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

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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.

Section snippets

Tweak, Fn14, And CD163

TWEAK activates the Fn14 receptor and is scavenged by macrophage-derived CD163 (Fig. 1). Described in 1997 as a weak inducer of cell death, TWEAK is the sole cytokine signaling through Fn14.12, 13 Type II transmembrane protein TWEAK is cleaved to generate a soluble cytokine. Both soluble and membrane TWEAK activate Fn14.12, 14, 15 The Fn14 intracellular domain is the shortest of the TNFR superfamily and lacks the characteristic death domain, but it contains TNFR-associated factor–binding

Tweak Actions On Renal Tubular Cells

TWEAK has actions on intrinsic kidney cells of potential pathophysiological relevance through Fn14-receptor signaling (Figure 2, Figure 3), including in podocytes and kidney fibroblasts.6, 39 However, the effects of TWEAK in tubular cells have been explored in the most detail and are discussed here in the context of AKI.

In cultured murine tubular cells, TWEAK activates MAPK such as extracellular signal-regulated kinase1/2 (ERK1/2) and p38 MAPK, phosphoinositide 3-kinase/Akt, JAK2 kinase, and

Tweak Interaction With Other Cytokine Systems And Toxins

Cell responses to TWEAK may be modified by the simultaneous presence in the cellular milieu of additional factors, cytokines, and toxins, and TWEAK may modulate other cytokine systems.

The proinflammatory effect of TWEAK on cultured tubular cells is enhanced by the simultaneous presence in the cell environment of additional inflammatory mediators, such as CXCL16, TNFα, and interferon-γ.40, 43 TWEAK alone does not promote renal tubular cell apoptosis.30, 45 However, an inflammatory milieu

Profibrotic Actions Of Tweak In Kidney Cells

The AKI-to-CKD transition is characterized by the development of kidney fibrosis and TWEAK may have a specific role at several steps of the process, beyond any indirect action resulting from inflammation and cell death (Fig. 3). Kidney fibrosis involves myofibroblast proliferation, increased extracellular matrix (ECM) synthesis and deposition, and transdifferentiation of tubular epithelial cells by epithelial to mesenchymal transition (EMT). Although the contribution of EMT to fibroblast

Systemic Tweak Effects On Healthy Kidneys

Systemic events leading to increased circulating TWEAK levels, as observed in sepsis,26 may impact normal kidneys. In general, actions of systemic TWEAK administration to experimental animals mirror results obtained in cultured renal cells. A single parenteral TWEAK injection in mice31, 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

Tweak As A Promoter Of Aki And Of The Aki-To-Ckd Transition

The potential role of TWEAK and Fn14 in kidney injury has been explored in experimental AKI using genetic approaches or antibodies to target TWEAK or Fn14 (Table 2). 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

Tweak/Fn14 Targeting In The Clinic

Phase 1 and phase 2 clinical trials exploring TWEAK/Fn14 targeting have been completed or terminated in autoimmune inflammation, cancer, and muscle atrophy (Table 1). A phase I dose-ranging clinical trial in rheumatoid arthritis showed that a single intravenous of the neutralizing anti-TWEAK antibody BIIB023 decreased serum TWEAK to undetectable levels for up to a month, and tended to decrease circulating inflammation mediators.62 However, a phase 2 randomized placebo-controlled clinical trial

Aki As A Therapeutic Target For Clinical Trials

An increasing body of evidence suggests that TWEAK has a deleterious role in sterile inflammation–associated kidney injury through actions on intrinsic renal cells that include further promotion of inflammation and cell death. The recent (October 2015) termination of a phase 2 anti-TWEAK antibody trial, which targeted autoimmune kidney disease, is bad news. However, the pathogenesis of AKI is different from lupus nephritis, and TWEAK/Fn14 targeting in oncology and other fields may provide

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    ☆☆

    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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