Department of Nephrology, Nanjing Drum Tower Hospital, the Affiliated Hospital of Nanjing University Medical School, Nanjing, China.
Institute of Nephrology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, China.
JCI Insight. 2023 Oct 23;8(20):e165817. doi: 10.1172/jci.insight.165817.
Albuminuria and podocyte injury are the key cellular events in the progression of diabetic nephropathy (DN). Acetyl-CoA synthetase 2 (ACSS2) is a nucleocytosolic enzyme responsible for the regulation of metabolic homeostasis in mammalian cells. This study aimed to investigate the possible roles of ACSS2 in kidney injury in DN. We constructed an ACSS2-deleted mouse model to investigate the role of ACSS2 in podocyte dysfunction and kidney injury in diabetic mouse models. In vitro, podocytes were chosen and transfected with ACSS2 siRNA and ACSS2 inhibitor and treated with high glucose. We found that ACSS2 expression was significantly elevated in the podocytes of patients with DN and diabetic mice. ACSS2 upregulation promoted phenotype transformation and inflammatory cytokine expression while inhibiting podocytes' autophagy. Conversely, ACSS2 inhibition improved autophagy and alleviated podocyte injury. Furthermore, ACSS2 epigenetically activated raptor expression by histone H3K9 acetylation, promoting activation of the mammalian target of rapamycin complex 1 (mTORC1) pathway. Pharmacological inhibition or genetic depletion of ACSS2 in the streptozotocin-induced diabetic mouse model greatly ameliorated kidney injury and podocyte dysfunction. To conclude, ACSS2 activation promoted podocyte injury in DN by raptor/mTORC1-mediated autophagy inhibition.
白蛋白尿和足细胞损伤是糖尿病肾病 (DN) 进展的关键细胞事件。乙酰辅酶 A 合成酶 2 (ACSS2) 是一种核质酶，负责调节哺乳动物细胞的代谢稳态。本研究旨在探讨 ACSS2 在 DN 肾损伤中的可能作用。我们构建了 ACSS2 缺失小鼠模型，以研究 ACSS2 在糖尿病小鼠模型中足细胞功能障碍和肾损伤中的作用。在体外，选择足细胞并转染 ACSS2 siRNA 和 ACSS2 抑制剂，并用高糖处理。我们发现，DN 患者和糖尿病小鼠的足细胞中 ACSS2 的表达明显升高。ACSS2 的上调促进了表型转化和炎性细胞因子的表达，同时抑制了足细胞的自噬。相反，ACSS2 抑制改善了自噬并减轻了足细胞损伤。此外，ACSS2 通过组蛋白 H3K9 乙酰化使 raptor 表达表观遗传激活，从而促进雷帕霉素复合物 1 (mTORC1) 途径的激活。在链脲佐菌素诱导的糖尿病小鼠模型中，ACSS2 的药理学抑制或基因耗竭极大地改善了肾脏损伤和足细胞功能障碍。总之，ACSS2 的激活通过 raptor/mTORC1 介导的自噬抑制促进了 DN 中的足细胞损伤。
