Abstract
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-1β in RTECs. Diabetic ACSS2-deficient mice exhibited reduced renal tubular injury and inflammatory responses. Similarly, ACSS2 knockdown or inhibition of ACSS2 by ACSS2i (10 µmol/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.
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Data supporting the concepts presented in this manuscript can be obtained upon reasonable request from the corresponding author.
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Acknowledgements
This research was 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), and the National Natural Science Foundation of China (82170736, 81970629). This research did not use artificial intelligence, language models, machine learning, or similar technologies to create content or assist with the writing or editing of manuscripts.
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The study was designed by JL and KLM. The experiments were conducted and diabetic mouse models established by JL, XQL, PPC, JXZ, and LL. Data analysis was performed by GHW and XQL. The manuscript was initially drafted by JL, while revisions were made by KLM and CMJ. All authors have approved the final version of the manuscript. Guarantor statement: KLM and CMJ have taken responsibility for the contents of the manuscript.
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Lu, J., Li, Xq., Chen, Pp. et al. Acetyl-CoA synthetase 2 promotes diabetic renal tubular injury in mice by rewiring fatty acid metabolism through SIRT1/ChREBP pathway. Acta Pharmacol Sin 45, 366–377 (2024). https://doi.org/10.1038/s41401-023-01160-0
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DOI: https://doi.org/10.1038/s41401-023-01160-0