HDAC3 inhibition mitigates acute kidney injury by alleviating RIPK1-mediated programmed necrosis
Acute kidney injury (AKI) refers to clinical syndromes culminating in rapidly reduced renal function associated with inflammation and the demise of renal tubular epithelial cells. Current research aims to develop strategies which prevent tubular cell death. Here, based on the involvement of histone...
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Frontiers Media S.A.
2025-04-01
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| Series: | Frontiers in Pharmacology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fphar.2025.1546950/full |
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| author | Manman Xie Manman Xie Rui Hou Runrun Shan Xinyu Cheng Pengcheng Wu Xiufeng Luo Yangyang Wei Li Gao Xiaoying Liu Xiaoying Liu Qi Chen |
| author_facet | Manman Xie Manman Xie Rui Hou Runrun Shan Xinyu Cheng Pengcheng Wu Xiufeng Luo Yangyang Wei Li Gao Xiaoying Liu Xiaoying Liu Qi Chen |
| author_sort | Manman Xie |
| collection | DOAJ |
| description | Acute kidney injury (AKI) refers to clinical syndromes culminating in rapidly reduced renal function associated with inflammation and the demise of renal tubular epithelial cells. Current research aims to develop strategies which prevent tubular cell death. Here, based on the involvement of histone deacetylases (HDACs) in renal physiology and their established role in renal fibrosis, we investigated the mechanistic contributions of HDACs using a mouse model together with in vitro studies employing human renal epithelial cells. We found HDAC3 expression was upregulated in mouse renal tubules after ischemia/reperfusion and cisplatin treatment. Instructively, treatment with the HDAC3 selective inhibitor RGFP966 exerted potent protective effects, attenuates acute kidney injury in both in vivo and in vitro models. Moreover, RGFP966 was found to reduce inflammation and injury caused by cisplatin and hypoxia-reoxygenation in HK2 cells with transcriptome sequencing revealing that RGFP966 significantly inhibited the upregulation of the necroptosis initiator, RIPK1. Cellular thermal displacement assay and molecular docking demonstrated the physical binding of RGFP966 to HDCA3. In addition, RIPK1 knockdown cell assay signified that RGFP966 targeted RIPK1 and inhibited RIPK1 kinase activity. In summary, these findings established the efficacy of the HDAC3 inhibitor RGFP966 in treating AKI. |
| format | Article |
| id | doaj-art-cf91a0abe93542329282a0ebff3317f4 |
| institution | DOAJ |
| issn | 1663-9812 |
| language | English |
| publishDate | 2025-04-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Pharmacology |
| spelling | doaj-art-cf91a0abe93542329282a0ebff3317f42025-08-20T03:14:20ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122025-04-011610.3389/fphar.2025.15469501546950HDAC3 inhibition mitigates acute kidney injury by alleviating RIPK1-mediated programmed necrosisManman Xie0Manman Xie1Rui Hou2Runrun Shan3Xinyu Cheng4Pengcheng Wu5Xiufeng Luo6Yangyang Wei7Li Gao8Xiaoying Liu9Xiaoying Liu10Qi Chen11School of Life Sciences, Anhui Medical University, Hefei, 230032, ChinaSchool of Pharmacy, Anhui Medical University, Hefei, 230032, ChinaSchool of Pharmacy, Anhui Medical University, Hefei, 230032, ChinaState Key Laboratory of Pharmaceutical Biotechnology, College of Life Sciences, Nanjing University, Nanjing, 210023, ChinaSchool of Life Sciences, Anhui Medical University, Hefei, 230032, ChinaSchool of Life Sciences, Anhui Medical University, Hefei, 230032, ChinaSchool of Life Sciences, Anhui Medical University, Hefei, 230032, ChinaThe Armed Police Corps Hospital of Anhui, Hefei, ChinaDepartment of Nephropathy, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, ChinaSchool of Life Sciences, Anhui Medical University, Hefei, 230032, ChinaHenan International Joint Laboratory of Non-coding RNA and Metabolism in Cancer, Henan Provincial Key Laboratory of Long Non-coding RNA and Cancer Metabolism, Translational Research Institute of Henan Provincial People’s Hospital and People’s Hospital of Zhengzhou University, Zhengzhou, Henan, ChinaSchool of Life Sciences, Anhui Medical University, Hefei, 230032, ChinaAcute kidney injury (AKI) refers to clinical syndromes culminating in rapidly reduced renal function associated with inflammation and the demise of renal tubular epithelial cells. Current research aims to develop strategies which prevent tubular cell death. Here, based on the involvement of histone deacetylases (HDACs) in renal physiology and their established role in renal fibrosis, we investigated the mechanistic contributions of HDACs using a mouse model together with in vitro studies employing human renal epithelial cells. We found HDAC3 expression was upregulated in mouse renal tubules after ischemia/reperfusion and cisplatin treatment. Instructively, treatment with the HDAC3 selective inhibitor RGFP966 exerted potent protective effects, attenuates acute kidney injury in both in vivo and in vitro models. Moreover, RGFP966 was found to reduce inflammation and injury caused by cisplatin and hypoxia-reoxygenation in HK2 cells with transcriptome sequencing revealing that RGFP966 significantly inhibited the upregulation of the necroptosis initiator, RIPK1. Cellular thermal displacement assay and molecular docking demonstrated the physical binding of RGFP966 to HDCA3. In addition, RIPK1 knockdown cell assay signified that RGFP966 targeted RIPK1 and inhibited RIPK1 kinase activity. In summary, these findings established the efficacy of the HDAC3 inhibitor RGFP966 in treating AKI.https://www.frontiersin.org/articles/10.3389/fphar.2025.1546950/fullacute kidney injurynecroptosisRGFP966inflammationHDAC3 abbreviations Cr: creatinineRG: RGFP966 |
| spellingShingle | Manman Xie Manman Xie Rui Hou Runrun Shan Xinyu Cheng Pengcheng Wu Xiufeng Luo Yangyang Wei Li Gao Xiaoying Liu Xiaoying Liu Qi Chen HDAC3 inhibition mitigates acute kidney injury by alleviating RIPK1-mediated programmed necrosis Frontiers in Pharmacology acute kidney injury necroptosis RGFP966 inflammation HDAC3 abbreviations Cr: creatinine RG: RGFP966 |
| title | HDAC3 inhibition mitigates acute kidney injury by alleviating RIPK1-mediated programmed necrosis |
| title_full | HDAC3 inhibition mitigates acute kidney injury by alleviating RIPK1-mediated programmed necrosis |
| title_fullStr | HDAC3 inhibition mitigates acute kidney injury by alleviating RIPK1-mediated programmed necrosis |
| title_full_unstemmed | HDAC3 inhibition mitigates acute kidney injury by alleviating RIPK1-mediated programmed necrosis |
| title_short | HDAC3 inhibition mitigates acute kidney injury by alleviating RIPK1-mediated programmed necrosis |
| title_sort | hdac3 inhibition mitigates acute kidney injury by alleviating ripk1 mediated programmed necrosis |
| topic | acute kidney injury necroptosis RGFP966 inflammation HDAC3 abbreviations Cr: creatinine RG: RGFP966 |
| url | https://www.frontiersin.org/articles/10.3389/fphar.2025.1546950/full |
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