期刊
KIDNEY INTERNATIONAL
卷 89, 期 2, 页码 399-410出版社
ELSEVIER SCIENCE INC
DOI: 10.1038/ki.2015.332
关键词
acute kidney injury; epigenetics; inflammation; mitochondria; tubular cell
资金
- ISCIII
- FEDER funds [PI13/00047, PIE13/00051]
- EUTOX [CP12/03262, CP14-00133]
- FRIAT Sociedad Espanola de Nefrologia
- ISCIII-RETIC REDinREN [RD012/0021]
- Comunidad de Madrid [CIFRA S2010/BMD-2378]
- ISCIII Miguel Servet [MS12/03262, MS14/00133]
- Programa Intensificacion Actividad Investigadora (ISCIII/Agencia Lain-Entralgo/CM)
- F.P.U.
Studies of mitochondria-targeted nephroprotective agents suggest a key role of mitochondrial injury in AKI. Here we tested whether an improved perception of factors responsible for mitochondrial biogenesis may provide clues to novel therapeutic approaches to AKI. TWEAK is an inflammatory cytokine which is upregulated in AKI. Transcriptomic analysis of TWEAK-stimulated cultured murine tubular epithelial cells and folic acid-induced AKI in mice identified downregulation of peroxisome proliferator-activated receptor-gamma coactivador-1 alpha (PGC-1 alpha) and its target genes (mitochondrial proteins Ndufs1, Sdha, and Tfam) as a shared feature. Neutralizing anti-TWEAK antibodies prevented the decrease in kidney PGC-1 alpha and its targets during AKI. TWEAK stimulation decreased kidney PGC-1 alpha expression in healthy mice and decreased expression of PGC-1 alpha and its targets as well as mitochondrial membrane potential in cultured tubular cells. Adenoviral-mediated PGC-1 alpha overexpression prevented TWEAK-induced downregulation of PGC-1 alpha-dependent genes and the decrease in mitochondrial membrane potential. TWEAK promoted histone H3 deacetylation at the murine PGC-1 alpha promoter. TWEAK-induced downregulation of PGC-1 alpha was prevented by histone deacetylase or NF-kappa B inhibitors. Thus, TWEAK decreases PGC-1 alpha and target gene expression in tubular cells in vivo and in vitro. Approaches that preserve mitochondrial function during kidney injury may be therapeutic for AKI.
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