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

Acta Pharmacologica Sinica volume 45, pages 366–377 (2024)Cite this article

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.

Metabolic inflammation in the renal region, driven by lipid metabolism disorder, is a key factor in renal injury in diabetic nephropathy (DN). Acetyl-CoA synthetase 2 (ACSS2) is abundantly expressed in renal tubular epithelial cells (RTECs) and highly upregulated in diabetic kidneys. Deleting ACSS2 reduces renal fatty acid accumulation and markers of renal tubular injury in diabetic mice. We demonstrate that ACSS2 deletion inhibits ChREBP-mediated fatty acid lipogenesis, mitochondrial oxidative stress, and inflammatory response in RTECs, which play a major role in the progression of diabetic renal tubular injury in the kidney. These findings support the potential use of ACSS2 inhibitors in treating patients with DN.

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Fig. 1: ACSS2 upregulation in renal tubular epithelial cells (RTECs) of in vivo murine STZ-induced diabetic models and patients with biopsy-proven DN.
Fig. 2: ACSS2’s role in the inflammatory response and mitochondrial oxidative stress in HK-2 cells under HG challenges.
Fig. 3: ACSS2 deletion protects against diabetes-induced renal tubular injury, mitochondrial oxidative stress, and inflammation.
Fig. 4: ACSS2 deficiency reduced fatty acid accumulation in RTECs of diabetic mice.
Fig. 5: ACSS2 inhibition reduced fatty acid synthesis-related gene expression in diabetic mice and HG-treated HK-2 cells.
Fig. 6: ACSS2 interacts with SIRT1 and suppresses SIRT1 expression.
Fig. 7: ACSS2 promoting inflammation and mitochondrial oxidative stress of RTECs by suppressing SIRT1 activity.

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Data availability

Data supporting the concepts presented in this manuscript can be obtained upon reasonable request from the corresponding author.

References

  1. Zeni L, Norden AGW, Cancarini G, Unwin RJ. A more tubulocentric view of diabetic kidney disease. J Nephrol. 2017;30:701–17.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  2. Ruiz-Ortega M, Rodrigues-Diez RR, Lavoz C, Rayego-Mateos S. Special Issue “Diabetic Nephropathy: Diagnosis, Prevention and Treatment”. J Clin Med. 2020;9:813.

  3. Nowak N, Skupien J, Niewczas MA, Yamanouchi M, Major M, Croall S, et al. Increased plasma kidney injury molecule-1 suggests early progressive renal decline in non-proteinuric patients with type 1 diabetes. Kidney Int. 2016;89:459–67.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  4. Vallon V, Thomson SC. The tubular hypothesis of nephron filtration and diabetic kidney disease. Nat Rev Nephrol. 2020;16:317–36.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  5. Tang SC, Lai KN. The pathogenic role of the renal proximal tubular cell in diabetic nephropathy. Nephrol Dial Transpl. 2012;27:3049–56.

    Article  CAS  Google Scholar 

  6. Tang SCW, Yiu WH. Innate immunity in diabetic kidney disease. Nat Rev Nephrol. 2020;16:206–22.

    Article  PubMed  CAS  Google Scholar 

  7. Veiras LC, Bernstein EA, Cao D, Okwan-Duodu D, Khan Z, Gibb DR, et al. Tubular IL-1beta induces salt sensitivity in diabetes by activating renal macrophages. Circ Res. 2022;131:59–73.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  8. Lumeng CN, Saltiel AR. Inflammatory links between obesity and metabolic disease. J Clin Invest. 2011;121:2111–7.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  9. Ding H, Li J, Li Y, Yang M, Nie S, Zhou M, et al. MicroRNA-10 negatively regulates inflammation in diabetic kidney via targeting activation of the NLRP3 inflammasome. Mol Ther. 2021;29:2308–20.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  10. Gao X, Lin SH, Ren F, Li JT, Chen JJ, Yao CB, et al. Acetate functions as an epigenetic metabolite to promote lipid synthesis under hypoxia. Nat Commun. 2016;7:11960.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  11. Huang Z, Zhang M, Plec AA, Estill SJ, Cai L, Repa JJ, et al. ACSS2 promotes systemic fat storage and utilization through selective regulation of genes involved in lipid metabolism. Proc Natl Acad Sci USA. 2018;115:E9499–506.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  12. Li X, Qian X, Lu Z. Local histone acetylation by ACSS2 promotes gene transcription for lysosomal biogenesis and autophagy. Autophagy. 2017;13:1790–1.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  13. Lakhter AJ, Hamilton J, Konger RL, Brustovetsky N, Broxmeyer HE, Naidu SR. Glucose-independent acetate metabolism promotes melanoma cell survival and tumor growth. J Biol Chem. 2016;291:21869–79.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  14. van der Rijt S, Leemans JC, Florquin S, Houtkooper RH, Tammaro A. Immunometabolic rewiring of tubular epithelial cells in kidney disease. Nat Rev Nephrol. 2022;18:588–603.

    Article  PubMed  Google Scholar 

  15. Lu J, Chen PP, Zhang JX, Li XQ, Wang GH, Yuan BY, et al. GPR43 activation-mediated lipotoxicity contributes to podocyte injury in diabetic nephropathy by modulating the ERK/EGR1 pathway. Int J Biol Sci. 2022;18:96–111.

    Article  PubMed  PubMed Central  Google Scholar 

  16. Guo Y, Ni J, Chen S, Bai M, Lin J, Ding G, et al. MicroRNA-709 mediates acute tubular injury through effects on mitochondrial function. J Am Soc Nephrol. 2018;29:449–61.

    Article  PubMed  CAS  Google Scholar 

  17. Wu L, Liu C, Chang DY, Zhan R, Zhao M, Man Lam S, et al. The attenuation of diabetic nephropathy by Annexin A1 via regulation of lipid metabolism through the AMPK/PPARalpha/CPT1b pathway. Diabetes. 2021;70:2192–203.

    Article  PubMed  CAS  Google Scholar 

  18. Wu H, Uchimura K, Donnelly EL, Kirita Y, Morris SA, Humphreys BD. Comparative analysis and refinement of human PSC-derived kidney organoid differentiation with single-cell transcriptomics. Cell Stem Cell. 2018;23:869–81.e868.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  19. Herman-Edelstein M, Scherzer P, Tobar A, Levi M, Gafter U. Altered renal lipid metabolism and renal lipid accumulation in human diabetic nephropathy. J Lipid Res. 2014;55:561–72.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  20. Opazo-Rios L, Mas S, Marin-Royo G, Mezzano S, Gomez-Guerrero C, Moreno JA, et al. Lipotoxicity and diabetic nephropathy: novel mechanistic insights and therapeutic opportunities. Int J Mol Sci. 2020;21:2632.

  21. Qi W, Hu C, Zhao D, Li X. SIRT1-SIRT7 in diabetic kidney disease: biological functions and molecular mechanisms. Front Endocrinol (Lausanne). 2022;13:801303.

    Article  PubMed  Google Scholar 

  22. Zhang N, Hu Y, Ding C, Zeng W, Shan W, Fan H, et al. Salvianolic acid B protects against chronic alcoholic liver injury via SIRT1-mediated inhibition of CRP and ChREBP in rats. Toxicol Lett. 2017;267:1–10.

    Article  PubMed  CAS  Google Scholar 

  23. Nicholas DA, Proctor EA, Agrawal M, Belkina AC, Van Nostrand SC, Panneerseelan-Bharath L, et al. Fatty acid metabolites combine with reduced beta oxidation to activate Th17 inflammation in human type 2 diabetes. Cell Metab. 2019;30:447–61.e445.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  24. Lee HK. Fatty acid overload to compromised oxidative phosphorylation activates inflammation in type 2 diabetes: hidden beasts and how to find them. J Diabetes Investig. 2020;11:290–3.

    Article  PubMed  Google Scholar 

  25. Freigang S, Ampenberger F, Weiss A, Kanneganti TD, Iwakura Y, Hersberger M, et al. Fatty acid-induced mitochondrial uncoupling elicits inflammasome-independent IL-1alpha and sterile vascular inflammation in atherosclerosis. Nat Immunol. 2013;14:1045–53.

    Article  PubMed  CAS  Google Scholar 

  26. Hou Y, Wang Q, Han B, Chen Y, Qiao X, Wang L. CD36 promotes NLRP3 inflammasome activation via the mtROS pathway in renal tubular epithelial cells of diabetic kidneys. Cell Death Dis. 2021;12:523.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  27. Ruan XZ, Varghese Z, Moorhead JF. An update on the lipid nephrotoxicity hypothesis. Nat Rev Nephrol. 2009;5:713–21.

    Article  PubMed  CAS  Google Scholar 

  28. Finucane OM, Lyons CL, Murphy AM, Reynolds CM, Klinger R, Healy NP, et al. Monounsaturated fatty acid-enriched high-fat diets impede adipose NLRP3 inflammasome-mediated IL-1beta secretion and insulin resistance despite obesity. Diabetes. 2015;64:2116–28.

    Article  PubMed  CAS  Google Scholar 

  29. Ralston JC, Lyons CL, Kennedy EB, Kirwan AM, Roche HM. Fatty acids and NLRP3 inflammasome-mediated inflammation in metabolic tissues. Annu Rev Nutr. 2017;37:77–102.

    Article  PubMed  CAS  Google Scholar 

  30. Swanson KV, Deng M, Ting JP. The NLRP3 inflammasome: molecular activation and regulation to therapeutics. Nat Rev Immunol. 2019;19:477–89.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  31. Ruysschaert JM, Lonez C. Role of lipid microdomains in TLR-mediated signalling. Biochim Biophys Acta. 2015;1848:1860–7.

    Article  PubMed  CAS  Google Scholar 

  32. O’Farrell M, Duke G, Crowley R, Buckley D, Martins EB, Bhattacharya D, et al. FASN inhibition targets multiple drivers of NASH by reducing steatosis, inflammation and fibrosis in preclinical models. Sci Rep. 2022;12:15661.

    Article  PubMed  PubMed Central  Google Scholar 

  33. Liu X, Cooper DE, Cluntun AA, Warmoes MO, Zhao S, Reid MA, et al. Acetate production from glucose and coupling to mitochondrial metabolism in mammals. Cell. 2018;175:502–13.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  34. Zhao S, Jang C, Liu J, Uehara K, Gilbert M, Izzo L, et al. Dietary fructose feeds hepatic lipogenesis via microbiota-derived acetate. Nature. 2020;579:586–91.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  35. Lu J, Chen PP, Zhang JX, Li XQ, Wang GH, Yuan BY, et al. GPR43 deficiency protects against podocyte insulin resistance in diabetic nephropathy through the restoration of AMPKalpha activity. Theranostics. 2021;11:4728–42.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

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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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  1. These authors contributed equally: Jian Lu, Xue-qi Li

Authors and Affiliations

  1. Department of Nephrology, Nanjing Drum Tower Hospital, the Affiliated Hospital of Medical School, Nanjing University, Nanjing, 210008, China

    Jian Lu & Chun-ming Jiang

  2. Institute of Nephrology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, 210009, China

    Xue-qi Li, Pei-pei Chen, Jia-xiu Zhang, Liang Li & Gui-hua Wang

  3. Department of Nephrology, the Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310003, China

    Xiao-qi Liu & Kun-ling Ma

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Contributions

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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Correspondence to Chun-ming Jiang or Kun-ling Ma.

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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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