Protective Role of AMPK in Sepsis‐Associated AKI

Acute kidney injury (AKI) significantly contributes to the morbidity and the mortality in critically ill patients. AKI is also an independent risk factor for developing and progression of chronic kidney disease. Effective therapeutic strategies for AKI are limited due to incomplete understanding its pathogenesis. In most eukaryotic cells, AMP‐activated protein kinase (AMPK) functions as a principle sensory protein, which monitors the cellular energy status and mediates metabolic adaptation through increasing ATP level and regulating mitochondrial hemostasis. Sepsis is the most common cause of AKI. Using a mouse s‐AKI model induced by cecal ligation and puncture (CLP), we investigated the role of AMPK in the pathogenesis of sepsis‐associated AKI (s‐AKI) and its underlying mechanisms. The GFR was measured by FITC inulin clearance method. At 24 hours post‐injury, the GFR was significantly reduced in CLP mice (345±19 vs. 155±35 uL/min; p=0.004). Treatments with AICAR (an AMPK activator) 24 hours prior to CLP significantly improved the GFR. Additionally, mitochondrial function was evaluated using Seahorse. A significantly increased maximum respiration rate observed in CLP mice was abolished by Pre‐treatment with AICAR. Moreover, mitochondrial DNA copy number and expression of PGC1α, a master regulator of mitochondrial biogenesis were initially increased at 4h’ post CLP injury; then significantly decreased at 24h’ post‐injury, suggesting mitochondrial volume and mitochondrial biogenesis were increased shortly after the injury but eventually dropped. Pre‐treatment with AICAR prevented these alterations at both 4 and 24 hours post CLP. Finally, an elevation of glycolysis, a less efficient pathway compared to oxidative phosphorylation, was observed in response to CLP. This elevation of glycolysis was prevented in mice pre‐treated with AICAR, suggesting activation of AMPK may prevent CLP‐induced alteration of mitochondrial metabolism. Increased glycolysis was not seen at 4h’ post CLP surgery (Figure 1). Our findings provide novel evidence supporting the critical role of activation of AMPK signaling pathway in preventing development and/or progression of AKI induced by sepsis. Activation of AKI may prevent renal dysfunction in s‐AKI through regulating mitochondrial function, biogenesis, and metabolism. AMPK and its signaling pathway may serve as novel therapeutic targets in s‐AKI. Support or Funding Information NIH R01DK107852 VA Merit Review BX002175 NIH R03 DK101841 This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .