Department of Pathophysiology, Xiangya School of Medicine, Central South University, Changsha, Hunan 410078, P.R. China.
Int J Mol Med. 2021 Mar;47(3). doi: 10.3892/ijmm.2021.4852. Epub 2021 Jan 15.
Metabolism reprogramming influences the severity of organ dysfunction, progression to fibrosis, and development of disease in acute kidney injury (AKI). Previously we showed that inhibition of aerobic glycolysis improved survival rates and protected septic mice from kidney injury. However, the underlying mechanisms remain unclear. In the present study, it was revealed that sepsis or lipopolysaccharide (LPS) enhanced aerobic glycolysis as evidenced by increased lactate production and upregulated mRNA expression of glycolysis‑related genes in kidney tissues and human renal tubular epithelial (HK‑2) cells. The aerobic glycolysis inhibitor 2‑deoxy‑D‑glucose (2‑DG) downregulated glycolysis, and improved kidney injury induced by sepsis. 2‑DG treatments increased the expression of sirtuin 3 (SIRT3) and phosphorylation‑AMP‑activated protein kinase (p‑AMPK), following promoted autophagy and attenuated apoptosis of tubular epithelial cells in septic mice and in LPS‑treated HK‑2 cells. However, the glycolysis metabolite lactate downregulated SIRT3 and p‑AMPK expression, inhibited autophagy and enhanced apoptosis in LPS‑treated HK‑2 cells. Furthermore, pharmacological blockade of autophagy with 3‑methyladenine (3‑MA) partially abolished the protective effect of 2‑DG in sepsis‑induced AKI. These findings indicated that inhibition of aerobic glycolysis protected against sepsis‑induced AKI by promoting autophagy via the lactate/SIRT3/AMPK pathway.
代谢重编程影响器官功能障碍的严重程度、向纤维化的进展以及急性肾损伤 (AKI) 的疾病发展。此前我们表明，抑制有氧糖酵解可提高存活率并保护脓毒症小鼠免受肾损伤。然而，其潜在机制尚不清楚。在本研究中，研究结果表明，脓毒症或脂多糖 (LPS) 增强了有氧糖酵解，这表现在肾脏组织和人肾小管上皮细胞 (HK-2) 中乳酸产量增加和糖酵解相关基因的 mRNA 表达上调。有氧糖酵解抑制剂 2-脱氧-D-葡萄糖 (2-DG) 下调糖酵解，并改善脓毒症引起的肾损伤。2-DG 处理增加了脓毒症小鼠和 LPS 处理的 HK-2 细胞中 SIRT3 和磷酸化 AMP 激活蛋白激酶 (p-AMPK) 的表达，随后促进了自噬并减轻了肾小管上皮细胞的凋亡。然而，糖酵解代谢物乳酸下调了 SIRT3 和 p-AMPK 的表达，抑制了 LPS 处理的 HK-2 细胞中的自噬并增强了凋亡。此外，用 3-甲基腺嘌呤 (3-MA) 抑制自噬可部分消除 2-DG 在脓毒症诱导的 AKI 中的保护作用。这些发现表明，抑制有氧糖酵解通过乳酸/SIRT3/AMPK 途径促进自噬来保护脓毒症引起的 AKI。
