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.
Keywords
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Article info
Footnotes
☆☆Financial support: Supported by FIS PI13/00047, PI14/0041, PI15/01460, CP14/00133, CP12/03262, PI15/00298, Instituto de Salud Carlos III-Redes Tematicas de Investigacion Cooperativa en Salud (ISCII-RETIC), REDinREN, Fondo Europeo de Desarrollo Regional (FEDER) funds, RD12/0021, Sociedad Española de Nefrologia, Fundacion Renal Iñigo Alvarez de Toledo (FRIAT), and Comunidad de Madrid/Consorcio de Investigacio de Fracaso Renal Agudo (CIFRA) S2010/BMD-2378. Salary support was provided by Fondo de Investigacion Sanitaria (FIS) (M.D.S.-N.) (Miguel Servet), Ana Belén Sanz (ABS) (Miguel Servet), Adrian Mario Ramos (AMR) (Miguel Servet-II), and Programa Intensificación Actividad Investigadora (ISCIII/Agencia Laín-Entralgo/Comunidad de Madrid (CM)) (A.O.).
Conflicts of interest statement: none.
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