Activation of AMP‐activated protein kinase during sepsis/inflammation improves survival by preserving cellular metabolic fitness. Issue 5 (4th April 2020)

• Record Type: Journal Article
• Authors: Jin, Kui; Ma, Yujie; Manrique‐Caballero, Carlos L.; Li, Hui; Emlet, David R.; Li, Shengnan; Baty, Catherine J.; Wen, Xiaoyan; Kim‐Campbell, Nahmah; Frank, Alicia; Menchikova, Elizabeth V.; Pastor‐Soler, Nuria M.; Hallows, Kenneth R.; Jackson, Edwin K.; Shiva, Sruti; Pinsky, Michael R.; Zuckerbraun, Brian S.; Kellum, John A.; Gómez, Hernando
• Is Part Of: FASEB journal. Volume 34:Issue 5(2020)
• Page Start: 7036
• Page End: 7057
• Publication Date: 2020-04-04
• Subjects: AMPK -- metabolism -- mitochondria -- Sirt3 -- tubular epithelial cell; Biology -- Periodicals; Biology, Experimental -- Periodicals; 570
• DOI: 10.1096/fj.201901900R
• Languages: English
• ISSNs: 0892-6638

Abstract

Abstract: 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.