<i>NAT10</i> exacerbates acute renal inflammation by enhancing N4-acetylcytidine modification of the CCL2/CXCL1 axis
Abstract
Inflammation plays an essential role in eliminating microbial pathogens and repairing tissues, while sustained inflammation accelerates kidney damage and disease progression. Therefore, understanding the mechanisms of the inflammatory response is vital for developing therapies for inflammatory kidney diseases like acute kidney injury (AKI), which currently lacks effective treatment. Here, we identified N-acetyltransferase 10 ( NAT10 ) as an important regulator for acute inflammation. NAT10 , the only known “writer” protein for N4-acetylcytidine (ac4C) acetylation, is elevated in renal tubules across various AKI models, human biopsies, and cultured tubular epithelial cells (TECs). Conditional knockout (cKO) of NAT10 in mouse kidneys attenuates renal dysfunction, inflammation, and infiltration of macrophages and neutrophils, whereas its conditional knock-in (cKI) exacerbates these effects. Mechanistically, our findings from ac4C-RIP-seq and RNA-seq analyses revealed that NAT10-mediated ac4C acetylation enhances the mRNA stability of a range of key chemokines, including C-C motif chemokine ligand 2 ( CCL2 ) and C-X-C motif chemokine ligand 1( CXCL1 ), promoting macrophage and neutrophil recruitment and accelerating renal inflammation. Additionally, CCL2 and CXCL1 neutralizing antibodies or their receptor inhibitors, abrogated renal inflammation in NAT10 -overexpression TECs or NAT10 -cKI mice. Importantly, inhibiting NAT10 , either through Adeno-associated virus 9 (AAV9)-mediated silencing or pharmacologically with our found inhibitor Cpd-155, significantly reduces renal inflammation and injury. Thus, targeting the NAT10/CCL2/CXCL1 axis presents a promising therapeutic strategy for treating inflammatory kidney diseases.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (27)
Jia-Nan Wang
Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences
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
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
Qi-chao Luo
School of Basic Medicine, Anhui Medical University
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
Meng-meng Zhang
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
Qi Zhu
Xin-ran Cheng
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 Hou
School of Basic Medicine, Anhui Medical University
Xin Chen
Fang Wang
Chuan-hui Xu
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
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
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
Dan-feng Zhang
Department of Nephrology, The Second Affiliated Hospital of Anhui Medical University
Xin-Ru Zhang
MOE Key Laboratory for UV Light-Emitting Materials and Technology
Zhi-juan Wang
Department of Nephrology, The Second Affiliated Hospital of Anhui Medical University
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
Sai Zhu
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
Li-jin Peng
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
Hai-yong Chen
School of Chinese Medicine, Li Ka Shing Faculty of Medicine
Tao Xu
Juan Jin
School of Basic Medicine, Anhui Medical University
Fei Xavier Chen
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