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Activation of AMP‐activated protein kinase during sepsis/inflammation improves survival by preserving cellular metabolic fitness
Author(s) -
Jin Kui,
Ma Yujie,
ManriqueCaballero Carlos L.,
Li Hui,
Emlet David R.,
Li Shengnan,
Baty Catherine J.,
Wen Xiaoyan,
KimCampbell Nahmah,
Frank Alicia,
Menchikova Elizabeth V.,
PastorSoler Nuria M.,
Hallows Kenneth R.,
Jackson Edwin K.,
Shiva Sruti,
Pinsky Michael R.,
Zuckerbraun Brian S.,
Kellum John A.,
Gómez Hernando
Publication year - 2020
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.201901900r
Subject(s) - ampk , amp activated protein kinase , sepsis , medicine , metformin , endocrinology , inflammation , oxidative stress , glycolysis , sirt3 , protein kinase a , biology , kinase , metabolism , microbiology and biotechnology , biochemistry , diabetes mellitus , sirtuin , acetylation , gene
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 O 2 consumption rates (OCR) and the membrane potential (Δψ m ). 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.