Dephosphorylation of AMP-activated protein kinase exacerbates ischemia/reperfusion-induced acute kidney injury via mitochondrial dysfunction

Haijian Ma; Xiaozhen Guo; Shichao Cui; Yongmei Wu; Yangming Zhang; Xiaoyan Shen; Cen Xie; Jingya Li

doi:10.1016/j.kint.2021.10.028

Dephosphorylation of AMP-activated protein kinase exacerbates ischemia/reperfusion-induced acute kidney injury via mitochondrial dysfunction

Kidney Int. 2022 Feb;101(2):315-330. doi: 10.1016/j.kint.2021.10.028. Epub 2021 Nov 11.

Authors

Haijian Ma¹, Xiaozhen Guo², Shichao Cui², Yongmei Wu³, Yangming Zhang⁴, Xiaoyan Shen⁵, Cen Xie⁶, Jingya Li⁷

Affiliations

¹ Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai, China.
² State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
³ School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, China.
⁴ State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China; Yantai Key Laboratory of Nanomedicine and Advanced Preparations, Yantai Institute of Materia Medica, Shandong, China.
⁵ Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai, China. Electronic address: shxiaoy@fudan.edu.cn.
⁶ State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China. Electronic address: xiecen@simm.ac.cn.
⁷ State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China; School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, Chinese Academy of Sciences, Hangzhou, China. Electronic address: jyli@simm.ac.cn.

PMID: 34774556
DOI: 10.1016/j.kint.2021.10.028

Abstract

Kidney tubular epithelial cells are high energy-consuming epithelial cells that depend mainly on fatty acid oxidation for an energy supply. AMP-activated protein kinase (AMPK) is a key regulator of energy production in most cells, but the function of AMPK in tubular epithelial cells in acute kidney disease is unclear. Here, we found a rapid decrease in Thr172-AMPKα phosphorylation after ischemia/reperfusion in both in vivo and in vitro models. Mice with kidney tubular epithelial cell-specific AMPKα deletion exhibited exacerbated kidney impairment and apoptosis of tubular epithelial cells after ischemia/reperfusion. AMPKα deficiency was accompanied by the accumulation of lipid droplets in the kidney tubules and the elevation of ceramides and free fatty acid levels following ischemia/reperfusion injury. Mechanistically, ischemia/reperfusion triggered ceramide production and activated protein phosphatase PP2A, which dephosphorylated Thr172-AMPKα. Decreased AMPK activity repressed serine/threonine kinase ULK1-mediated autophagy and impeded clearance of the dysfunctional mitochondria. Targeting the PP2A-AMPK axis by the allosteric AMPK activator C24 restored fatty acid oxidation and reduced tubular cell apoptosis during ischemia/reperfusion-induced injury, by antagonizing PP2A dephosphorylation and promoting the mitophagy process. Thus, our study reveals that AMPKα plays an important role in protecting against tubular epithelial cell injury in ischemia/reperfusion-induced acute kidney injury. Hence, activation of AMPK could be a potential therapeutic strategy for acute kidney injury treatment.

Keywords: AMPK; acute kidney injury; autophagy; lipid metabolism; mitochondrial biogenesis.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

AMP-Activated Protein Kinases / metabolism
Acute Kidney Injury* / chemically induced
Animals
Apoptosis
Ischemia / metabolism
Kidney / metabolism
Mice
Mitochondria / metabolism
Reperfusion
Reperfusion Injury* / complications
Reperfusion Injury* / metabolism

Substances

AMP-Activated Protein Kinases