Inhibition of aerobic glycolysis alleviates sepsis‑induced acute kidney injury by promoting lactate/Sirtuin 3/AMPK‑regulated autophagy

Tan,Chuyi; Gu,Jia; Li,Tao; Chen,Huan; Liu,Ke; Liu,Meidong; Zhang,Huali; Xiao,Xianzhong

doi:10.3892/ijmm.2021.4852

Inhibition of aerobic glycolysis alleviates sepsis‑induced acute kidney injury by promoting lactate/Sirtuin 3/AMPK‑regulated autophagy

Authors:
- Chuyi Tan
- Jia Gu
- Tao Li
- Huan Chen
- Ke Liu
- Meidong Liu
- Huali Zhang
- Xianzhong Xiao
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Affiliations: Department of Pathophysiology, Xiangya School of Medicine, Central South University, Changsha, Hunan 410078, P.R. China
Published online on: January 12, 2021 https://doi.org/10.3892/ijmm.2021.4852
Article Number: 19
Copyright: © Tan et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

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.

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