The facilitator in acute kidney injury: TWEAK

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Concepción Izquierdo, Juan Antonio Moreno, Alvaro C. Ucero, Alberto Benito-Martín, Beatríz Santamaria, Carolina Burgos, Jesús Egido, Alberto Ortíz, Marta Ruíz-Ortega, Luis Miguel Blanco-Colio, Adrián Ramos, Sergio Berzal, Eliécer Coto" "autores" => array:15 [ 0 => array:3 [ "nombre" => "Ana Belén" "apellidos" => "Sanz" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "affa" ] ] ] 1 => array:3 [ "nombre" => "María Dolores" "apellidos" => "Sánchez-Nino" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "affa" ] ] ] 2 => array:3 [ "nombre" => "M. Concepción" "apellidos" => "Izquierdo" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "affa" ] ] ] 3 => array:3 [ "nombre" => "Juan Antonio" "apellidos" => "Moreno" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "affa" ] ] ] 4 => array:3 [ "nombre" => "Alvaro" "apellidos" => "C. 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Loss of renal tubular cells characterizes both acute and chronic failure of renal function1. Tubular cells may be lost by shedding, death or differentiation into fibroblasts. In human studies tubular cell death was the best histopathological correlate of renal dysfunction during acute kidney injury (AKI).2,3 In addition sublethally injured tubular cells secrete mediators of inflammation that further aggravate AKI. However, the factors that modulate tubular cell injury and the interplay between different factors is incompletely understood. In fact, AKI is a paradigmatic situation in which an insufficient understanding of the mechanisms of injury precludes the implementation of effective physiopathology-based approaches for prevention and treatment. Numerous factors contributing to injury have been identified and many of them have been shown to be effective targets in animal models of injury.4 However the few attempts to translate this information to the clinical situation have failed. We now review the evidence involving a novel cytokine-ligand pair, TWEAK and Fn14, in AKI.5-7 We feel that they may become important targets in the treatment of AKI because they are «team players», they behave as «facilitators» that amplify injurious responses initiated by other stimuli. Thus their targeting has the potential to dampen injury induced by a wide range of stimuli. THE STARS: TWEAK AND Fn14 Tumor necrosis factor-like weak inducer of apoptosis (TWEAK, Apo3L, TNFSF12) is a member of the tumor necrosis factor superfamily (TNFSF) of structurally-related cytokines8 (fig. 1). The human TWEAK gene is located at chromosome 17 and encodes a 249- amino acid (aa) type II transmembrane glycoprotein (30 kDa). The intracellular domain contains a putative serine phosphorylation site. The extracellular domain contains the receptor-binding site. TWEAK may be expressed as a membrane-bound protein (mTWEAK) and as a 156-aa, 18kDa soluble protein, (sTWEAK) that results from proteolysis of mTWEAK.9,10 mTWEAK, but not sTWEAK, may enter the cell nucleus, although the relevance of this observation is unknown.11 The TWEAK receptor was initially and erroneously reported to be the tumor necrosis factor receptor superfamily (TNFRSF) member death receptor 3 (DR3).12 In 2001 the TWEAK receptor was cloned and shown to be the previously described human fibroblast growth factorinducible 14 (Fn14, TNFRSF12A)13-15 (fig. 1). The human Fn14 gene is located at chromosome 16 and encodes a 129-aa type I transmembrane protein (14 kDa). Fn14 is processed into a 102- aa mature protein, making it the smallest TNFRSF member to date.9,16 The Fn14 extracellular domain (53-aa) contains the TWEAK-binding site.17 The intracellular domain (29-aa) contains a TNFR-associated factor (TRAF)-binding site with three potentially phosphorylated threonines. TRAF binding has been implicated in signal transduction.18 TWEAK trimerizes and binds to Fn14 monomers, promoting receptor trimerization and signal transduction.18-21 Although Fn14 was the only characterized TWEAK receptor, some TWEAK actions may be mediated independently of Fn14.22 Indeed CD163 was recently shown to either act as a TWEAK scavenger in pathological conditions or serve as an alternate receptor for TWEAK in cells lacking Fn14/TweakR.23 Human and murine TWEAK are closely related, with a 93% homology in the receptor-binding domain. Furthermore, human and murine Fn14 have a 90% homology in their overall sequences, human TWEAK can bind to murine Fn14 and vice-versa.24 In fact this pathway is remarkably conserved throughout evolution and putative TWEAK and Fn14 ESTs can be found in species as primitive as zebrafish.25 The phylogenetical conservation suggests an important biological role. TWEAK is widely expressed, and can be found at high levels in pancreas, intestine, heart, brain, lung, ovary and skeletal muscle, and at lower levels in liver and kidney.8,26 TWEAK mRNA levels were initially reported to be reduced in mice with both acute (induced by lipopolysaccharide) or chronic (autoimmune pathologies like lupus erythematosus or hemolytic anemia) inflammatory processes in numerous tissues and peritoneal macrophages.27 In the same line of evidence, normal human arteries release sTWEAK but sTWEAK release from atherosclerotic arteries is reduced.28 Low serum sTWEAK is a marker for subclinical atherosclerosis of potential clinical relevance.28 However, elevated TWEAK expression was found in other inflammatory conditions such as experimental autoimmune encephalitis. 29 By contrast to TWEAK, resting tissue levels of Fn14 are usually low. As an example, it is undetectable in normal arteries.28 Fn14 initially was identified as an early response gene whose transcription was induced by FGF-1 (fibroblast growth factor-1) in fibroblasts.14 Numerous cell culture and in vivo studies have demonstrated rapid induction and increased expression of Fn14 upon activation of diverse cell types by multiple stimuli, as well as in vivo in the course of liver, artery, central nervous system or kidney injury or in tumor cells.19,16,13,30,31 It has been postulated that a reduced Fn14 expression limits the actions of TWEAK in healthy tissues and rapid and quantitatively important upregulation of this receptor sensitizes to TWEAK actions28,32 (fig. 2). This sensitization would promote TWEAK activity in the presence of only mildly increased or even reduced TWEAK expression. In experimental models of AKI and autoimmune injury renal TWEAK and, more significantly, Fn14 expression is upregulated.31,33 The potential sources of TWEAK in the kidney include infiltrating monocytes and T lymphocytes.34,35 In particular T cells from lupus patients express TWEAK.34 Other renal sources of TWEAK include tubular epithelial cells.31 In addition, mesangial cells also express TWEAK and Fn14.36 Defining the role of a pleiotropic cytokine such as TWEAK in AKI is a challenge that has been approached by functional studies in cell cultures and experimental models.32 THE ROLES: HEROES AND VILLAINS Evidence suggests that TWEAK and Fn14 play a role in the pathogenesis of human diseases, including atherosclerosis, stroke, rheumatoid arthritis, autoimmune kidney injury, AKI and cancer.5-7,37,38,25 TWEAK stimulates, in a cell-type- and microenvironment-dependent fashion, cell proliferation,39-43 survival, 44 migration,41,45,46 cell growth9 and apoptosis.8,47-51 TWEAK can also promote22 or inhibit52-54 cell  differentiation. Finally, TWEAK induces the expression of pro-inflammatory molecules. 8,27,36,41,45,55-58 In vivo, TWEAK can stimulate blood vessel formation (angiogenesis) 40,59 and regulates neurovascular unit permeability.60 A CROWDED PLACE: TWEAK AND INFLAMMATION TWEAK promotes sustained NFκB activation in murine tubular epithelial cells. In tubular cells TWEAK increased NFκB DNA-binding and transcriptional activity, IκB-α phosphorylation and RelA nuclear translocation via Fn14.32 As a consequence, TWEAK induced the mRNA expression and secretion of MCP-1, IL-6 and RANTES, which was prevented by the RelA inhibitor parthenolide. The effect of TWEAK on chemokines (previously known as  intercrines), 61 such as MCP-1 and RANTES is particularly interesting as it allows the recruitment of further inflammatory cells and amplification of inflammation. TNFα, used as a control for NFκB activation, yielded a different pattern of NFκB DNA-binding complexes.32 This suggests that TWEAK induces other biological responses also dependent on NFκB that differ from those elicited by TNFα. Thus, TNFα and TWEAK would not be redundant cytokines in renal injury. In this regard, the persistent NFκB activation induced by TWEAK in tubular cells is consistent with the recently identified non-canonical NFκB activation, which is not activated by TNFα.62 Systemic administration of TWEAK activates kidney NFκB and has a proinflammatory effect in the renal tubulointerstitium characterized by increased MCP-1, RANTES and IL-6 mRNA.32 Immunohistochemistry showed that RelA translocated to the nucleus of tubular cells and that these cells were the main site of expression of MCP-1 and RANTES. The expression of chemokines by tubular cells was followed by increased renal expression of the mRNA for the MCP-1 receptor, CCR2, which is expressed by macrophages, as well as by an increased number of interstitial macrophages. This demonstrates that TWEAK induces tubulointerstitial inflammation in vivo. However, TWEAK alone did not modify serum creatinine. TWEAK had recently been found to increase MCP-1 expression in cultured glomerular mesangial cells and to upregulate whole kidney MCP-1 mRNA.36 However, that report did not address whether there was a concomitant increase of chemokine protein, which were the cells responsible for mRNA expression and whether TWEAK elicited renal inflammation. In fact, the context of the report (cell culture studies in mesangial cells) suggested that the site of action of TWEAK would be the glomerulus. Our findings demonstrate that in normal kidneys TWEAK elicits tubulointerstitial, but not glomerular inflammation.32 TWEAK contributes to glomerular injury when the Fn14 receptor has been previously upregulated locally by injurious stimuli.33 THE KILLING FIELDS Apoptosis contributes to renal cell loss.63 In addition to nephrotoxins and other forms of cell stress,64,65 several members of the TNF ligand superfamily induce apoptotic renal cell death, including TRAIL, FasL and TNF-α.66-68 The name TWEAK derives from its weak capacity to induce apoptosis. TWEAK frequently requires co-stimuli, such as IFNγ, to induce apoptosis. 35 However, TWEAK alone may induce apoptosis in primary neurons and mesangial cells and this effect is magnified in the presence of IFNγ.36,48 TWEAK also mediates activated CD4+T cell-induced apoptosis of monocytes and macrophages (T cells presumably release concomitantly other mediators).69 By contrast, non-stimulated tubular epithelial cells are resistant to TWEAKinduced apoptosis and the lethal effect only becomes apparent in the presence of several (not one) inflammatory mediators released during AKI, such as IFNγ and TNF-α.31,70,71 This requirement for both IFNγ and TNFα in order to sensitize to cell death in the presence of TWEAK is novel. TNFα/IFNγ increased Fn14 expression in tubular cells. Upregulation of Fn14 expression may underlie the sensitization to apoptosis. However, the level of Fn14 expression is not the only mechanism involved, since IFNγ or TNFα alone also increase Fn14 expression but do not sensitize to cell death. Functional inhibition studies suggested that autocrine activation of the FasL/Fas system mildly contributed to cell death.31,72 The signaling pathways leading from Fn14 to cell death remains poorly understood and there is evidence that it may differ with cell type and the cell microenvironment. The lack of a death domain (DD) suggests that direct recruitment of DD-containing adaptor proteins is not the primary mode of inducing cell death. Evidence from caspase inhibitor studies also points to several pathways for cell death. In tubular cells, the combination of TWEAK, TNFα and IFNγ resulted in activation of caspase-8, proteolysis of Bid, release of cytochrome c to the cytosol and activation of caspase-9 and caspase-3, suggesting activation of a canonical cell death receptor pathway with recruitment of the mitochondrial pathway. No evidence supporting the participation of endoplasmic reticulum stress was found. The apoptotic endoplasmic reticulum response is preserved in tubular cells exposed to paracetamol or tunicamycin.64 Most extracellular inputs are not processed in isolation, rather, multiple inputs are perceived by cells in a proinflammatory milieu.73 Thus, it is difficult to assign the final output to a single stimulus. It is conceivable that similar apoptotic pathways engaged by both TNFα and TWEAK in the presence of IFNγ cooperate in cell death induction. Indeed, TNFα may induce a delayed apoptosis in tubular cells, but the time-course differs from that induced by TWEAK/TNFα/IFNγ, as there is a lag period of 48 h, which was confirmed in cells treated with TNFa/IFNγ. 31 In addition, the intracellular molecular mechanisms differ between death induced by TNF alone and by the cytokine combination. The pancaspase inhibitor zVAD prevented the activation of caspases, and also prevented apoptosis induced by TWEAK/TNFα/IFNγ.31 However, zVAD transformed the mode of cell death to necrosis and even increased the rate of cell death. Although the induction of necrosis in cells exposed to members of the TNF superfamily when caspases are inhibited had been previously observed,74 zVAD did not promote TNFα-induced necrosis in tubular epithelium.31 This response is cell type-specific and suggests that pan-caspase inhibition may not be an adequate therapeutic approach to renal injury in which inflammation is contributing the cell death. In tubular cells Fn14 and reactive oxygen species were required for the necrotic response. THE OUTCOME: PROTECTION As outlined above cell culture data suggest that TWEAK may be deleterious in inflamed kidney. However, potential proliferative actions of TWEAK on tubular cells or progenitor cells or the recruitment of macrophages that participate in tissue repair might confer a protective role for TWEAK.25 In this regard, an initial interpretation of the low serum levels of TWEAK in atherosclerosis was that they may be contributing to injury. Functional inhibition of TWEAK in vivo was required to understand the outcome of these different potential actions of TWEAK and the end-result of its interactions with different components of the microenvironment. AKI induced by a folic acid overdose is an animal model which has a human counterpart in the rare cases of accidental parental overdose of folic acid.75 In addition, it shares with human AKI processes such as tubular cell death, inflammation, and tubular cell proliferation leading to spontaneous recovery and mild fibrosis.70,76 In this model, expression of TWEAK and Fn14 increased both at the mRNA and protein level.31 There was a 13-fold increase in Fn14 mRNA and a 2.5-fold increase in tubular cell Fn14 receptor. Fn14 was localized to injured, dilated proximal and distal tubules.31 While Fn14 was already very high at 24 h, TWEAK expression progressively increased, peaking at 72 h. In addition, renal expression of IFNγ and TNFα is increased in AKI.70,32 A neutralizing anti-TWEAK antibody decreased peak serum creatinine and did not interfere with recovery which was achieved by day 7 in control and treated mice.32 Neutralization of TWEAK also resulted in significantly milder histological injury. TWEAK did not participate in the early (24 h) inflammatory response, which was TWEAK-independent. However, it amplified subsequent inflammation and when TWEAK was neutralized the tubular expression of certain inflammatory molecules (MCP-1, RANTES) and interstitial inflammation by macrophages was decreased at 72 h. The in vivo effect of TWEAK on inflammatory mediators appears to be  selective. As an example, kidney IL-6 in the course of injury was TWEAK-independent. Thus, although TWEAK may modulate IL-6 expression in cultured tubular cells, other stimuli are more important regulators of IL-6 expression in AKI. EPILOGUE The Oxford English dictionary defines TWEAK as «improving by making fine adjustments». This meaning closely represents the role of TWEAK in kidney injury. TWEAK regulates a wide range of cellular processes that are involved both in the generation and the recovery from renal injury. Interestingly the precise effect of TWEAK over kidney cells is modulated by the cell microenvironment, allowing it to fine-tune the renal response to injury (fig. 3). TWEAK interacts with the cell microenvironment to elicit cell-specific responses. In the context of kidney inflammation during AKI the overall effect of TWEAK is negative for the kidney, promoting inflammation and cell death. In this context, TWEAK antagonism improves renal function. TWEAK regulates a wide range of cellular processes that are involved both in the generation of and the recovery from renal injury. Given the pleiotropic actions of TWEAK, that include modulating the proliferation of progenitor cells,77 agonism of TWEAK should also be explored in certain clinical contexts. In addition, the possible role of TWEAK as a biomarker should be studied as urinary TWEAK levels were found to be elevated in patients with active lupus nephritis78 and low serum TWEAK levels are a marker for subclinical atherosclerosis.28 ACKNOWLEDGMENTS This work was supported by grants from FIS 06/0046 and ISCIII-RETICS REDINREN RD 06/0016, MEC (SAF 03/884), Sociedad Espanola de Nefrologia. JAM, AR and AS were supported by FIS, MDSN and ACU by MEC, ACU, MCI, SB and BS by Fundacion Conchita Rabago and AO by the Programa de Intensificación de la Actividad Investigadora in the Sistema Nacional de Salud of the Instituto de Salud Carlos III and the Agencia «Pedro Lain Entralgo» of the Comunidad de Madrid and FRACAM S-BIO 0283/2006. " "pdfFichero" => "P-E-S-A327-EN.pdf" "tienePdf" => true "PalabrasClave" => array:2 [ "es" => array:6 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec440407" "palabras" => array:1 [ 0 => "apoptosis" ] ] 1 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec440409" "palabras" => array:1 [ 0 => "Fn14" ] ] 2 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec440411" "palabras" => array:1 [ 0 => "TWEAK" ] ] 3 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec440413" "palabras" => array:1 [ 0 => "fracaso renal agudo" ] ] 4 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec440415" "palabras" => array:1 [ 0 => "inflamación" ] ] 5 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec440417" "palabras" => array:1 [ 0 => "células tubulares" ] ] ] "en" => array:6 [ 0 => array:3 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec440408" ] 1 => array:3 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec440410" ] 2 => array:3 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec440412" ] 3 => array:3 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec440414" ] 4 => array:3 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec440416" ] 5 => array:3 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec440418" ] ] ] "tieneResumen" => true "resumen" => array:2 [ "es" => array:1 [ "resumen" => "RESUMEN TWEAK es una citoquina de la superfamilia de las TNF que activa el receptor Fn14. TWEAK regula la proliferación celular, la muerte celular, la angiogénesis y la inflamación. La expresión de TWEAK y de su receptor Fn14 aumenta en células tubulares en caso de lesión renal. Las citoquinas proinflamatorias incrementan la expresión del receptor Fn14 en las células tubulares y TWEAK induce apoptosis en un medio inflamatorio. Además TWEAK induce la expresión de quimiocinas y citoquinas proinflamatorias. Estos resultados en células cultivadas se han reproducido en modelos experimentales de insuficiencia renal aguda. El antagonismo de TWEAK protegió la función renal y redujo la inflamación en esos modelos. En conjunto estos datos sugieren que TWEAK promueve la inflamación y la lesión tisular inflamatoria y que podría ser una nueva diana terapéutica en el daño renal. " ] "en" => array:1 [ "resumen" => "ABSTRACT TWEAK is a cytokine of the TNF superfamiliy that activates the Fn14 receptor. TWEAK may regulate cell proliferation, cell death, cell differentiation, angiogenesis and inflammation. The expression of TWEAK and Fn14 is increased in tubular cells during acute kidney injury. Inflammatory cytokines increase Fn14 receptor expression in tubular cells and, in a proinflammatory milieu, TWEAK induces tubular cell apoptosis. In addition, TWEAK itself contributes to renal inflammation by promoting the secretion of chemokines and inflammatory cytokines by tubular cells. Confirmation of its role in acute kidney injury came from functional studies in the experimental model of folic acid overdose. TWEAK antagonism preserved renal function and reduced inflammation in this model. The available evidence suggests that TWEAK might be a target for therapeutic intervention in kidney injury and its role in different forms of renal injury should be further explored. 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TWEAK, el facilitador del daño renal agudo

Ana Belén Sanza, María Dolores Sánchez-Ninoa, M. Concepción Izquierdoa, Juan Antonio Morenoa, Alvaro C. Uceroa, Alberto Benito-Martína, Beatríz Santamariaa, Carolina Burgosa, Jesús Egidob, Alberto Ortízb, Marta Ruíz-Ortegaa, Luis Miguel Blanco-Colioa, Adrián Ramos, Sergio Berzal, Eliécer Cotod

a Fundacion Jiménez Díaz, Universidad Autónoma de Madrid, Madrid, Madrid, España,

b Fundacion Jiménez Díaz, Universidad Autónoma de Madrid, Fundación Renal Íñigo Álvarez de Toledo, Madrid, Madrid, España,

d Fundación Renal Íñigo Álvarez de Toledo, Genética Molecular-Hospital Central de Asturias, Madrid, Oviedo, Madrid, Asturias, España,

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    "textoCompleto" => "<p class="elsevierStylePara">THE PLOT&#58; ACUTE KIDNEY INJURY<br></br><br></br>Most of the mass of the kidneys is composed of tubular cells&#46; Loss of renal tubular cells characterizes both acute and chronic failure of renal function1&#46; Tubular cells may be lost by shedding&#44; death or differentiation into fibroblasts&#46;<br></br>In human studies tubular cell death was the best histopathological correlate of renal dysfunction during acute kidney<br></br>injury &#40;AKI&#41;&#46;2&#44;3 In addition sublethally injured tubular cells secrete mediators of inflammation that further aggravate AKI&#46; However&#44; the factors that modulate tubular cell injury and the interplay between different factors is incompletely understood&#46; In fact&#44; AKI is a paradigmatic situation in which an insufficient understanding of the mechanisms of injury precludes the implementation of effective physiopathology-based approaches for prevention and treatment&#46; Numerous factors contributing to injury have been identified and many of them have been shown to be effective targets in animal models of injury&#46;4 However the few attempts to translate this information to the clinical situation have failed&#46; We now review the evidence involving a novel cytokine-ligand pair&#44; TWEAK and Fn14&#44; in AKI&#46;5-7 We feel that they may become important targets in the treatment of AKI because they are &#171;team players&#187;&#44; they behave as &#171;facilitators&#187; that amplify injurious responses initiated by other stimuli&#46; Thus their targeting has the potential to dampen injury induced by a wide range of stimuli&#46;<br></br><br></br>THE STARS&#58; TWEAK AND Fn14<br></br><br></br>Tumor necrosis factor-like weak inducer of apoptosis &#40;TWEAK&#44; Apo3L&#44; TNFSF12&#41; is a member of the tumor necrosis factor superfamily &#40;TNFSF&#41; of structurally-related cytokines8 &#40;fig&#46; 1&#41;&#46; The human TWEAK gene is located at<br></br>chromosome 17 and encodes a 249- amino acid &#40;aa&#41; type II transmembrane glycoprotein &#40;30 kDa&#41;&#46; The intracellular domain contains a putative serine phosphorylation site&#46; The extracellular domain contains the receptor-binding site&#46; TWEAK may be expressed as a membrane-bound protein &#40;mTWEAK&#41; and as a 156-aa&#44; 18kDa soluble protein&#44; &#40;sTWEAK&#41; that results from proteolysis of mTWEAK&#46;9&#44;10 mTWEAK&#44; but not sTWEAK&#44; may enter the cell nucleus&#44; although the relevance of this observation is unknown&#46;11<br></br><br></br>The TWEAK receptor was initially and erroneously reported to be the tumor necrosis factor receptor superfamily<br></br>&#40;TNFRSF&#41; member death receptor 3 &#40;DR3&#41;&#46;12 In 2001 the TWEAK receptor was cloned and shown to be the previously described human fibroblast growth factorinducible 14 &#40;Fn14&#44; TNFRSF12A&#41;13-15 &#40;fig&#46; 1&#41;&#46; The human Fn14 gene is located at chromosome 16 and encodes a 129-aa type I transmembrane protein &#40;14 kDa&#41;&#46; Fn14 is processed into a 102- aa mature protein&#44; making it the smallest TNFRSF member to date&#46;9&#44;16 The Fn14 extracellular domain &#40;53-aa&#41; contains the TWEAK-binding site&#46;17 The intracellular domain &#40;29-aa&#41; contains a<br></br>TNFR-associated factor &#40;TRAF&#41;-binding site with three potentially phosphorylated threonines&#46; TRAF binding has been implicated in signal transduction&#46;18 TWEAK trimerizes and binds to Fn14 monomers&#44; promoting receptor trimerization and signal transduction&#46;18-21<br></br><br></br>Although Fn14 was the only characterized TWEAK receptor&#44; some TWEAK actions may be mediated independently<br></br>of Fn14&#46;22 Indeed CD163 was recently shown to either act as a TWEAK scavenger in pathological conditions or serve as an alternate receptor for TWEAK in cells lacking Fn14&#47;TweakR&#46;23<br></br><br></br>Human and murine TWEAK are closely related&#44; with a 93&#37; homology in the receptor-binding domain&#46; Furthermore&#44;<br></br>human and murine Fn14 have a 90&#37; homology in their overall sequences&#44; human TWEAK can bind to murine<br></br>Fn14 and vice-versa&#46;24 In fact this pathway is remarkably conserved throughout evolution and putative TWEAK and<br></br>Fn14 ESTs can be found in species as primitive as zebrafish&#46;25 The phylogenetical conservation suggests an important biological role&#46;<br></br><br></br>TWEAK is widely expressed&#44; and can be found at high levels in pancreas&#44; intestine&#44; heart&#44; brain&#44; lung&#44; ovary and<br></br>skeletal muscle&#44; and at lower levels in liver and kidney&#46;8&#44;26 TWEAK mRNA levels were initially reported to be<br></br>reduced in mice with both acute &#40;induced by lipopolysaccharide&#41; or chronic &#40;autoimmune pathologies like lupus<br></br>erythematosus or hemolytic anemia&#41; inflammatory processes in numerous tissues and peritoneal macrophages&#46;27 In the same line of evidence&#44; normal human arteries release sTWEAK but sTWEAK release from atherosclerotic arteries is reduced&#46;28 Low serum sTWEAK is a marker for subclinical atherosclerosis of potential clinical relevance&#46;28 However&#44; elevated TWEAK expression was found in other inflammatory conditions such as experimental autoimmune encephalitis&#46; 29<br></br><br></br>By contrast to TWEAK&#44; resting tissue levels of Fn14 are usually low&#46; As an example&#44; it is undetectable in normal<br></br>arteries&#46;28 Fn14 initially was identified as an early response gene whose transcription was induced by FGF-1 &#40;fibroblast growth factor-1&#41; in fibroblasts&#46;14 Numerous cell culture and in vivo studies have demonstrated rapid induction and increased expression of Fn14 upon activation of diverse cell types by multiple stimuli&#44; as well as in vivo in the course of liver&#44; artery&#44; central nervous system or kidney injury or in tumor cells&#46;19&#44;16&#44;13&#44;30&#44;31 It has been postulated that a reduced Fn14 expression limits the actions of TWEAK in healthy tissues and rapid and quantitatively important upregulation of this receptor sensitizes to TWEAK actions28&#44;32 &#40;fig&#46; 2&#41;&#46; This sensitization would promote TWEAK activity in the presence of only mildly increased or even reduced TWEAK expression&#46;<br></br><br></br>In experimental models of AKI and autoimmune injury renal TWEAK and&#44; more significantly&#44; Fn14 expression is<br></br>upregulated&#46;31&#44;33 The potential sources of TWEAK in the kidney include infiltrating monocytes and T lymphocytes&#46;34&#44;35 In particular T cells from lupus patients express TWEAK&#46;34 Other renal sources of TWEAK include tubular epithelial cells&#46;31 In addition&#44; mesangial cells also express TWEAK and Fn14&#46;36 Defining the role of a pleiotropic cytokine such as TWEAK in AKI is a challenge that has been approached by functional studies in cell cultures and experimental models&#46;32<br></br><br></br>THE ROLES&#58; HEROES AND VILLAINS<br></br><br></br>Evidence suggests that TWEAK and Fn14 play a role in the pathogenesis of human diseases&#44; including atherosclerosis&#44; stroke&#44; rheumatoid arthritis&#44; autoimmune kidney injury&#44; AKI and cancer&#46;5-7&#44;37&#44;38&#44;25 TWEAK stimulates&#44; in a cell-type- and microenvironment-dependent fashion&#44; cell proliferation&#44;39-43 survival&#44; 44 migration&#44;41&#44;45&#44;46 cell growth9 and apoptosis&#46;8&#44;47-51 TWEAK can also promote22 or inhibit52-54 cell&#160; differentiation&#46; Finally&#44; TWEAK induces the expression of pro-inflammatory molecules&#46; 8&#44;27&#44;36&#44;41&#44;45&#44;55-58 In vivo&#44; TWEAK can stimulate blood vessel formation &#40;angiogenesis&#41; 40&#44;59 and regulates neurovascular unit permeability&#46;60<br></br><br></br>A CROWDED PLACE&#58; TWEAK AND INFLAMMATION<br></br><br></br>TWEAK promotes sustained NF&#954;B activation in murine tubular epithelial cells&#46; In tubular cells TWEAK increased<br></br>NF&#954;B DNA-binding and transcriptional activity&#44; I&#954;B-&#945; phosphorylation and RelA nuclear translocation via Fn14&#46;32 As a consequence&#44; TWEAK induced the mRNA expression and secretion of MCP-1&#44; IL-6 and RANTES&#44; which was prevented by the RelA inhibitor parthenolide&#46; The effect of TWEAK on chemokines &#40;previously known as&#160; intercrines&#41;&#44; 61 such as MCP-1 and RANTES is particularly interesting as it allows the recruitment of further<br></br>inflammatory cells and amplification of inflammation&#46;<br></br><br></br>TNF&#945;&#44; used as a control for NF&#954;B activation&#44; yielded a different pattern of NF&#954;B DNA-binding complexes&#46;32 This<br></br>suggests that TWEAK induces other biological responses also dependent on NF&#954;B that differ from those elicited by<br></br>TNF&#945;&#46; Thus&#44; TNF&#945; and TWEAK would not be redundant cytokines in renal injury&#46; In this regard&#44; the persistent NF&#954;B activation induced by TWEAK in tubular cells is consistent with the recently identified non-canonical NF&#954;B activation&#44; which is not activated by TNF&#945;&#46;62<br></br><br></br>Systemic administration of TWEAK activates kidney NF&#954;B and has a proinflammatory effect in the renal tubulointerstitium characterized by increased MCP-1&#44; RANTES and IL-6 mRNA&#46;32 Immunohistochemistry showed that RelA translocated to the nucleus of tubular cells and that these cells were the main site of expression of MCP-1<br></br>and RANTES&#46; The expression of chemokines by tubular cells was followed by increased renal expression of the<br></br>mRNA for the MCP-1 receptor&#44; CCR2&#44; which is expressed by macrophages&#44; as well as by an increased number of<br></br>interstitial macrophages&#46; This demonstrates that TWEAK induces tubulointerstitial inflammation in vivo&#46; However&#44; TWEAK alone did not modify serum creatinine&#46;<br></br><br></br>TWEAK had recently been found to increase MCP-1 expression in cultured glomerular mesangial cells and to upregulate whole kidney MCP-1 mRNA&#46;36 However&#44; that report did not address whether there was a concomitant increase of chemokine protein&#44; which were the cells responsible for mRNA expression and whether TWEAK elicited<br></br>renal inflammation&#46; In fact&#44; the context of the report &#40;cell culture studies in mesangial cells&#41; suggested that the site<br></br>of action of TWEAK would be the glomerulus&#46; Our findings demonstrate that in normal kidneys TWEAK elicits<br></br>tubulointerstitial&#44; but not glomerular inflammation&#46;32 TWEAK contributes to glomerular injury when the Fn14 receptor has been previously upregulated locally by injurious stimuli&#46;33<br></br><br></br>THE KILLING FIELDS<br></br><br></br>Apoptosis contributes to renal cell loss&#46;63 In addition to nephrotoxins and other forms of cell stress&#44;64&#44;65 several<br></br>members of the TNF ligand superfamily induce apoptotic renal cell death&#44; including TRAIL&#44; FasL and TNF-&#945;&#46;66-68<br></br>The name TWEAK derives from its weak capacity to induce apoptosis&#46; TWEAK frequently requires co-stimuli&#44; such as IFN&#947;&#44; to induce apoptosis&#46; 35 However&#44; TWEAK alone may induce apoptosis in primary neurons and mesangial cells and this effect is magnified in the presence of IFN&#947;&#46;36&#44;48 TWEAK also mediates activated CD4&#43;T cell-induced apoptosis of monocytes and macrophages &#40;T cells presumably release concomitantly other mediators&#41;&#46;69 By contrast&#44; non-stimulated tubular epithelial cells are resistant to TWEAKinduced apoptosis and the lethal effect only becomes apparent in the presence of several &#40;not one&#41; inflammatory mediators released during AKI&#44; such as IFN&#947; and TNF-&#945;&#46;31&#44;70&#44;71 This requirement for both IFN&#947; and TNF&#945; in order to sensitize to cell death in the presence of<br></br>TWEAK is novel&#46; TNF&#945;&#47;IFN&#947; increased Fn14 expression in tubular cells&#46; Upregulation of Fn14 expression may underlie the sensitization to apoptosis&#46; However&#44; the level of Fn14 expression is not the only mechanism involved&#44;<br></br>since IFN&#947; or TNF&#945; alone also increase Fn14 expression but do not sensitize to cell death&#46; Functional inhibition studies suggested that autocrine activation of the FasL&#47;Fas system mildly contributed to cell death&#46;31&#44;72<br></br><br></br>The signaling pathways leading from Fn14 to cell death remains poorly understood and there is evidence that it may differ with cell type and the cell microenvironment&#46; The lack of a death domain &#40;DD&#41; suggests that direct<br></br>recruitment of DD-containing adaptor proteins is not the primary mode of inducing cell death&#46; Evidence from caspase inhibitor studies also points to several pathways for cell death&#46; In tubular cells&#44; the combination of TWEAK&#44; TNF&#945; and IFN&#947; resulted in activation of caspase-8&#44; proteolysis of Bid&#44; release of cytochrome c to the cytosol and activation of caspase-9 and caspase-3&#44; suggesting activation of a canonical cell death receptor pathway with recruitment of the mitochondrial pathway&#46; No evidence supporting the participation of endoplasmic reticulum stress was found&#46; The apoptotic endoplasmic reticulum response is preserved in tubular cells exposed to paracetamol or tunicamycin&#46;64 Most extracellular inputs are not processed in isolation&#44; rather&#44; multiple inputs are perceived by cells in a proinflammatory milieu&#46;73 Thus&#44; it is difficult to assign the final output to a single stimulus&#46; It is conceivable that similar apoptotic pathways engaged by both TNF&#945; and TWEAK in the presence of IFN&#947; cooperate in cell death induction&#46; Indeed&#44; TNF&#945; may induce a delayed apoptosis in tubular cells&#44; but the time-course differs from that induced by TWEAK&#47;TNF&#945;&#47;IFN&#947;&#44; as there is a lag period of 48 h&#44; which was confirmed in cells treated with TNFa&#47;IFN&#947;&#46; 31 In addition&#44; the intracellular molecular mechanisms differ between death induced by TNF alone and by the cytokine combination&#46; The pancaspase inhibitor zVAD prevented the activation of caspases&#44; and also prevented<br></br>apoptosis induced by TWEAK&#47;TNF&#945;&#47;IFN&#947;&#46;31 However&#44; zVAD transformed the mode of cell death to necrosis and even increased the rate of cell death&#46; Although the induction of necrosis in cells exposed to members of the TNF superfamily when caspases are inhibited had been previously observed&#44;74 zVAD did not promote TNF&#945;-induced<br></br>necrosis in tubular epithelium&#46;31 This response is cell type-specific and suggests that pan-caspase inhibition may not be an adequate therapeutic approach to renal injury in which inflammation is contributing the cell death&#46; In tubular cells Fn14 and reactive oxygen species were required for the necrotic response&#46;<br></br><br></br>THE OUTCOME&#58; PROTECTION<br></br><br></br>As outlined above cell culture data suggest that TWEAK may be deleterious in inflamed kidney&#46; However&#44; potential<br></br>proliferative actions of TWEAK on tubular cells or progenitor cells or the recruitment of macrophages that participate<br></br>in tissue repair might confer a protective role for TWEAK&#46;25 In this regard&#44; an initial interpretation of the low serum levels of TWEAK in atherosclerosis was that they may be contributing to injury&#46; Functional inhibition of TWEAK in vivo was required to understand the outcome of these different potential actions of TWEAK and the end-result of its interactions with different components of the microenvironment&#46; AKI induced by a folic acid overdose is an animal model which has a human counterpart in the rare cases of accidental parental overdose of folic acid&#46;75 In addition&#44; it shares with human AKI processes such as tubular cell death&#44; inflammation&#44; and tubular cell proliferation leading to spontaneous recovery and mild fibrosis&#46;70&#44;76 In this model&#44; expression of TWEAK and Fn14 increased both at the mRNA and protein level&#46;31 There was a 13-fold increase in Fn14 mRNA and a 2&#46;5-fold increase in tubular cell Fn14 receptor&#46; Fn14 was localized to injured&#44; dilated proximal and distal tubules&#46;31 While Fn14 was already very high at 24 h&#44; TWEAK expression progressively increased&#44; peaking at 72 h&#46; In addition&#44; renal expression of IFN&#947; and TNF&#945; is<br></br>increased in AKI&#46;70&#44;32 A neutralizing anti-TWEAK antibody decreased peak serum creatinine and did not interfere<br></br>with recovery which was achieved by day 7 in control and treated mice&#46;32 Neutralization of TWEAK also resulted in significantly milder histological injury&#46; TWEAK did not participate in the early &#40;24 h&#41; inflammatory response&#44; which<br></br>was TWEAK-independent&#46; However&#44; it amplified subsequent inflammation and when TWEAK was neutralized the<br></br>tubular expression of certain inflammatory molecules &#40;MCP-1&#44; RANTES&#41; and interstitial inflammation by macrophages was decreased at 72 h&#46; The in vivo effect of TWEAK on inflammatory mediators appears to be&#160; selective&#46; As an example&#44; kidney IL-6 in the course of injury was TWEAK-independent&#46; Thus&#44; although TWEAK may modulate IL-6 expression in cultured tubular cells&#44; other stimuli are more important regulators of IL-6 expression in AKI&#46;<br></br><br></br>EPILOGUE<br></br><br></br>The Oxford English dictionary defines TWEAK as &#171;improving by making fine adjustments&#187;&#46; This meaning closely<br></br>represents the role of TWEAK in kidney injury&#46; TWEAK regulates a wide range of cellular processes that are<br></br>involved both in the generation and the recovery from renal injury&#46; Interestingly the precise effect of TWEAK over kidney cells is modulated by the cell microenvironment&#44; allowing it to fine-tune the renal response to injury &#40;fig&#46; 3&#41;&#46; TWEAK interacts with the cell microenvironment to elicit cell-specific responses&#46; In the context of kidney inflammation during AKI the overall effect of TWEAK is negative for the kidney&#44; promoting inflammation and cell death&#46; In this context&#44; TWEAK antagonism improves renal function&#46; TWEAK regulates a wide range of cellular processes that are involved both in the generation of and the recovery from renal injury&#46; Given the pleiotropic<br></br>actions of TWEAK&#44; that include modulating the proliferation of progenitor cells&#44;77 agonism of TWEAK should also be explored in certain clinical contexts&#46; In addition&#44; the possible role of TWEAK as a biomarker should be studied as urinary TWEAK levels were found to be elevated in patients with active lupus nephritis78 and low serum TWEAK levels are a marker for subclinical atherosclerosis&#46;28<br></br><br></br>ACKNOWLEDGMENTS<br></br><br></br>This work was supported by grants from FIS 06&#47;0046 and ISCIII-RETICS REDINREN RD 06&#47;0016&#44; MEC &#40;SAF 03&#47;884&#41;&#44; Sociedad Espanola de Nefrologia&#46; JAM&#44; AR and AS were supported by FIS&#44; MDSN and ACU by MEC&#44; ACU&#44; MCI&#44; SB and BS by Fundacion Conchita Rabago and AO by the Programa de Intensificaci&#243;n de la Actividad<br></br>Investigadora in the Sistema Nacional de Salud of the Instituto de Salud Carlos III and the Agencia &#171;Pedro Lain Entralgo&#187; of the Comunidad de Madrid and FRACAM S-BIO 0283&#47;2006&#46;<br></br></p>"
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        "resumen" => "RESUMEN TWEAK es una citoquina de la superfamilia de las TNF que activa el receptor Fn14&#46; TWEAK regula la proliferaci&#243;n celular&#44; la muerte celular&#44; la angiog&#233;nesis y la inflamaci&#243;n&#46; La expresi&#243;n de TWEAK y de su receptor Fn14 aumenta en c&#233;lulas tubulares en caso de lesi&#243;n renal&#46; Las citoquinas proinflamatorias incrementan la expresi&#243;n del receptor Fn14 en las c&#233;lulas tubulares y TWEAK induce apoptosis en un medio inflamatorio&#46; Adem&#225;s TWEAK induce la expresi&#243;n de quimiocinas y citoquinas proinflamatorias&#46; Estos resultados en c&#233;lulas cultivadas se han reproducido en modelos experimentales de insuficiencia renal aguda&#46; El antagonismo de TWEAK protegi&#243; la funci&#243;n renal y redujo la inflamaci&#243;n en esos modelos&#46; En conjunto estos datos sugieren que TWEAK promueve la inflamaci&#243;n y la lesi&#243;n tisular inflamatoria y que podr&#237;a ser una nueva diana terap&#233;utica en el da&#241;o renal&#46; "
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        "resumen" => "ABSTRACT TWEAK is a cytokine of the TNF superfamiliy that activates the Fn14 receptor&#46; TWEAK may regulate cell proliferation&#44; cell death&#44; cell differentiation&#44; angiogenesis and inflammation&#46; The expression of TWEAK and Fn14 is increased in tubular cells during acute kidney injury&#46; Inflammatory cytokines increase Fn14 receptor expression in tubular cells and&#44; in a proinflammatory milieu&#44; TWEAK induces tubular cell apoptosis&#46; In addition&#44; TWEAK itself contributes to renal inflammation by promoting the secretion of chemokines and inflammatory cytokines by tubular cells&#46; Confirmation of its role in acute kidney injury came from functional studies in the experimental model of folic acid overdose&#46; TWEAK antagonism preserved renal function and reduced inflammation in this model&#46; The available evidence suggests that TWEAK might be a target for therapeutic intervention in kidney injury and its role in different forms of renal injury should be further explored&#46; "
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Article information

ISSN: 20132514
Original language: English

DOI:

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Year/Month	Html	Pdf	Total

2024 November	12	16	28
2024 October	62	83	145
2024 September	56	37	93
2024 August	73	87	160
2024 July	76	30	106
2024 June	81	37	118
2024 May	69	36	105
2024 April	99	34	133
2024 March	59	25	84
2024 February	52	263	315
2024 January	60	34	94
2023 December	51	29	80
2023 November	57	38	95
2023 October	85	30	115
2023 September	63	31	94
2023 August	48	27	75
2023 July	54	30	84
2023 June	47	21	68
2023 May	60	30	90
2023 April	32	22	54
2023 March	54	17	71
2023 February	48	24	72
2023 January	40	21	61
2022 December	59	33	92
2022 November	54	28	82
2022 October	33	27	60
2022 September	49	36	85
2022 August	52	47	99
2022 July	32	39	71
2022 June	41	19	60
2022 May	64	36	100
2022 April	61	47	108
2022 March	67	57	124
2022 February	65	50	115
2022 January	48	30	78
2021 December	43	37	80
2021 November	36	27	63
2021 October	37	41	78
2021 September	37	40	77
2021 August	25	36	61
2021 July	46	28	74
2021 June	50	24	74
2021 May	46	33	79
2021 April	81	46	127
2021 March	32	26	58
2021 February	29	25	54
2021 January	35	24	59
2020 December	16	9	25
2020 November	41	24	65
2020 October	28	19	47
2020 September	26	4	30
2020 August	39	13	52
2020 July	21	9	30
2020 June	33	11	44
2020 May	45	16	61
2020 April	37	11	48
2020 March	35	20	55
2020 February	33	19	52
2020 January	47	22	69
2019 December	41	28	69
2019 November	49	15	64
2019 October	22	14	36
2019 September	28	10	38
2019 August	23	9	32
2019 July	29	25	54
2019 June	19	7	26
2019 May	27	11	38
2019 April	49	30	79
2019 March	18	10	28
2019 February	16	17	33
2019 January	23	20	43
2018 December	49	27	76
2018 November	72	20	92
2018 October	40	28	68
2018 September	38	11	49
2018 August	32	16	48
2018 July	31	10	41
2018 June	37	22	59
2018 May	32	11	43
2018 April	35	10	45
2018 March	42	20	62
2018 February	25	4	29
2018 January	27	9	36
2017 December	37	14	51
2017 November	32	5	37
2017 October	32	13	45
2017 September	20	5	25
2017 August	24	12	36
2017 July	35	11	46
2017 June	23	13	36
2017 May	26	18	44
2017 April	28	15	43
2017 March	22	10	32
2017 February	14	8	22
2017 January	17	10	27
2016 December	79	16	95
2016 November	94	6	100
2016 October	101	16	117
2016 September	121	6	127
2016 August	180	3	183
2016 July	174	6	180
2016 June	122	0	122
2016 May	127	0	127
2016 April	96	0	96
2016 March	97	0	97
2016 February	96	0	96
2016 January	108	0	108
2015 December	107	0	107
2015 November	90	0	90
2015 October	81	0	81
2015 September	67	0	67
2015 August	78	0	78
2015 July	56	0	56
2015 June	37	0	37
2015 May	51	0	51
2015 April	16	0	16

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