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.