Artesunate Mitigates Sepsis-Induced Acute Kidney Injury via Lactate/AMPK/mTOR-Regulated Autophagy Based on Multi-Omics

Abstract

Background: Sepsis-induced acute kidney injury (S-AKI) is a form of acute renal failure resulting from a systemic inflammatory response triggered by infection, and has emerged as a significant public health challenge. Prior studies have demonstrated that artesunate (ART) exerts therapeutic effects on S-AKI by mitigating inflammation and oxidative stress. However, the precise regulatory mechanisms remain to be fully elucidated. Methods: This study investigates the impact of ART on renal function in a sepsis mouse model and its effect on LPS-induced cytotoxicity in HK-2 cells, aiming to clarify the potential therapeutic mechanisms underlying ART's efficacy in S-AKI. We evaluated changes in body weight, kidney index, biochemical markers, and histopathological alterations in mice, as well as proliferation and apoptosis in HK-2 cells. Additionally, metabolomics and transcriptomics were employed to identify key pathways involved in ART's therapeutic actions. Results: Our findings indicate that ART significantly improves renal function in sepsis mice, evidenced by increased body weight, reduced kidney index, and diminished pathological damage. Furthermore, ART alleviates LPS-induced cytotoxicity in HK-2 cells, reduce the levels of pro-inflammatory cytokines IL-1β, IL-6, and TNF-α, and increase the levels of antioxidant GSH. Integrative analysis of metabolomics and transcriptomics reveals that ART intervention markedly decreases lactate levels, inhibits excessive AMPK activation, relieves mTOR pathway suppression, and suppresses excessive autophagy, thereby attenuating inflammation and oxidative stress, and mitigating renal cell injury. Conclusion: The findings suggest that ART may mitigate inflammation and oxidative stress while improving renal function in S-AKI by modulating the lactate/AMPK/mTOR pathway and inhibiting excessive autophagy.

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