Histone deacetylase 9 promotes osteogenic trans-differentiation of vascular smooth muscle cells via ferroptosis in chronic kidney disease vascular calcification
Lin Xiong,
Qiong Xiao,
Rong Chen,
Liming Huang,
Jun Gao,
Li Wang,
Guisen Li,
Yi Li
Affiliations
Lin Xiong
Department of Nephrology and Institute of Nephrology, Sichuan Provincial People’s Hospital, School of Medicine, University of Electronic Science and Technology of China, Sichuan Clinical Research Centre for Kidney Diseases, Clinical Immunology Translational Medicine Key Laboratory of Sichuan Province, Chengdu, China
Qiong Xiao
Department of Nephrology and Institute of Nephrology, Sichuan Provincial People’s Hospital, School of Medicine, University of Electronic Science and Technology of China, Sichuan Clinical Research Centre for Kidney Diseases, Clinical Immunology Translational Medicine Key Laboratory of Sichuan Province, Chengdu, China
Rong Chen
Department of Nephrology and Institute of Nephrology, Sichuan Provincial People’s Hospital, School of Medicine, University of Electronic Science and Technology of China, Sichuan Clinical Research Centre for Kidney Diseases, Clinical Immunology Translational Medicine Key Laboratory of Sichuan Province, Chengdu, China
Liming Huang
Department of Nephrology and Institute of Nephrology, Sichuan Provincial People’s Hospital, School of Medicine, University of Electronic Science and Technology of China, Sichuan Clinical Research Centre for Kidney Diseases, Clinical Immunology Translational Medicine Key Laboratory of Sichuan Province, Chengdu, China
Jun Gao
Department of Toxicological Inspection Sichuan Provincial Centre for Disease Prevention and Control, Chengdu, China
Li Wang
Department of Nephrology and Institute of Nephrology, Sichuan Provincial People’s Hospital, School of Medicine, University of Electronic Science and Technology of China, Sichuan Clinical Research Centre for Kidney Diseases, Clinical Immunology Translational Medicine Key Laboratory of Sichuan Province, Chengdu, China
Guisen Li
Department of Nephrology and Institute of Nephrology, Sichuan Provincial People’s Hospital, School of Medicine, University of Electronic Science and Technology of China, Sichuan Clinical Research Centre for Kidney Diseases, Clinical Immunology Translational Medicine Key Laboratory of Sichuan Province, Chengdu, China
Yi Li
Department of Nephrology and Institute of Nephrology, Sichuan Provincial People’s Hospital, School of Medicine, University of Electronic Science and Technology of China, Sichuan Clinical Research Centre for Kidney Diseases, Clinical Immunology Translational Medicine Key Laboratory of Sichuan Province, Chengdu, China
Vascular calcification, a common complication of chronic kidney disease (CKD), remains an unmet therapeutic challenge. The trans-differentiation of vascular smooth muscle cells (VSMCs) into osteoblast-like cells is crucial in the pathogenesis of vascular calcification in CKD. Despite ferroptosis promotes vascular calcification in CKD, the upstream or downstream regulatory mechanisms involved remains unclear. In this study, we aimed to investigate the regulatory mechanism involved in ferroptosis in CKD vascular calcification. Transcriptome sequencing revealed a potential relationship between HDAC9 and ferroptosis in CKD vascular calcification. Subsequently, we observed increased expression of HDAC9 in calcified arteries of patients undergoing hemodialysis and in a rat model of CKD. We further demonstrated that knockout of HDAC9 attenuates osteogenic trans-differentiation and ferroptosis in VSMCs stimulated by high calcium and phosphorus. In addition, RSL3 exacerbated ferroptosis and osteogenic trans-differentiation of VSMCs exposed to high levels of calcium and phosphorus, and these effects were suppressed to some extent by HDAC9 knockout. In summary, our findings suggest that HDAC9 promotes VSMCs osteogenic trans-differentiation involving ferroptosis, providing new insights for the therapy of CKD vascular calcification.
