Premium
Protective Role of AMPK in Sepsis Associated AKI
Author(s) -
Li Ying,
Nourbakhsh Noureddin,
Hall Elanore,
Hepokoski Mark,
Pham Hai,
Thomas Joanna,
Singh Prabhleen
Publication year - 2016
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/fasebj.30.1_supplement.1217.18
Subject(s) - mfn2 , autophagy , ampk , pathogenesis , sepsis , medicine , ulk1 , apoptosis , mitochondrial fusion , western blot , activator (genetics) , cancer research , pharmacology , protein kinase a , chemistry , kinase , biology , microbiology and biotechnology , mitochondrial dna , receptor , biochemistry , gene
Sepsis‐associated acute kidney injury (AKI) is frequently observed and has poor prognosis with no effective treatments. The lack of complete understanding of its pathogenesis is a significant barrier to progress and fresh insights into its pathogenesis are critically needed. We examined renal function by FITC inulin clearance and other functional and molecular analyses to examine mitochondrial dysfunction in the pathogenesis of sepsis using a model of cecal ligation and puncture (CLP) at 24 hours post‐injury. We also evaluated therapies targeting mitochondrial dysfunction. GFR was significantly reduced in CLP mice 345±19 vs. 155±35 uL/min; p=0.004. ATP generation was significantly lower in the mitochondria isolated from CLP kidneys along with decreased expression of complex V. With western blot expression, we found decreased expression of AMP Kinase, along with fusion proteins (Mfn1, Mfn2 and OPA1). We also observed decreased expression of autophagy markers (Beclin, ULK, LC3I) and increased apoptosis (cleaved caspase 3). We treated mice with AMPK activator, AICAR, prior to CLP. AMPK treated mice demonstrated significant improvement in GFR 24 hours post CLP compared to untreated mice (p=0.02). AMPK treatment also increased expression of fusion and autophagy proteins and decreased expression of apoptosis proteins. AMPK treatment also increased ATP levels (See Figure). Our findings indicate cellular stress with decreased AMPK, mitochondrial fusion and autophagy and increased apoptosis, which may play an important role in the pathogenesis of sepsis associated AKI. Targeting AMPK improved several parameters demonstrating it's potential as a novel therapeutic option. Additional mechanistic investigations to confirm the significance of this pathway are being conducted. Support or Funding Information NIDDK Grant K08‐DK‐084305 (P. Singh), Veterans Affairs (VA) Merit Award BX002175 (P. Singh), NIDDK R03 DK101841(P.Singh) the University of Alabama at Birmingham‐University of California San Diego O'Brien Center (P30‐DK‐079337)AMPK activation in CLP. Black bar‐ controls, Grey bar‐CLP, Striped bar CLP+AICAR. Increased AMPK, Mfn1, Mfn2, and decreased cleaved caspase 3 expression in AICAR treated CLP kidneys. Beclin, ULK1 are increased and LC31 is decreased with AICAR consistent with increased autophagy. Western blot denistometry normalized to b‐actin or GAPDH. ATP levels increased with AICAR treatment. *p<0.05 CLP vs. control and CLP vs. CLP+AICAR. N=4–6 per group. Improved GFR post‐CLP with AICAR (*p=0.02).