Activation of AMP‐activated protein kinase during sepsis/inflammation improves survival by preserving cellular metabolic fitness

The purpose was to determine the role of AMPK activation in the renal metabolic response to sepsis, the development of sepsis‐induced acute kidney injury (AKI) and on survival. In a prospective experimental study, 167 10‐ to 12‐week‐old C57BL/6 mice underwent cecal ligation and puncture (CLP) and human proximal tubule epithelial cells (TEC; HK2) were exposed to inflammatory mix (IM), a combination of lipopolysaccharide (LPS) and high mobility group box 1 (HMGB1). Renal/TEC metabolic fitness was assessed by monitoring the expression of drivers of oxidative phosphorylation (OXPHOS), the rates of utilization of OXPHOS/glycolysis in response to metabolic stress, and mitochondrial function by measuring O2 consumption rates (OCR) and the membrane potential (Δψm). Sepsis/IM resulted in AKI, increased mortality, and in renal AMPK activation 6‐24 hours after CLP/IM. Pharmacologic activation of AMPK with 5‐aminoimidazole‐4‐carboxamide ribonucleotide (AICAR) or metformin during sepsis improved the survival, while AMPK inhibition with Compound C increased mortality, impaired mitochondrial respiration, decreased OCR, and disrupted TEC metabolic fitness. AMPK‐driven protection was associated with increased Sirt 3 expression and restoration of metabolic fitness. Renal AMPK activation in response to sepsis/IM is an adaptive mechanism that protects TEC, organs, and the host by preserving mitochondrial function and metabolic fitness likely through Sirt3 signaling.