title: Out of the TWEAKlight: Elucidating the Role of Fn14 and TWEAK in Acute Kidney Injury.
abstract: Tumor necrosis factor-like weak inducer of apoptosis (TWEAK) is a tumor necrosis factor superfamily cytokine that activates the fibroblast growth factor-inducible-14 (Fn14) receptor. Functional studies have established a role of TWEAK/Fn14 in experimental acute kidney injury (AKI) and the AKI to chronic kidney disease transition through actions on tubular cells and renal fibroblasts. The renal cell expression of TWEAK and Fn14 is increased in human and experimental AKI and targeting TWEAK or Fn14 by genetic means or neutralizing antibodies was protective in kidney injury induced by folic acid overdose, ischemia-reperfusion, or unilateral ureteral obstruction. TWEAK/Fn14 targeting preserved renal function, and reduced tubular cell injury and death, nuclear factor-κB activation, chemokine expression, inflammatory cell infiltration by macrophages and T cells, myofibroblast numbers, and extracellular matrix deposition, while preserving the expression of the anti-aging factor klotho and the mitochondrial regulator Peroxisome proliferator-activated receptor gamma coactivator 1-alpha(PGC1α), as well as of PGC1α-dependent genes. The beneficial in vivo effects of TWEAK/Fn14 targeting are consistent with known actions of TWEAK on kidney cells. We review the literature on TWEAK and AKI and propose further avenues of research to unravel the contribution of TWEAK to kidney injury. Although a randomized clinical trial of neutralizing anti-TWEAK antibodies for lupus nephritis recently was terminated for futility, AKI represents a potential target for clinical development because it is potentially lethal and, as opposed to severe lupus nephritis, is very common, lacks effective therapy, and is not autoimmune in nature.
authors.affiliation: Instituto de Investigacion Sanitaria (IIS)-Fundacion Jimenez Diaz, Nepfrology, Madrid, Spain; Red de Investigacion Renal (REDinREN), Universidad de Madrid, Facultad de Medicina, Madrid, Spain.
authors.forename: Ana B
authors.initials: AB
authors.lastname: Sanz
authors.affiliation: Instituto de Investigacion Sanitaria (IIS)-Fundacion Jimenez Diaz, Nepfrology, Madrid, Spain; Red de Investigacion Renal (REDinREN), Universidad de Madrid, Facultad de Medicina, Madrid, Spain.
authors.forename: Olga
authors.initials: O
authors.lastname: Ruiz-Andres
authors.affiliation: Instituto de Investigacion Sanitaria (IIS)-Fundacion Jimenez Diaz, Nepfrology, Madrid, Spain; Red de Investigacion Renal (REDinREN), Universidad de Madrid, Facultad de Medicina, Madrid, Spain.
authors.forename: Maria Dolores
authors.initials: MD
authors.lastname: Sanchez-Niño
authors.affiliation: Instituto de Investigacion Sanitaria (IIS)-Fundacion Jimenez Diaz, Nepfrology, Madrid, Spain; Red de Investigacion Renal (REDinREN), Universidad de Madrid, Facultad de Medicina, Madrid, Spain; Universidad Autonoma de Madrid, Madrid, Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: Ruiz-Ortega
authors.affiliation: Instituto de Investigacion Sanitaria (IIS)-Fundacion Jimenez Diaz, Nepfrology, Madrid, Spain; Red de Investigacion Renal (REDinREN), Universidad de Madrid, Facultad de Medicina, Madrid, Spain.
authors.forename: Adrian M
authors.initials: AM
authors.lastname: Ramos
authors.affiliation: Instituto de Investigacion Sanitaria (IIS)-Fundacion Jimenez Diaz, Nepfrology, Madrid, Spain; Red de Investigacion Renal (REDinREN), Universidad de Madrid, Facultad de Medicina, Madrid, Spain; Universidad Autonoma de Madrid, Madrid, Spain; Instituto Reina Sofia de Investigaciones Nefrologicas (IRSIN), Universidad de Madrid, Facultad de Medicina, Madrid, Spain. Electronic address: aortiz@fjd.es.
authors.forename: Alberto
authors.initials: A
authors.lastname: Ortiz
mesh_terms: D058186:Acute Kidney Injury / Q000378:metabolism*; D018925:Chemokines / Q000378:metabolism; D000074049:Cytokine TWEAK / Q000378:metabolism*; D018450:Disease Progression; D005966:Glucuronidase / Q000378:metabolism; D006801:Humans; D000090265:Klotho Proteins; D016328:NF-kappa B / Q000378:metabolism; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha / Q000378:metabolism; D051436:Renal Insufficiency, Chronic / Q000378:metabolism*; D000074050:TWEAK Receptor / Q000378:metabolism*
chemical_list: D018925:Chemokines; D000074049:Cytokine TWEAK; D016328:NF-kappa B; C486497:PPARGC1A protein, human; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C000613297:TNFRSF12A protein, human; C109743:TNFSF12 protein, human; D000074050:TWEAK Receptor; D005966:Glucuronidase; D000090265:Klotho Proteins
keywords: Apoptosis; acute kidney injury; clinical trials; fibrosis; human; inflammation; kidney; klotho; mitochondria; necroptosis; therapy