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

  • Ana B. Sanz
    Affiliations
    Instituto de Investigacion Sanitaria (IIS)-Fundacion Jimenez Diaz, Nepfrology, Madrid, Spain

    Red de Investigacion Renal (REDinREN), Universidad de Madrid, Facultad de Medicina, Madrid, Spain
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  • Olga Ruiz-Andres
    Affiliations
    Instituto de Investigacion Sanitaria (IIS)-Fundacion Jimenez Diaz, Nepfrology, Madrid, Spain

    Red de Investigacion Renal (REDinREN), Universidad de Madrid, Facultad de Medicina, Madrid, Spain
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  • Maria Dolores Sanchez-Niño
    Affiliations
    Instituto de Investigacion Sanitaria (IIS)-Fundacion Jimenez Diaz, Nepfrology, Madrid, Spain

    Red de Investigacion Renal (REDinREN), Universidad de Madrid, Facultad de Medicina, Madrid, Spain
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  • Marta Ruiz-Ortega
    Affiliations
    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
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  • Adrian M. Ramos
    Affiliations
    Instituto de Investigacion Sanitaria (IIS)-Fundacion Jimenez Diaz, Nepfrology, Madrid, Spain

    Red de Investigacion Renal (REDinREN), Universidad de Madrid, Facultad de Medicina, Madrid, Spain
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  • Alberto Ortiz
    Correspondence
    Address reprint requests to Alberto Ortiz, MD, PhD, Dialysis Unit, Fundación Jiménez Díaz, Avd. Reyes Católicos 2, 28040 Madrid, Spain
    Affiliations
    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
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      Summary

      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.

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