The m5C orchestrator NSUN7 drives SPARC/HMGB1 axis–mediated inflammation to exacerbate kidney injury
Abstract
Growing evidence indicates that kidney inflammation is a major contributor to the pathogenesis of various renal diseases, including acute kidney injury (AKI). Although RNA modifications have been implicated in regulating kidney inflammation, their precise roles remain largely unknown. Here, we show that kidney inflammation and injury were associated with elevated RNA 5-methylcytosine (m5C) modifications, primarily driven by the NOP2/Sun RNA methyltransferase family member 7 (NSUN7). Both global and kidney-specific deletion of Nsun7 in mice reduced m5C abundance, attenuated inflammatory responses, and decreased macrophage infiltration, underscoring its proinflammatory role in the kidney. Mechanistically, we identified secreted protein acidic and cysteine-rich (SPARC) as a major downstream effector of NSUN7. SPARC upregulation amplified inflammatory responses in renal tubular epithelial cells by interacting with high mobility group box 1 and further promoted proinflammatory macrophage infiltration via tubular-macrophage crosstalk. Notably, therapeutic silencing of Nsun7 using a kidney-specific DNA tetrahedral molecular carrier developed for this study effectively alleviated inflammation and improved renal outcomes in AKI models. Collectively, our findings identify NSUN7 as a key driver of renal inflammation via SPARC regulation and underscore its potential as a therapeutic target in inflammatory kidney diseases.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (25)
Yu-hang Dong
Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, The Key Laboratory of Anti-Inflammatory of Immune Medicines, Ministry of Education, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University
Shuai-shuai Xie
Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, The Key Laboratory of Anti-Inflammatory of Immune Medicines, Ministry of Education, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University
Shuai Sun
Center of Nanomaterials for Renewable Energy, State Key Laboratory of Electrical Insulation and Power Equipment, School of Electrical Engineering
Yu Ren
Department of Medicine, The University of Oklahoma Health Sciences Center
Qin Yang
Department of Chemical and Biomolecular Engineering
Jie Wei
College of Energy, College of Materials, State Key Laboratory of Physical Chemistry of Solid Surfaces, College of Chemistry and Chemical Engineering, School of Life Sciences, College of Physical Science and Technology, Discipline of Intelligent Instrument and Equipment, iChEM, Fujian Key Laboratory of Advanced Materials
Rui Hou
Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, The Key Laboratory of Anti-inflammatory of Immune Medicines, Ministry of Education, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University
Xiang-Yu Li
Beijing Key Laboratory for Green Catalysis and Separation and Department of Chemical Engineering, College of Materials Science & Engineering
Jing-wen Wu
School of Medicine, Tongji University
Wen-xian Ma
Department of Immunology, School of Basic Medical Sciences, Anhui Medical University
Ju-tao Yu
Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, The Key Laboratory of Anti-Inflammatory of Immune Medicines, Ministry of Education, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University
Meng-ting He
Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, The Key Laboratory of Anti-inflammatory of Immune Medicines, Ministry of Education, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University
Chao Li
Jia-Nan Wang
Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences
Ming-lu Ji
Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, The Key Laboratory of Anti-Inflammatory of Immune Medicines, Ministry of Education, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University
Zi-yi Liu
Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, The Key Laboratory of Anti-inflammatory of Immune Medicines, Ministry of Education, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University
Ze-hui Dong
Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, The Key Laboratory of Anti-inflammatory of Immune Medicines, Ministry of Education, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University
Xiao-yu Shen
Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, The Key Laboratory of Anti-inflammatory of Immune Medicines, Ministry of Education, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University
Xin-yu Chen
Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, The Key Laboratory of Anti-inflammatory of Immune Medicines, Ministry of Education, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University
Xiao-guo Suo
Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, The Key Laboratory of Anti-Inflammatory of Immune Medicines, Ministry of Education, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University
Wei Dong
Hangzhou Institute of Medicine Chinese Academy of Sciences
Juan Jin
School of Basic Medicine, Anhui Medical University
Jie Wang
State Key Laboratory of Molecular Oncology, Beijing Key Laboratory, CAMS Key Laboratory of Translational Research on Lung Cancer, Department of Medical Oncology Cancer Hospital, Chinese Academy of Medical Sciences Beijing China
Wen-bin Wang
Department of General Surgery, The Second Affiliated Hospital of Anhui Medical University
Xiao-ming Meng
Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, The Key Laboratory of Anti-Inflammatory of Immune Medicines, Ministry of Education, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University