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.

Out of the TWEAKlight: Elucidating the Role of Fn14 and TWEAK in Acute Kidney Injury

“…In general, actions of systemic TWEAK administration to experimental animals mirror results obtained in cultured renal cells. A single parenteral TWEAK injection in mice 31,41,42,45,60,61 induced tubulointerstitial inflammation, decreased kidney klotho and PGC-1α expression, and promoted tubular cell proliferation within 4 to 24 hours. 31,44 TWEAK activated canonical (RelA) and noncanonical (RelB/p52) NF-κB pathways, resulting in early RelA and delayed RelB and p52 nuclear translocation in tubular cells, 41,42 expression of chemokines, [41][42][43]60,61 and interstitial macrophage and CD3 þ cell infiltration.…”

“…31,[40][41][42] TWEAK activation of the canonical NF-κB pathway and p65/RelA nuclear translocation results in the upregulation of inflammatory cytokines, such as Monocyte chemoattractant protein-1 (MCP-1/CCL2), interleukin-6, chemokine (C-C motif) ligand 5 (CCL5/RANTES), and chemokine (C-X-C Motif) ligand 16 (CXCL16), 41,43,44 and down-regulation of the expression of klotho and peroxisome proliferator-activated receptor gamma coactivator 1-alpha(PGC1α). 41,[43][44][45] Klotho is an antiaging protein with anti-inflammatory and antifibrotic actions, and klotho down-regulation may contribute to kidney injury. [46][47][48][49] PGC-1α is a transcriptional coactivator that regulates energy homeostasis, mitochondrial biogenesis, fatty acid oxidation, and glucose metabolism, and, thus, may protect from kidney injury.…”

“…In this regard, TWEAK caused loss of mitochondrial membrane potential without inducing cell death. 45 TWEAK also activates the noncanonical NF-κB pathway, triggering the nuclear translocation of NF-κB2 p52 and RelB, and inducing the expression of specific targets of this pathway such as chemokine (C-C motif) ligand 21 and 19 (CCL20 and CCL19 respectively). 42 TWEAK promotes renal tubular cell proliferation in culture and in vivo.…”

“…40,43 TWEAK alone does not promote renal tubular cell apoptosis. 30,45 However, an inflammatory milieu composed of TNFα and interferon-γ leads to accelerated (within 18-24 h) tubular cell apoptosis, 30 whereas TNFα alone promotes milder and delayed (48-72 h) apoptosis. 30,50 Caspase inhibition prevents features of TWEAK/TNFα/interferon-γ-induced apoptosis, but increases overall cell death through a reactive oxygen species-dependent necrotic pathway 30 (Fig.…”

“…This has uncovered functional in vivo evidence for the role of TWEAK/Fn14 in AKI and in the AKI-to-CKD transition. 7,39,[41][42][43][44][45] Tubular cell Fn14 is up-regulated within 24 hours in experimental AKI induced by a folic acid overdose or by renal ischemia-reperfusion, and at 3 days after ureteral obstruction as well as in human ischemic AKI and in acute or chronic human tubulointerstitial inflammation associated with glomerular injury or caused by acute tubulointerstitial nephritis. 30,32,39,43 Kidney TWEAK also was increased in experimental renal injury, but to a lesser extent than Fn14.…”