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Changes in mitochondrial metabolism and morphology contribute to sepsis‐associated acute kidney injury (1134.10)
Author(s) -
Thomas Joanna,
Ayoyama Koji,
Nourbakhsh Noureddin,
Singh Prabhleen
Publication year - 2014
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.28.1_supplement.1134.10
Subject(s) - mitochondrion , sepsis , mitochondrial biogenesis , oxidative stress , kidney , western blot , tfam , reactive oxygen species , acute kidney injury , oxidative phosphorylation , biology , medicine , chemistry , endocrinology , microbiology and biotechnology , biochemistry , gene
Acute Kidney Injury (AKI) is commonly seen in septic patients, but there are no effective treatments to prevent or treat it. New perspectives on the pathogenesis of AKI in sepsis are needed to improve the current standard of treatment. We examined renal mitochondrial function and expression of proteins with known roles in mitochondrial function and dynamics in the cecal ligation and puncture (CLP) model of sepsis in rats. At 24 hrs post CLP or sham surgery, kidney tissue and mitochondria were isolated for protein expression analyses and mitochondrial functional assays including mitochondrial oxygen consumption (QO2), ATP generation and reactive oxygen species (ROS) generation. Data represents mean ± SEM. In isolated mitochondria, QO2 rates were higher in CLP compared to sham; with the largest difference observed during state 3 (199.9 ± 31.6 pMol/min vs. 163.2 ± 28.81 pMol/min, p<0.05). However, ATP generation was significantly lower in the mitochondria from CLP kidneys. With western blot expression, we found increased expression of mitochondrial fission proteins DRP1 (1.9‐fold higher in CLP, P<.0004) and Fis1 (trend for higher expression) in CLP kidneys. We also observed decreased expression of PGC‐1α, a key transcription factor in mitochondrial biogenesis. Analysis of the expression of the expression of the ETC complexes in the mitochondrial fraction showed a 25% reduction (P 蠄 .001) in Complex Va and Complex III in CLP mitochondria. In conclusion, our data indicate significant increase in renal oxidative metabolism but without the associated ATP generation and reduction in the expression of ETC complexes. Mitochondrial analyses reveal increased mitochondrial fission but with reduced biogenesis, indicating increased mitochondrial stress. Additional morphological and functional analyses are being conducted. We are also evaluating mechanisms underlying the altered mitochondrial function to identify potential therapeutic targets for the treatment of kidney injury during sepsis. Grant Funding Source : NIH