Acetyl-CoA synthetase 2 promotes diabetic renal tubular injury in mice by rewiring fatty acid metabolism through SIRT1/ChREBP pathway  

作　　者：Jian Lu Xue-qi Li Pei-pei Chen Jia-xiu Zhang Liang Li Gui-hua Wang Xiao-qi Liu Chun-ming Jiang Kun-ling Ma 

机构地区：[1]Department of Nephrology,Nanjing Drum Tower Hospital,the Affiliated Hospital of Medical School,Nanjing University,Nanjing 210008,China [2]Institute of Nephrology,Zhongda Hospital,School of Medicine,Southeast University,Nanjing 210009,China [3]Department of Nephrology,the Second Affiliated Hospital,School of Medicine,Zhejiang University,Hangzhou 310003,China

出　　处：《Acta Pharmacologica Sinica》2024年第2期366-377,共12页中国药理学报（英文版）

基　　金：supported by the Jiangsu Innovative and Entrepreneurial Talent Programme(JSSCBS20211515);the Nanjing Postdoctoral Science Foundation,the Medical Science and Technology Development Foundation’s Key Project,Nanjing Department of Health(YKK21094);the National Natural Science Foundation of China(82170736,81970629).

摘　　要：Diabetic nephropathy(DN)is characterized by chronic low-grade renal inflammatory responses,which greatly contribute to disease progression.Abnormal glucose metabolism disrupts renal lipid metabolism,leading to lipid accumulation,nephrotoxicity,and subsequent aseptic renal interstitial inflammation.In this study,we investigated the mechanisms underlying the renal inflammation in diabetes,driven by glucose-lipid metabolic rearrangement with a focus on the role of acetyl-CoA synthetase 2(ACSS2)in lipid accumulation and renal tubular injury.Diabetic models were established in mice by the injection of streptozotocin and in human renal tubular epithelial HK-2 cells cultured under a high glucose(HG,30 mmol/L)condition.We showed that the expression levels of ACSS2 were significantly increased in renal tubular epithelial cells(RTECs)from the diabetic mice and human diabetic kidney biopsy samples,and ACSS2 was co-localized with the pro-inflammatory cytokine IL-1βin RTECs.Diabetic ACSS2-deficient mice exhibited reduced renal tubular injury and inflammatory responses.Similarly,ACSS2 knockdown or inhibition of ACSS2 by ACSS2i(10µmol/L)in HK-2 cells significantly ameliorated HG-induced inflammation,mitochondrial stress,and fatty acid synthesis.Molecular docking revealed that ACSS2 interacted with Sirtuin 1(SIRT1).In HG-treated HK-2 cells,we demonstrated that ACSS2 suppressed SIRT1 expression and activated fatty acid synthesis by modulating SIRT1-carbohydrate responsive element binding protein(ChREBP)activity,leading to mitochondrial oxidative stress and inflammation.We conclude that ACSS2 promotes mitochondrial oxidative stress and renal tubular inflammation in DN by regulating the SIRT1-ChREBP pathway.This highlights the potential therapeutic value of pharmacological inhibition of ACSS2 for alleviating renal inflammation and dysregulation of fatty acid metabolic homeostasis in DN.

关 键 词：diabetic nephropathy renal tubular cell Acetyl-CoA synthetase 2 SIRT1 CHREBP fatty acid metabolism 

分 类 号：R692[医药卫生—泌尿科学] R587.1[医药卫生—外科学]