title: The inflammatory cytokine TWEAK decreases PGC-1α expression and mitochondrial function in acute kidney injury.
abstract: 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-γ coactivador-1α (PGC-1α) and its target genes (mitochondrial proteins Ndufs1, Sdha, and Tfam) as a shared feature. Neutralizing anti-TWEAK antibodies prevented the decrease in kidney PGC-1α and its targets during AKI. TWEAK stimulation decreased kidney PGC-1α expression in healthy mice and decreased expression of PGC-1α and its targets as well as mitochondrial membrane potential in cultured tubular cells. Adenoviral-mediated PGC-1α overexpression prevented TWEAK-induced downregulation of PGC-1α-dependent genes and the decrease in mitochondrial membrane potential. TWEAK promoted histone H3 deacetylation at the murine PGC-1α promoter. TWEAK-induced downregulation of PGC-1α was prevented by histone deacetylase or NF-κB inhibitors. Thus, TWEAK decreases PGC-1α 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.
authors.forename: Olga
authors.initials: O
authors.lastname: Ruiz-Andres
authors.forename: Beatriz
authors.initials: B
authors.lastname: Suarez-Alvarez
authors.forename: Cristina
authors.initials: C
authors.lastname: Sánchez-Ramos
authors.forename: Maria
authors.initials: M
authors.lastname: Monsalve
authors.forename: Maria D
authors.initials: MD
authors.lastname: Sanchez-Niño
authors.forename: Marta
authors.initials: M
authors.lastname: Ruiz-Ortega
authors.forename: Jesús
authors.initials: J
authors.lastname: Egido
authors.forename: Alberto
authors.initials: A
authors.lastname: Ortiz
authors.forename: Ana B
authors.initials: AB
authors.lastname: Sanz
mesh_terms: D058186:Acute Kidney Injury / Q000378:metabolism*; D000818:Animals; D002478:Cells, Cultured; D000074049:Cytokine TWEAK; D015536:Down-Regulation; D044127:Epigenesis, Genetic; D005260:Female; D006655:Histone Deacetylases / Q000378:metabolism; D007668:Kidney / Q000378:metabolism; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D001678:Organelle Biogenesis; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha / Q000378:metabolism*; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism; D000074050:TWEAK Receptor; D048069:Tumor Necrosis Factors / Q000378:metabolism*
chemical_list: D000074049:Cytokine TWEAK; D016328:NF-kappa B; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D018124:Receptors, Tumor Necrosis Factor; D000074050:TWEAK Receptor; C491645:Tnfsf12 protein, mouse; D048069:Tumor Necrosis Factors; D006655:Histone Deacetylases