Lithium targeting of AMPK protects against cisplatin-induced acute kidney injury by enhancing autophagy in renal proximal tubular epithelial cells.

Abstract

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 whether its autophagic activity is associated with a beneficial effect on renal tubular cells in AKI. This study aimed to examine the effect of lithium on renal autophagy in cisplatin-induced AKI. 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. 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 microtubule-associated protein 1A/1B-light chain 3 (LC3)BII/I expression and autophagosome formation. Consistently, in cisplatin-injured renal tubular cells in vitro, lithium enhanced autophagic activities, improved cell viability, and attenuated cell death. Mechanistically, lithium triggered AMPK-α phosphorylation and activation, which in turn positively correlated with the induced expression of autophagy-related molecules, like mammalian target of rapamycin and LC3BII/I. AMPK-α activation is likely required for lithium-induced tubular cell autophagy and protection in cisplatin-induced AKI because blockade of AMPK-α phosphorylation by compound C markedly abrogated lithium-induced autophagosome formation and mitigated the protective effect of lithium on AKI. Our findings suggest that lithium represents a promising therapeutic strategy for protecting renal tubular cells against cisplatin-induced AKI by enhancing autophagy via AMPK-α activation.-Bao, H., Zhang, Q., Liu, X., Song, Y., Li, X., Wang, Z., Li, C., Peng, A., Gong, R. Lithium targeting of AMPK protects against cisplatin-induced acute kidney injury by enhancing autophagy in renal proximal tubular epithelial cells.