II levels in kidney and serum, ameliorating HFD-induced hypertension. Thus, the abnormal HDAC1/2 in the kidney may be responsible for the upregulation of the Agt gene expression and hypertension. The results expose the pathologic HDAC1/c-myc signaling axis in kidney as a promising therapeutic target for obesity-associated resistant hypertension. |
| first_indexed | 2024-03-13T04:56:47Z |
| format | Article |
| id | doaj.art-7f00379e746c48fe95e05fa9aa96c857 |
| institution | Directory Open Access Journal |
| issn | 0753-3322 |
| language | English |
| last_indexed | 2024-03-13T04:56:47Z |
| publishDate | 2023-08-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Biomedicine & Pharmacotherapy |
| spelling | doaj.art-7f00379e746c48fe95e05fa9aa96c8572023-06-18T05:00:43ZengElsevierBiomedicine & Pharmacotherapy0753-33222023-08-01164114926Pathologic HDAC1/c-Myc signaling axis is responsible for angiotensinogen transcription and hypertension induced by high-fat dietEui Kyung Youn0Hyun Min Cho1Jin Ki Jung2Ga-Eun Yoon3Masumi Eto4Jee In Kim5Department of Molecular Medicine, Keimyung University School of Medicine, Daegu 42601, Republic of KoreaDepartment of Molecular Medicine, Keimyung University School of Medicine, Daegu 42601, Republic of KoreaDepartment of Molecular Medicine, Keimyung University School of Medicine, Daegu 42601, Republic of KoreaDepartment of Molecular Medicine, Keimyung University School of Medicine, Daegu 42601, Republic of KoreaDepartment of Veterinary Medicine, Okayama University of Science, Ehime 794–8555, JapanDepartment of Molecular Medicine, Keimyung University School of Medicine, Daegu 42601, Republic of Korea; Correspondence to: Department of Molecular Medicine, Keimyung University School of Medicine 1095 Dalgubeol-daero, Dalseo-gu Daegu 42601, Republic of Korea.High-fat diet (HFD)-induced obesity is a cause of resistant hypertension. We have shown a possible link between histone deacetylases (HDACs) and renal angiotensinogen (Agt) upregulation in the HFD-induced hypertension, whereas the underlying mechanisms remain to be elucidated. Here, using a HDAC1/2 inhibitor romidepsin (FK228) and siRNAs, we determined roles of HDAC1 and HDAC2 in HFD-induced hypertension and found the pathologic signaling axis between HDAC1 and Agt transcription. Treatment with FK228 canceled the increased blood pressure of male C57BL/6 mice induced by HFD. FK228 also blocked upregulation of renal Agt mRNA, protein, angiotensin II (Ang II) or serum Ang II. Activation and nuclear accumulation of both HDAC1 and HDAC2 occurred in the HFD group. The HFD-induced HDAC activation was associated with an increase in deacetylated c-Myc transcription factor. Silencing of HDAC1, HDAC2 or c-Myc in HRPTEpi cells decreased Agt expression. However, only HDAC1 knockdown, but not HDAC2, increased c-Myc acetylation, suggesting selective roles in two enzymes. Chromatin immunoprecipitation assay revealed that HFD induced the binding of HDAC1 and deacetylated c-Myc at the Agt gene promoter. A putative c-Myc binding sequence in the promotor region was necessary for Agt transcription. Inhibition of c-Myc downregulated Agt and Ang II levels in kidney and serum, ameliorating HFD-induced hypertension. Thus, the abnormal HDAC1/2 in the kidney may be responsible for the upregulation of the Agt gene expression and hypertension. The results expose the pathologic HDAC1/c-myc signaling axis in kidney as a promising therapeutic target for obesity-associated resistant hypertension.http://www.sciencedirect.com/science/article/pii/S0753332223007163Obesity-associated hypertensionHistone deacetylase 1Cellular myelocytomatosis oncogeneAngiotensinogenEpigenetic regulation |
| spellingShingle | Eui Kyung Youn Hyun Min Cho Jin Ki Jung Ga-Eun Yoon Masumi Eto Jee In Kim Pathologic HDAC1/c-Myc signaling axis is responsible for angiotensinogen transcription and hypertension induced by high-fat diet Biomedicine & Pharmacotherapy Obesity-associated hypertension Histone deacetylase 1 Cellular myelocytomatosis oncogene Angiotensinogen Epigenetic regulation |
| title | Pathologic HDAC1/c-Myc signaling axis is responsible for angiotensinogen transcription and hypertension induced by high-fat diet |
| title_full | Pathologic HDAC1/c-Myc signaling axis is responsible for angiotensinogen transcription and hypertension induced by high-fat diet |
| title_fullStr | Pathologic HDAC1/c-Myc signaling axis is responsible for angiotensinogen transcription and hypertension induced by high-fat diet |
| title_full_unstemmed | Pathologic HDAC1/c-Myc signaling axis is responsible for angiotensinogen transcription and hypertension induced by high-fat diet |
| title_short | Pathologic HDAC1/c-Myc signaling axis is responsible for angiotensinogen transcription and hypertension induced by high-fat diet |
| title_sort | pathologic hdac1 c myc signaling axis is responsible for angiotensinogen transcription and hypertension induced by high fat diet |
| topic | Obesity-associated hypertension Histone deacetylase 1 Cellular myelocytomatosis oncogene Angiotensinogen Epigenetic regulation |
| url | http://www.sciencedirect.com/science/article/pii/S0753332223007163 |
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