AMPK/mTOR Signaling in Autophagy Regulation During Cisplatin-Induced Acute Kidney Injury.

Ying Wang,Shaoqun Shu,Zhiwen Liu,Chengyuan Tang,Juan Cai,Zheng Dong

doi:10.3389/fphys.2020.619730

Abstract

Autophagy is a conserved, multistep pathway that degrades and recycles dysfunctional organelles and macromolecules to maintain cellular homeostasis. Mammalian target of rapamycin (mTOR) and adenosine-monophosphate activated-protein kinase (AMPK) are major negative and positive regulators of autophagy, respectively. In cisplatin-induced acute kidney injury (AKI) or nephrotoxicity, autophagy is rapidly induced in renal tubular epithelial cells and acts as a cytoprotective mechanism for cell survival. Both mTOR and AMPK have been implicated in the regulation of autophagy in cisplatin-induced AKI. Targeting mTOR and/or AMPK may offer effective strategies for kidney protection during cisplatin-mediated chemotherapy.

Highlights

Macroautophagy, referred to hereafter as autophagy, is a process of “self-eating” in cells that contributes to the resolving and recycling of various cytoplasmic components by the lysosomal degradation pathway (Feng et al, 2014; Kaushal and Shah, 2016)
These findings demonstrate that AMPK/Mammalian target of rapamycin (mTOR)-mediated autophagy plays an important role in cisplatin nephrotoxicity
This study suggested that the protective effect of the AMPK activator AICAR might alleviate cisplatin-induced acute kidney injury (AKI) through Janus kinase 2 (JAK2)/signal transducer and activator of transcription 1 (STAT1)/suppressor of cytokine signaling 1 (SOCS1) pathway (Tsogbadrakh et al, 2019)

Summary

INTRODUCTION

Macroautophagy, referred to hereafter as autophagy, is a process of “self-eating” in cells that contributes to the resolving and recycling of various cytoplasmic components by the lysosomal degradation pathway (Feng et al, 2014; Kaushal and Shah, 2016). Blockade of autophagy by pharmacological inhibitors or autophagygene knockdown increased renal tubular cell apoptosis during cisplatin treatment, suggesting a protective role of autophagy (Ji et al, 2015). These observations were verified by Kaushal and colleagues (Yang et al, 2018). Later studies showed an increase of autophagosome formation in renal tubular cells during cisplatin treatment of GFP-LC3 autophagy reporter mice (Inoue et al, 2010; Takahashi et al, 2012). Autophagy is an important protective mechanism that can up-regulate for kidney protection during cisplatininduced AKI

AMPK AND MTOR SIGNALING

UPSTREAM REGULATORY MOLECULES OF AMPK OR MTOR

AMPK AND MTOR IN AUTOPHAGY DURING CISPLATIN NEPHROTOXICITY

TARGETING AMPK FOR THERAPY IN CISPLATIN NEPHROTOXICITY

CONCLUSION