足细胞
自噬
下调和上调
细胞生物学
糖尿病肾病
链脲佐菌素
mTORC1型
肾
化学
癌症研究
生物
内分泌学
信号转导
糖尿病
生物化学
基因
PI3K/AKT/mTOR通路
细胞凋亡
蛋白尿
作者
Jian Lu,Xue Qi Li,Pei Pei Chen,Jia Xiu Zhang,Liang Liu,Gui Hua Wang,Xiao Qi Liu,Ting Jiang,Meng Ying Wang,Wen Tao Liu,Xiong Z. Ruan,Kun Ling
出处
期刊:JCI insight
[American Society for Clinical Investigation]
日期:2023-10-23
卷期号:8 (20)
被引量:1
标识
DOI:10.1172/jci.insight.165817
摘要
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.
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