Lithium Targeting of AMPK Protects Against Cisplatin-Induced Acute Kidney Injury by Enhancing Autophagy in Renal Proximal Tubular Epithelial Cells

Abstract

Background: Autophagy has been demonstrated to be vital for kidney homeostasis and is centrally implicated in the pathogenesis of cisplatin-induced acute kidney injury (AKI). Lithium is a potent autophagy inducer in a number of cell types. However, it remains uncertain if its autophagic activity is associated with a beneficial effect on renal tubular cell in AKI. This study aimed to examine the effect of lithium on renal autophagy in cisplatin-induced AKI. Methods: Mice or renal proximal tubular epithelial cells in culture were exposed to cisplatin-induced acute injury in the presence or absence of lithium treatment. AKI or tubular cell injury was evaluated and cell signaling associated with autophagy was examined. Findings: Lithium pretreatment prominently ameliorated acute renal tubular damage in mice exposed to cisplatin insult, associated with enhanced autophagy in renal tubules, as assessed by measuring LC3BII/I expression and autophagosome formation. Consistently, in cisplatininjured renal tubular cells in vitro, lithium enhanced autophagic activities, improved cell viability and attenuated cell death. Mechanistically, lithium triggered AMP-activated protein kinase (AMPK)α phosphorylation and activation, which in turn positively correlated with the induced expression of autophagy-related molecules, like mTOR and LC3BII/I. AMPKα activation is likely required for lithium-induced tubular cell autophagy and protection in cisplatin-induced AKI, because blockade of AMPKα phosphorylation by compound C markedly abrogated lithium-induced autophagosome formation and mitigated the protective effect of lithium on AKI. Interpretation: Our findings suggest that lithium represent a promising therapeutic strategy for protecting renal tubular cells against cisplatin-induced AKI by enhancing autophagy via AMPKα activation. Funding Statement: Shanghai International Cooperation Program (16410724200), Fundamental Research Funds for the Central Universities (22120180390), Natural Science Foundation of China (Grant Nos.81500508, 81770732). The funders had no role in study design, data collection, data analysis, interpretation, writing of the report. Declaration of Interests: The authors agree with the content of this manuscript and declare there are no competing interests about this study. Ethics Approval Statement: All experimental protocols were approved by the Animal Experimental Ethics Committee of Shanghai Tenth People’s Hospital of Tongji University School of Medicine. Animal experiments were conducted after approval from the Institutional Research Ethics Committee (Approval Number: SHDSYY-2018-3342).