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oai:repisalud.isciii.es:20.500.12105/173912024-09-21T10:16:15Zcom_20.500.12105_19604com_20.500.12105_2051col_20.500.12105_19605

00925njm 22002777a 4500 dc Ruiz-Andres, Olga author Suarez-Alvarez, Beatriz author Sánchez-Ramos, Cristina author Monsalve, Maria author Sanchez-Niño, Maria D author Ruiz-Ortega, Marta author Egido, Jesús author Ortiz, Alberto author Sanz, Ana B author 2016-02 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. Kidney Int. 2016 Feb;89(2):399-410. 10.1038/ki.2015.332 1523-1755 Kidney international 26535995 http://hdl.handle.net/20.500.12105/17391 The inflammatory cytokine TWEAK decreases PGC-1α expression and mitochondrial function in acute kidney injury.