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          "en" => "Gene expression for representative mediators of inflammation and ageing in experimental acute kidney injury &#40;AKI&#41;&#58; Transcriptomics results of kidney tissue"
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    "textoCompleto" => "<p class="elsevierStylePara"><span class="elsevierStyleBold">ACUTE KIDNEY INJURY AND CHRONIC KIDNEY DISEASE</span></p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara">Acute kidney injury &#40;AKI&#41; is a syndrome characterized by tubular injury and a sudden drop in glomerular filtration&#46; Our current understanding of the pathophysiology of AKI is incomplete and this accounts for the lack of specific therapy&#46; One key feature that has emerged in recent years is the close relationship between AKI and chronic kidney disease &#40;CKD&#41;&#46;<span class="elsevierStyleSup">1</span> Thus&#44; CKD is the main risk factor for AKI and AKI contributes to progression of CKD&#46; This suggests that AKI and CKD share pathogenic factors&#58; from a pathogenic point of view CKD may be considered a low level&#44; persistent AKI&#46; Since pathogenic events are magnified in AKI and AKI has a shorter time course&#44; AKI has advantages as a model for the identification and assessment of pathogenic factors&#46; In this regard&#44; proposed biomarkers of AKI are also altered in CKD&#44; including Klotho&#46;<span class="elsevierStyleSup">2&#44;3</span></p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara"><span class="elsevierStyleBold"><span class="elsevierStyleBold">TRANSCRIPTOMICS</span></span></p><p class="elsevierStylePara"><span class="elsevierStyleBold">&#160;</span></p><p class="elsevierStylePara">High throughput techniques such as transcriptomics and proteomics&#44; may help identify novel potential pathogenic factors&#44; therapeutic targets and biomarkers in a non-biased way&#46;<span class="elsevierStyleSup">4-6</span> Transcriptomics is a high throughput technique that allows the identification of thousands of differentially expressed candidate genes&#46; Such patterns of expression may themselves be used for diagnostic or prognostic purposes&#46; Bioinformatics and biostatistics tools allow to manage thousands of genes simultaneous and help to prioritize molecules for further confirmatory studies&#46; Novel therapeutic targets may be uncovered&#46; We recently used a transcriptomic approach to identify new genes involved in AKI that could serve as biomarkers or therapeutic targets&#46;<span class="elsevierStyleSup">7&#44;8</span> This approach has successfully identified new players in diabetic nephropathy such as the lethal cytokine TRAIL&#59; the MIF receptor CD74 and the intracellular lethal protein BASP1&#46;<span class="elsevierStyleSup">9-12</span><span class="elsevierStyleBold">&#160;</span></p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara"><span class="elsevierStyleBold"><span class="elsevierStyleBold">TWEAK AND Fn14</span></span></p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara">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;&#46;<span class="elsevierStyleSup">13-15</span> Other members of the family include TNF and Fas ligand&#44; both of which play a key role in kidney injury&#46;<span class="elsevierStyleSup">16-18</span> TNFSF ligands bind to one or more members of the TNF receptor superfamily &#40;TNFRSF&#41;&#46;<span class="elsevierStyleSup">19&#44;20</span></p><p class="elsevierStylePara">The human TWEAK gene encodes a type II transmembrane glycoprotein&#46; The TWEAK C-terminal extracellular domain contains the TNF homology domain that mediates self-trimerization and receptor-binding&#46;<span class="elsevierStyleSup">13</span> The N-terminal intracellular domain contains several nuclear localization sequences &#40;NLS&#41;<span class="elsevierStyleSup">13&#44;21-23</span>&#160;and a furin recognition site&#44; suggesting that TWEAK can be cleaved&#46;<span class="elsevierStyleSup">24</span> Most cells can express full-length membrane-anchored TWEAK &#40;mTWEAK&#41; and soluble TWEAK &#40;sTWEAK&#41;&#46;<span class="elsevierStyleSup">24&#44;25</span> sTWEAK is formed by proteolysis of membrane TWEAK&#46;<span class="elsevierStyleSup">13&#44;25&#44;26</span></p><p class="elsevierStylePara">Both sTWEAK and mTWEAK bind and activate fibroblast growth factor-inducible-14 &#40;Fn14&#44; TWEAK receptor&#44; TNFRSF12A&#44; CD266&#41;&#46;<span class="elsevierStyleSup">24&#44;27-29</span> Fn14 was initially described in fibroblasts as a growth factor-regulated early response gene&#46;<span class="elsevierStyleSup">30</span> Fn14 is a type I transmembrane protein that when mature has 102-aa&#46; Fn14 is the smallest member of TNFRSF&#46; The intracellular Fn14 domain contains TNFR-associated factor &#40;TRAF&#41;-binding sites which activate signal cascade&#46; Unlike TNF or Fas&#44; Fn14 does not contain a death domain &#40;DD&#41;&#46;<span class="elsevierStyleSup">31</span> In addition&#44; CD163 binds TWEAK and is thought to be a TWEAK scavenger receptor&#44; since TWEAK-induced signaling through CD163 was not observed&#46;<span class="elsevierStyleSup">32&#44;33</span></p><p class="elsevierStylePara">TWEAK has multiple functions with potential physiopathological relevance for kidney injury that depend on the microenvironment&#44; the cell type and the cell state of activation&#46; TWEAK can regulate cell proliferation&#44; cell death&#44; cell migration&#44; cell differentiation&#44; tissue regeneration&#44; neoangiogenesis and inflammation&#46;<span class="elsevierStyleSup">34-43</span> TWEAK contributes to tissue injury in the central nervous system&#44; liver&#44; gut&#44; the vasculature&#44; skeletal muscle&#44; heart and kidney&#46;<span class="elsevierStyleSup">40&#44;44-49</span></p><p class="elsevierStylePara">In the kidney TWEAK actions have been extensively studied in tubular epithelium&#46; TWEAK induces proliferation in non-stressed renal tubular cells<span class="elsevierStyleSup">50</span>&#160;and apoptosis in tubular cells stressed by an inflammatory milieu&#46;<span class="elsevierStyleSup">14&#44;51</span> Furthermore TWEAK activates both canonical and non-canonical NF&#954;B transcription factor signaling<span class="elsevierStyleSup">&#46;<span class="elsevierStyleSup">14&#44;52-54</span></span> Through these actions TWEAK promotes tubular injury in ischemic or toxic AKI<span class="elsevierStyleSup">54&#44;55</span>&#160;and kidney hyperplasia following unilateral nephrectomy&#46;<span class="elsevierStyleSup">56</span> Furthermore&#44; TWEAK contributes to vascular injury and in CKD patients soluble TWEAK behaves as a biomarker of outcome&#44; especially when interpreted in the context of systemic inflammation&#46;<span class="elsevierStyleSup">57-61</span> A recent transcriptomics analysis of kidney tissue in AKI confirmed highly upregulated levels of Fn14 mRNA &#40;Figure 1&#41;&#46; Regulation of the TWEAK&#47;Fn14 system often takes places through upregulation of receptor expression and&#44; thus&#44; of cell sensitivity to TWEAK actions&#46;</p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara"><span class="elsevierStyleBold"><span class="elsevierStyleBold">CXCL16</span></span></p><p class="elsevierStylePara"><span class="elsevierStyleBold"><span class="elsevierStyleBold">&#160;</span></span></p><p class="elsevierStylePara">Chemokines are small cytokines formerly known as intercrines<span class="elsevierStyleSup">62</span>&#160;that in the kidney tubulointerstitium may be expressed by both tubular cells and fibroblasts&#46;<span class="elsevierStyleSup">63</span> Chemokines promote leukocyte trafficking&#44; growth and activation in inflammatory sites&#46;<span class="elsevierStyleSup">64</span> Chemokines promote kidney tubulointerstitial inflammation<span class="elsevierStyleSup">&#46;<span class="elsevierStyleSup">65&#44;66</span></span> Leukocytes recruited by chemokines have a key role in kidney tubulointerstitial tissue injury during AKI and CKD&#46;<span class="elsevierStyleSup">67&#44;68</span> Several chemokines were upregulated in the transcriptome of murine AKI&#46;<span class="elsevierStyleSup">8</span> Some of them&#44; such as MCP-1 and Rantes&#44; had already been studied&#46;<span class="elsevierStyleSup">54</span> These chemokines share with most chemokines their release as soluble mediators&#46;<span class="elsevierStyleSup">65</span> CX3CL1 &#40;fractalkine&#41; and CXCL16 &#40;SR-PSOX&#41; were also found upregulated in the murine AKI the transcriptome&#46;<span class="elsevierStyleSup">8</span> CX3CL1 and CXCL16 are the only two known membrane-anchored chemokines&#46;<span class="elsevierStyleSup">69</span> CX3CL1 and CXCL16 are synthesized as transmembrane molecules and&#44; as such&#44; have specific functions that may go beyond their chemokines role&#46; In addition&#44; they can be cleaved from the cell surface to release a soluble chemoattractant that behaves as a classical chemokine&#46;<span class="elsevierStyleSup">69</span> Fractalkine has been extensively studied in the context of kidney disease&#46;<span class="elsevierStyleSup">70</span> However&#44; much less was known about CXCL16 and kidney injury&#46; Furthermore&#44; CXCL16 expression correlated more closely than CX3CL1 with Fn14 expression&#46;<span class="elsevierStyleSup">8</span> In addition&#44; there is evidence that in humans urinary TWEAK and CXCL16 may be a potential diagnostic biomarkers of kidney diseases such as lupus nephritis&#46;<span class="elsevierStyleSup">71&#44;72</span> TWEAK is known to regulate the expression of several chemokines&#46; These peculiarities made a complete understanding of the relationship between TWEAK and CXCL16 regulation in kidney cells of particular interest&#46;&#160;</p><p class="elsevierStylePara">CXCL16 was identified by different groups as a ligand for the CXC-chemokine receptor CXCR6<span class="elsevierStyleSup">73</span>&#160;and as a scavenger receptor for phosphatidylserine and oxidized low density lipoprotein &#40;oxLDL&#41; and therefore was also termed SR-PSOX&#46;<span class="elsevierStyleSup">74</span> Full length CXCL16 consists of an extracellular N-terminal chemokine domain&#44; a glycosylated mucin-like stalk&#44; a transmembrane-spanning region and a short cytoplasmic tail&#46;<span class="elsevierStyleSup">73</span> Like CX3CL1&#44; CXCL16 potentially functions as both a soluble chemokine and a membrane-bound adhesion molecule&#46;<span class="elsevierStyleSup">75-78</span> CXCL16 regulated leukocyte chemotaxis&#44; T cell recruitment and cell proliferation&#46;<span class="elsevierStyleSup">79-87</span></p><p class="elsevierStylePara">In the kidney&#44; CXCL16 is constitutively expressed in human mesangial cells&#44; podocytes and tubular cells&#46;<span class="elsevierStyleSup">79&#44;86&#44;87</span> There is evidence for differential regulation of CXCL16 expression in glomeruli or different tubular segments and in tubular injury of diverse etiology&#46; CXCL16 expression is increased in various animal models of kidney injury and human nephropathies&#46;<span class="elsevierStyleSup">72&#44;79&#44;86-89</span></p><p class="elsevierStylePara">Glomerular CXCL16 expression is increased in human membranous nephropathy&#46;<span class="elsevierStyleSup">87</span> Glomerular and tubular CXCL16 was also increased in lupus mice and in anti-GBM nephritis&#46;<span class="elsevierStyleSup">72&#44;88&#44;89</span> Functional studies suggest that CXCL16 promotes progression of damage in experimental glomerulonephritis&#46;<span class="elsevierStyleSup">88</span> CXCL16 blockade significantly decreased monocyte&#47;macrophage infiltration and glomerular and tubular injury&#46;<span class="elsevierStyleSup">88&#44;89</span> In this regard&#44; besides effects on leukocytes&#44; CXCL16 has direct actions on glomerular cells&#46; Podocyte CXCL16 may regulate the uptake of oxLDL&#44;<span class="elsevierStyleSup">87</span> while mesangial cell CXCL16 promotes mesangial cell migration and proliferation<span class="elsevierStyleSup">&#46;<span class="elsevierStyleSup">79</span></span></p><p class="elsevierStylePara">In human allograft AKI&#44; CXCL16 expression was increased focally in the apical side of tubules&#46;<span class="elsevierStyleSup">86</span> By contrast&#44; a low tubular CXCL16 expression was observed in interstitial rejection that was attributed to increases CXCL16 shedding&#46; Thus&#44; remnant CXCL16 was located to the basolateral membrane and surrounded by T cell infiltrates&#46; In experimental toxic AKI&#44; both prominent apical and basolateral CXCL16 expression were noted&#46;<span class="elsevierStyleSup">8</span> Thus&#44; other tubular cells&#44; the interstitium and the tubular lumen were exposed to CXCL16 derived from tubular cells&#46; Interestingly&#44; both patterns did not overlap in many tubules&#46;</p><p class="elsevierStylePara">No in vivo functional studies of CXCL16 targeting in tubulointerstitial kidney disease have been reported&#46; In cell culture CXCL16 did not induce murine tubular epithelial cell proliferation or apoptosis&#44; either alone or in combination with TWEAK&#46;<span class="elsevierStyleSup">8</span> However&#44; CXCL16 had a proinflammatory effect and increased TWEAK-induced gene expression of ICAM-1&#44; MCP-1 and RANTES&#46; In this regard&#44; tubular cells expressed the CXCR6 receptor&#46;<span class="elsevierStyleSup">8</span></p><p class="elsevierStylePara">In cultured glomerular cells CXCL16 is upregulated by TNF-&#945; and IFN-&#947;&#46;<span class="elsevierStyleSup">79&#44;86&#44;87</span> IFN-&#947; increased CXCL16 expression in cultured primary thick ascending limb cells and early distal tubular cells&#46;<span class="elsevierStyleSup">86</span> TWEAK is a novel regulator of CXCL16 expression in tubular epithelial cells&#46;<span class="elsevierStyleSup">8</span> TWEAK promoted CXCL16 expression through the canonical NF&#954;B pathway in cultured tubular cells&#46;<span class="elsevierStyleSup">8</span> Moreover&#44; TWEAK increased renal CXCL16 expression and interstitial CD3 positive lymphocytes&#46; Since neutralization of TWEAK decreased CXCL16 and CD3 lymphocyte infiltration in experimental AKI&#44; TWEAK-induced CXCL16 expression may contribute to T cell recruitment and collaborate with TWEAK in promoting inflammation&#46;</p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara"><span class="elsevierStyleBold"><span class="elsevierStyleBold">KLOTHO</span></span></p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara">Klotho is a protein with anti-aging properties which is highly expressed in tubular renal cells&#46;<span class="elsevierStyleSup">90&#44;91</span>&#160;Klotho is a single-pass transmembrane protein&#46; The extracellular domain of Klotho may be proteolytically processed by ADAM10&#47;17 and secreted&#46; In addition&#44; alternative splicing may give rise to a soluble secreted isoform&#46;<span class="elsevierStyleSup">92</span> Trasmembrane Klotho binds to multiple fibroblast growth factor &#40;FGF&#41; receptors conferring them specific and high affinity for FGF23&#46; FGF23 is a bone-derived hormone that regulates phosphate homeostasis and vitamin D metabolism&#46; Thus&#44; the main known function of Klotho is regulation of phosphate metabolism and evidence from mice in which phosphate was manipulated genetically or through diet suggests that aberrant phosphate homeostasis is a key contributor to the accelerated aging syndrome of Klotho -&#47;- mice&#46;<span class="elsevierStyleSup">93</span> Klotho also protects cells and tissues from oxidative stress and has anti-inflammatory properties through modulation of NF&#954;B signaling&#46;<span class="elsevierStyleSup">94</span></p><p class="elsevierStylePara">Klotho is downregulated during kidney diseases&#44; such as long-term hypertension&#44; diabetes mellitus&#44; CKD&#44;<span class="elsevierStyleSup">95</span> and in experimental AKI induced by ischemia-reperfusion or a folic acid overdose&#46;<span class="elsevierStyleSup">7&#44;96</span> In addition kidney Klotho was decreased in the course of systemic inflammation caused by inflammatory bowel disease and a neutralizing anti-TNF antibody attenuated bowel inflammation and reversed the repression of kidney Klotho expression&#46;<span class="elsevierStyleSup">97</span> Consistent with these data&#44; Klotho was downregulated in the transcriptome of murine AKI and Klotho expression was inversely correlated with Fn14 expression&#44; suggesting that TWEAK&#44; like TNF&#44; may regulate Klotho expression&#46; The reduction of kidney Klotho during nephrotoxic AKI persisted beyond recovery of renal function and was associated with decreased circulating Klotho&#46; The persistent decrease in Klotho might be related to the increased mortality of AKI patients following recovery from AKI&#46; Since Klotho may be nephroprotective&#44;<span class="elsevierStyleSup">96&#44;98-100</span> the persistent decrease in Klotho might also predispose to progression of CKD&#46; However&#44; these hypotheses await formal confirmation&#46;</p><p class="elsevierStylePara">In nephrotoxic AKI&#44; Klotho expression and renal function were preserved by TWEAK targeting thus identifying a potential regulator of Klotho expression in cultured cells&#46;<span class="elsevierStyleSup">7</span> Indeed&#44; in cultured tubular cells of proximal origin TWEAK and TNF promoted the NF&#954;B-dependent downregulation of Klotho expression&#46;<span class="elsevierStyleSup">7</span> TWEAK and TNF activate the canonical pathway for NF&#954;B activation&#44; but only TWEAK activates the non-canonical pathway&#46;<span class="elsevierStyleSup">14&#44;53</span> The reported downregulation of Klotho by TNF<span class="elsevierStyleSup"><span class="elsevierStyleSup">7&#44;97</span></span>&#160;and the time course of Klotho mRNA downregulation&#44; that is already observed at 3h&#44; suggest activation of the canonical NF&#954;B pathway&#46; Indeed&#44; RelA was necessary for TWEAK- and TNF-induced Klotho repression&#46; For the first time it was observed TWEAK downregulates NF&#954;B-mediated gene expression&#46; Regulation of NF&#954;B activation function is controlled through different mechanism&#44; such as interaction of the p65&#47;RelA subunit with histone deacetylase &#40;HDAC&#41; corepresor proteins<span class="elsevierStyleSup">&#46;<span class="elsevierStyleSup">101-103</span></span> In this regard&#44; HDAC inhibitors prevented repression of Klotho induced by TWEAK or TNF&#46; In addition&#44; recruitment of NFkB to chromatin is regulated in a promoter-specific manner&#46; TWEAK induced histone H3 and H4 deacetylation at the murine Klotho promoter in renal tubular cells&#46;&#160;</p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara"><span class="elsevierStyleBold"><span class="elsevierStyleBold">INTERACTION BETWEEN INFLAMMATION AND AGEING&#58; NF</span><span class="elsevierStyleBold">&#954;</span><span class="elsevierStyleBold">B</span></span></p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara">From the above mentioned studies the NF&#954;B emerges as a family of pleiotropic transcription factors with a key role at the interface between inflammation and ageing&#46;<span class="elsevierStyleSup">52&#44;104-107</span> This notion had been advanced before by proponents of the inflamma-aging concept&#46;<span class="elsevierStyleSup">108</span> The term inflamm-aging has been used to describe the age-related increase in the systemic pro-inflammatory status of humans&#46;<span class="elsevierStyleSup">109</span><span class="elsevierStyleBold">&#160;</span></p><p class="elsevierStylePara">A wide range of stimuli relevant to tissue injury activate NF&#954;B&#44; including cytokines&#44; growth factors&#44; immune mediators&#44; proteinuria and genotoxic or mechanical stretch<span class="elsevierStyleSup">&#46;<span class="elsevierStyleSup">110&#44;111</span></span> Activation of NF&#954;B can proceed through classical&#47;canonical&#44; alternative&#47;non-canonical NF&#954;B and hybrid pathways<span class="elsevierStyleSup">&#46;<span class="elsevierStyleSup">104&#44;106&#44;112</span></span> Classical NF&#954;B activation<span class="elsevierStyleBold"><span class="elsevierStyleBold">&#160;</span></span>is usually a rapid and transient response to a wide range of stimuli&#46; Under basal conditions NF&#954;B is inactive in the cytosol because it is bound to inhibitory I&#954;B proteins&#46; Activating stimuli activate the inhibitor of &#954;B kinases &#40;IKK&#41;&#44; which phosphorylate I&#954;Bs&#44; marking them for degradation by the proteasome&#46; Degradation of I&#954;B releases and activates NF&#954;B dimers&#44; such as those containing RelA&#46; RelA containing dimers then migrate to the nucleus where they bind to &#954;B DNA sequences in promoters and enhancers of target genes&#46; In general canonical NF&#954;B promote the transcription and expression of proinflammatory genes&#44; as observed for CXCL16 in TWEAK-stimulated tubular cells&#46; There are several negative feed-back mechanisms&#46; Thus&#44; suppressors of cytokine signaling &#40;SOCS&#41;-1 promotes the ubiquitination and proteasomal degradation of RelA-containing dimers&#44; thus quenching the NF&#954;B response&#46;<span class="elsevierStyleSup">113</span> The SOCS1 overexpression decreases inflammation in experimental DN<span class="elsevierStyleSup">&#46;<span class="elsevierStyleSup">114</span></span></p><p class="elsevierStylePara">As a result of NF&#954;B integration of stimulus information it may both induce or repress individual gene transcription&#46;<span class="elsevierStyleSup">115</span> However&#44; the fact that NF&#954;B can function as a repressor of gene expression is less well-known&#46; Gene expression repression by NF&#954;B may suppress the inflammatory response by recruiting inhibitory components of the NF&#954;B system&#46; Thus&#44; antiinflammatory cytokines&#44; such as IL-10 promote synthesis of nuclear located atypical I&#954;B proteins B-cell lymphoma 3 &#40;BCL-3&#41;&#44; I&#954;B&#950; and I&#954;BNS&#44; which bind to DNA-bound NF&#954;B dimers and may repress transcription of inflammatory genes&#46;<span class="elsevierStyleSup">113</span> In addition repression of gene expression by NF&#954;B has been implicated in sepsis-induced downregulation of kidney aquaporin&#47;V2 receptor and may have a role in resolution of inflammation&#46;<span class="elsevierStyleSup">116&#44;117</span> However&#44; classical NF&#954;B dimers containing RelA may also downregulate Klotho mRNA and Klotho-dependent anti-inflammatory and ageing pathways&#44; as observed for TWEAK and TNF&#44; and&#44; thus&#44; promote further injury in and outside the kidney&#46;</p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara"><span class="elsevierStyleBold"><span class="elsevierStyleBold">CONCLUSIONS</span></span></p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara">In summary&#44; transcriptomics of AKI tissue has identified TWEAK as a novel regulator of CXCL16 expression in renal tubular cells through activation of the RelA NF&#954;B transcription factor&#46; In addition&#44; TWEAK&#44; like TNF&#945;&#44; downregulated Klotho in renal tubular cells through a similar NF&#954;B RelA-dependent mechanism&#46; Since Klotho has anti-ageing and anti-inflammatory properties&#44; these findings may have therapeutic implications in kidney injury and also for inflammation-associated premature aging&#46; Thus targeting either TWEAK&#44; through neutralizing anti-TWEAK antibodies currently undergoing clinical trials in lupus nephritis&#44; or targeting NF&#954;B&#44; may potentially limit inflammation and the adverse consequences of inflammation on ageing&#46;</p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara"><span class="elsevierStyleBold"><span class="elsevierStyleBold">Acknowledgments</span></span></p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara">This work has been supported by Sociedad Espa&#241;ola de Nefrolog&#237;a&#46; Additional funding for the group&#58; FIS PS09&#47;00447&#44; CP07&#47;0020&#44; PI08&#47;1083&#44; PI081564&#44; ISCIII-RETIC REDinREN&#47;RD06&#47;0016&#44; Comunidad de Madrid S2010&#47;BMD-2378&#44; SAF 2007-60896&#44; Ministerio de Ciencia y Tecnolog&#237;a PI10&#47;00072&#46; Salary&#58; FIS to MCI and FIS Sara Borrel to ABS&#44; MDSN&#44; Programa Intensificaci&#243;n Actividad Investigadora &#40;ISCIII&#47;Agencia La&#237;n-Entralgo&#47;CM&#41; to AO&#46;</p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara"><span class="elsevierStyleBold">Conflict of interest<br></br>&#160;<br></br><br></br></span></p><p class="elsevierStylePara">The authors declare that there is no conflict of interest associated with this manuscript&#46;</p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara"><span class="elsevierStyleBold">Key concepts</span></p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara">1&#46; Tissue transcriptomics allows the non-biased analysis of gene expression and identification of potential novel therapeutic targets in tissue injury&#46;</p><p class="elsevierStylePara">2&#46; Acute kidney injury transcriptomics identified the simultaneous upregulation of inflammatory genes such as the TWEAK receptor FN14 and chemokines like CXCL16 and the downregulation of anti-inflammatory&#47;anti-ageing genes such as Klotho&#46;</p><p class="elsevierStylePara">3&#46; TWEAK stimulation of tubular cells in culture reproduced the findings in AKI&#46;</p><p class="elsevierStylePara">4&#46; The transcription factor NF&#954;B appears to be the key to both upregulation of proinflammatory genes and downregulation of Klotho in response to TWEAK&#46;</p><p class="elsevierStylePara">5&#46; Thus either targeting TWEAK&#44; through neutralizing anti-TWEAK antibodies currently undergoing clinical trials in lupus nephritis&#44; or targeting NF&#954;B&#44; may potentially limit inflammation and the adverse consequences of inflammation on ageing&#46;</p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara"><a href="grande&#47;11667&#95;16025&#95;34732&#95;en&#95;f111667&#95;copia&#46;jpg" class="elsevierStyleCrossRefs"><img src="11667_16025_34732_en_f111667_copia.jpg" alt="Gene expression for representative mediators of inflammation and ageing in experimental acute kidney injury &#40;AKI&#41;&#58; Transcriptomics results of kidney tissue"></img></a></p><p class="elsevierStylePara">Figure 1&#46; Gene expression for representative mediators of inflammation and ageing in experimental acute kidney injury &#40;AKI&#41;&#58; Transcriptomics results of kidney tissue</p>"
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        "resumen" => "<p class="elsevierStylePara">No existen estrategias terap&#233;uticas y fisiopatol&#243;gicas para el fracaso renal agudo &#40;FRA&#41;&#44; por lo que los niveles de mortalidad contin&#250;an siendo elevados&#46; Adem&#225;s&#44; la enfermedad renal cr&#243;nica &#40;ERC&#41; predispone a sufrir FRA y el FRA&#44; a su vez&#44; contribuye a que la ERC avance&#46; Recientemente&#44; una estrategia transcript&#243;mica revel&#243; una relaci&#243;n entre el FRA&#44; la inflamaci&#243;n y la regulaci&#243;n del envejecimiento&#46; Un an&#225;lisis transcript&#243;mico de modelos experimentales de FRA revel&#243; un aumento de la expresi&#243;n renal de Fn14 y la quimiocina transmembrana CXCL16&#44; as&#237; como un descenso en la expresi&#243;n de la hormona Klotho antienvejecimiento secretada por el ri&#241;&#243;n&#46; Fn14 es el receptor de la citoquina tumor necrosis factor-like weak inducer of apoptosis &#40;TWEAK&#41;&#44; miembro de la superfamilia de factor de necrosis tumoral&#46; En los ri&#241;ones con FRA&#44; exist&#237;a una correlaci&#243;n positiva entre Fn14 y la expresi&#243;n de ARNm de CXCL16 y una correlaci&#243;n inversa entre Fn14 y el ARNm de Klotho&#46; El lugar donde se da la expresi&#243;n in vivo de Fn14&#44; CXCL16 y Klotho es las c&#233;lulas tubulares&#46; La investigaci&#243;n en las relaciones entre estas tres mol&#233;culas revel&#243; que la activaci&#243;n de Fn14 por TWEAK provoc&#243; la inflamaci&#243;n mediante la secreci&#243;n de quimiocinas como la CXCL16 en c&#233;lulas tubulares&#44; tanto en cultivo como in vivo&#46; Adem&#225;s&#44; la activaci&#243;n de Fn14 por TWEAK disminuy&#243; la expresi&#243;n de ARNm de Klotho y de prote&#237;na&#44; en cultivo y in vivo&#46; Curiosamente&#44; tanto la activaci&#243;n TWEAK de la trascripci&#243;n de ARNm de CXCL16 y la supresi&#243;n de la trascripci&#243;n de ARNm de Klotho estuvieron mediadas por el factor de transcripci&#243;n NF-kB&#46; Como conclusi&#243;n&#44; la uni&#243;n de TWEAK y Fn14 es un elemento clave en promover de la activaci&#243;n mediada por NF-kB de las v&#237;as de inflamaci&#243;n y en la supresi&#243;n de las v&#237;as antiinflamatorias y antienvejecimiento&#46; Esta informaci&#243;n puede influir en las futuras estrategias terap&#233;uticas para el FRA y la inflamaci&#243;n&#47;envejecimiento&#46;</p>"
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        "resumen" => "<p class="elsevierStylePara">There are no pathophysiolgical therapeutic approaches to acute kidney injury &#40;AKI&#41; and the mortality remains high&#46; In addition chronic kidney disease &#40;CKD&#41; predisposes to AKI and AKI contributes to progression of CKD&#46; Recently a transcriptomics approach unveiled a relationship between AKI&#44; inflammation and the regulation of ageing&#46; A transcriptomics analysis of experimental AKI revealed increased kidney expression of Fn14 and transmembrane chemokine CXCL16&#44; as well as a decreased expression of the kidney-secreted anti-ageing hormone Klotho&#46; Fn14 is the receptor for tumor necrosis factor-like weak inducer of apoptosis &#40;TWEAK&#41;&#44; a member of the TNF superfamily&#46; In AKI kidneys there was a positive correlation between Fn14 and CXCL16 mRNA expression and an inverse correlation between Fn14 and Klotho mRNA&#46; Tubular cells were the site of Fn14&#44; CXCL16 and Klotho expression in vivo&#46; Research on the relationships between these three molecules disclosed that TWEAK activation of Fn14 promoted inflammation through secretion of chemokines such as CXL16 in tubular cells in culture and in vivo&#46; Furthermore&#44; TWEAK activation of Fn14 decreased expression of Klotho mRNA and protein in culture and in vivo&#46; Interestingly&#44; both TWEAK activation of CXCL16 mRNA transcription and suppression of Klotho mRNA transcription were mediated by the NF&#954;B transcription factor&#46; In conclusion&#44; TWEAK engagement of Fn14 is a central event promoting NF&#954;B-mediated activation of inflammation pathways and suppression of anti-inflammatory&#47;anti-ageing pathways&#46; This information may influence future therapeutic approaches to AKI and inflammation&#47;aging&#46;</p>"
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Acute kidney injury transcriptomics unveils a relationship between inflammation and ageing
La transcriptómica del fracaso renal agudo revela una relación entre inflamación y envejecimiento
M. Concepción Izquierdoa, María Concepción Izquierdob, Ana B. Sanzc, Ana B. Sanzd, M. Dolores Sánchez-Niñoc, María Dolores Sánchez-Niñod, M. Vanessa Pérez-Gómeza, María Vanessa Perez-Gomezb, Marta Ruiz-Ortegab, Jonay Povedae, Jonay Povedaf, Olga Ruiz-Andrése, Olga Ruiz-Andresf, Adrián M. Ramosf, Juan A. Morenof, Jesús Egidoe, Jesús Egidof, Alberto Ortize, Alberto Ortizf
a IIS-Fundación Jiménez Díaz, Universidad Autónoma de Madrid and Fundación Renal Iñigo Álvarez de Toledo, Madrid,
b IIS-Fundación Jiménez Díaz, Universidad Autónoma de Madrid and Fundación Renal Iñigo Álvarez de Toledo, Madrid, Spain,
c Servicio de Nefrología, IdiPAZ, Madrid,
d Servicio de Nefrología, IdiPAZ, Madrid, Spain,
e IIS-Fundación Jiménez Díaz. Universidad Autónoma, Madrid,
f IIS-Fundación Jiménez Díaz. Universidad Autónoma, Madrid, Spain,
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In this regard&#44; proposed biomarkers of AKI are also altered in CKD&#44; including Klotho&#46;<span class="elsevierStyleSup">2&#44;3</span></p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara"><span class="elsevierStyleBold"><span class="elsevierStyleBold">TRANSCRIPTOMICS</span></span></p><p class="elsevierStylePara"><span class="elsevierStyleBold">&#160;</span></p><p class="elsevierStylePara">High throughput techniques such as transcriptomics and proteomics&#44; may help identify novel potential pathogenic factors&#44; therapeutic targets and biomarkers in a non-biased way&#46;<span class="elsevierStyleSup">4-6</span> Transcriptomics is a high throughput technique that allows the identification of thousands of differentially expressed candidate genes&#46; Such patterns of expression may themselves be used for diagnostic or prognostic purposes&#46; Bioinformatics and biostatistics tools allow to manage thousands of genes simultaneous and help to prioritize molecules for further confirmatory studies&#46; 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both of which play a key role in kidney injury&#46;<span class="elsevierStyleSup">16-18</span> TNFSF ligands bind to one or more members of the TNF receptor superfamily &#40;TNFRSF&#41;&#46;<span class="elsevierStyleSup">19&#44;20</span></p><p class="elsevierStylePara">The human TWEAK gene encodes a type II transmembrane glycoprotein&#46; The TWEAK C-terminal extracellular domain contains the TNF homology domain that mediates self-trimerization and receptor-binding&#46;<span class="elsevierStyleSup">13</span> The N-terminal intracellular domain contains several nuclear localization sequences &#40;NLS&#41;<span class="elsevierStyleSup">13&#44;21-23</span>&#160;and a furin recognition site&#44; suggesting that TWEAK can be cleaved&#46;<span class="elsevierStyleSup">24</span> Most cells can express full-length membrane-anchored TWEAK &#40;mTWEAK&#41; and soluble TWEAK &#40;sTWEAK&#41;&#46;<span class="elsevierStyleSup">24&#44;25</span> sTWEAK is formed by proteolysis of membrane TWEAK&#46;<span class="elsevierStyleSup">13&#44;25&#44;26</span></p><p class="elsevierStylePara">Both sTWEAK and mTWEAK bind and activate fibroblast growth factor-inducible-14 &#40;Fn14&#44; 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growth and activation in inflammatory sites&#46;<span class="elsevierStyleSup">64</span> Chemokines promote kidney tubulointerstitial inflammation<span class="elsevierStyleSup">&#46;<span class="elsevierStyleSup">65&#44;66</span></span> Leukocytes recruited by chemokines have a key role in kidney tubulointerstitial tissue injury during AKI and CKD&#46;<span class="elsevierStyleSup">67&#44;68</span> Several chemokines were upregulated in the transcriptome of murine AKI&#46;<span class="elsevierStyleSup">8</span> Some of them&#44; such as MCP-1 and Rantes&#44; had already been studied&#46;<span class="elsevierStyleSup">54</span> These chemokines share with most chemokines their release as soluble mediators&#46;<span class="elsevierStyleSup">65</span> CX3CL1 &#40;fractalkine&#41; and CXCL16 &#40;SR-PSOX&#41; were also found upregulated in the murine AKI the transcriptome&#46;<span class="elsevierStyleSup">8</span> CX3CL1 and CXCL16 are the only two known membrane-anchored chemokines&#46;<span class="elsevierStyleSup">69</span> CX3CL1 and CXCL16 are synthesized as transmembrane molecules and&#44; as such&#44; have specific functions that may go beyond their chemokines role&#46; In addition&#44; they can be cleaved from the cell surface to release a soluble chemoattractant that behaves as a classical chemokine&#46;<span class="elsevierStyleSup">69</span> Fractalkine has been extensively studied in the context of kidney disease&#46;<span class="elsevierStyleSup">70</span> However&#44; much less was known about CXCL16 and kidney injury&#46; Furthermore&#44; CXCL16 expression correlated more closely than CX3CL1 with Fn14 expression&#46;<span class="elsevierStyleSup">8</span> In addition&#44; there is evidence that in humans urinary TWEAK and CXCL16 may be a potential diagnostic biomarkers of kidney diseases such as lupus nephritis&#46;<span class="elsevierStyleSup">71&#44;72</span> TWEAK is known to regulate the expression of several chemokines&#46; These peculiarities made a complete understanding of the relationship between TWEAK and CXCL16 regulation in kidney cells of particular interest&#46;&#160;</p><p class="elsevierStylePara">CXCL16 was identified by different groups as a ligand for the CXC-chemokine receptor CXCR6<span class="elsevierStyleSup">73</span>&#160;and as a scavenger receptor for phosphatidylserine and oxidized low density lipoprotein &#40;oxLDL&#41; and therefore was also termed SR-PSOX&#46;<span class="elsevierStyleSup">74</span> Full length CXCL16 consists of an extracellular N-terminal chemokine domain&#44; a glycosylated mucin-like stalk&#44; a transmembrane-spanning region and a short cytoplasmic tail&#46;<span class="elsevierStyleSup">73</span> Like CX3CL1&#44; CXCL16 potentially functions as both a soluble chemokine and a membrane-bound adhesion molecule&#46;<span class="elsevierStyleSup">75-78</span> CXCL16 regulated leukocyte chemotaxis&#44; T cell recruitment and cell proliferation&#46;<span class="elsevierStyleSup">79-87</span></p><p class="elsevierStylePara">In the kidney&#44; CXCL16 is constitutively expressed in human mesangial cells&#44; podocytes and tubular cells&#46;<span class="elsevierStyleSup">79&#44;86&#44;87</span> There is evidence for differential regulation of CXCL16 expression in glomeruli or different tubular segments and in tubular injury of diverse etiology&#46; CXCL16 expression is increased in various animal models of kidney injury and human nephropathies&#46;<span class="elsevierStyleSup">72&#44;79&#44;86-89</span></p><p class="elsevierStylePara">Glomerular CXCL16 expression is increased in human membranous nephropathy&#46;<span class="elsevierStyleSup">87</span> Glomerular and tubular CXCL16 was also increased in lupus mice and in anti-GBM nephritis&#46;<span class="elsevierStyleSup">72&#44;88&#44;89</span> Functional studies suggest that CXCL16 promotes progression of damage in experimental glomerulonephritis&#46;<span class="elsevierStyleSup">88</span> CXCL16 blockade significantly decreased monocyte&#47;macrophage infiltration and glomerular and tubular injury&#46;<span class="elsevierStyleSup">88&#44;89</span> In this regard&#44; besides effects on leukocytes&#44; CXCL16 has direct actions on glomerular cells&#46; Podocyte CXCL16 may regulate the uptake of oxLDL&#44;<span class="elsevierStyleSup">87</span> while mesangial cell CXCL16 promotes mesangial cell migration and proliferation<span class="elsevierStyleSup">&#46;<span class="elsevierStyleSup">79</span></span></p><p class="elsevierStylePara">In human allograft AKI&#44; CXCL16 expression was increased focally in the apical side of tubules&#46;<span class="elsevierStyleSup">86</span> By contrast&#44; a low tubular CXCL16 expression was observed in interstitial rejection that was attributed to increases CXCL16 shedding&#46; Thus&#44; remnant CXCL16 was located to the basolateral membrane and surrounded by T cell infiltrates&#46; In experimental toxic AKI&#44; both prominent apical and basolateral CXCL16 expression were noted&#46;<span class="elsevierStyleSup">8</span> Thus&#44; other tubular cells&#44; the interstitium and the tubular lumen were exposed to CXCL16 derived from tubular cells&#46; Interestingly&#44; both patterns did not overlap in many tubules&#46;</p><p class="elsevierStylePara">No in vivo functional studies of CXCL16 targeting in tubulointerstitial kidney disease have been reported&#46; In cell culture CXCL16 did not induce murine tubular epithelial cell proliferation or apoptosis&#44; either alone or in combination with TWEAK&#46;<span class="elsevierStyleSup">8</span> However&#44; CXCL16 had a proinflammatory effect and increased TWEAK-induced gene expression of ICAM-1&#44; MCP-1 and RANTES&#46; In this regard&#44; tubular cells expressed the CXCR6 receptor&#46;<span class="elsevierStyleSup">8</span></p><p class="elsevierStylePara">In cultured glomerular cells CXCL16 is upregulated by TNF-&#945; and IFN-&#947;&#46;<span class="elsevierStyleSup">79&#44;86&#44;87</span> IFN-&#947; increased CXCL16 expression in cultured primary thick ascending limb cells and early distal tubular cells&#46;<span class="elsevierStyleSup">86</span> TWEAK is a novel regulator of CXCL16 expression in tubular epithelial cells&#46;<span class="elsevierStyleSup">8</span> TWEAK promoted CXCL16 expression through the canonical NF&#954;B pathway in cultured tubular cells&#46;<span class="elsevierStyleSup">8</span> Moreover&#44; TWEAK increased renal CXCL16 expression and interstitial CD3 positive lymphocytes&#46; Since neutralization of TWEAK decreased CXCL16 and CD3 lymphocyte infiltration in experimental AKI&#44; TWEAK-induced CXCL16 expression may contribute to T cell recruitment and collaborate with TWEAK in promoting inflammation&#46;</p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara"><span class="elsevierStyleBold"><span class="elsevierStyleBold">KLOTHO</span></span></p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara">Klotho is a protein with anti-aging properties which is highly expressed in tubular renal cells&#46;<span class="elsevierStyleSup">90&#44;91</span>&#160;Klotho is a single-pass transmembrane protein&#46; The extracellular domain of Klotho may be proteolytically processed by ADAM10&#47;17 and secreted&#46; In addition&#44; alternative splicing may give rise to a soluble secreted isoform&#46;<span class="elsevierStyleSup">92</span> Trasmembrane Klotho binds to multiple fibroblast growth factor &#40;FGF&#41; receptors conferring them specific and high affinity for FGF23&#46; FGF23 is a bone-derived hormone that regulates phosphate homeostasis and vitamin D metabolism&#46; Thus&#44; the main known function of Klotho is regulation of phosphate metabolism and evidence from mice in which phosphate was manipulated genetically or through diet suggests that aberrant phosphate homeostasis is a key contributor to the accelerated aging syndrome of Klotho -&#47;- mice&#46;<span class="elsevierStyleSup">93</span> Klotho also protects cells and tissues from oxidative stress and has anti-inflammatory properties through modulation of NF&#954;B signaling&#46;<span class="elsevierStyleSup">94</span></p><p class="elsevierStylePara">Klotho is downregulated during kidney diseases&#44; such as long-term hypertension&#44; diabetes mellitus&#44; CKD&#44;<span class="elsevierStyleSup">95</span> and in experimental AKI induced by ischemia-reperfusion or a folic acid overdose&#46;<span class="elsevierStyleSup">7&#44;96</span> In addition kidney Klotho was decreased in the course of systemic inflammation caused by inflammatory bowel disease and a neutralizing anti-TNF antibody attenuated bowel inflammation and reversed the repression of kidney Klotho expression&#46;<span class="elsevierStyleSup">97</span> Consistent with these data&#44; Klotho was downregulated in the transcriptome of murine AKI and Klotho expression was inversely correlated with Fn14 expression&#44; suggesting that TWEAK&#44; like TNF&#44; may regulate Klotho expression&#46; The reduction of kidney Klotho during nephrotoxic AKI persisted beyond recovery of renal function and was associated with decreased circulating Klotho&#46; The persistent decrease in Klotho might be related to the increased mortality of AKI patients following recovery from AKI&#46; Since Klotho may be nephroprotective&#44;<span class="elsevierStyleSup">96&#44;98-100</span> the persistent decrease in Klotho might also predispose to progression of CKD&#46; However&#44; these hypotheses await formal confirmation&#46;</p><p class="elsevierStylePara">In nephrotoxic AKI&#44; Klotho expression and renal function were preserved by TWEAK targeting thus identifying a potential regulator of Klotho expression in cultured cells&#46;<span class="elsevierStyleSup">7</span> Indeed&#44; in cultured tubular cells of proximal origin TWEAK and TNF promoted the NF&#954;B-dependent downregulation of Klotho expression&#46;<span class="elsevierStyleSup">7</span> TWEAK and TNF activate the canonical pathway for NF&#954;B activation&#44; but only TWEAK activates the non-canonical pathway&#46;<span class="elsevierStyleSup">14&#44;53</span> The reported downregulation of Klotho by TNF<span class="elsevierStyleSup"><span class="elsevierStyleSup">7&#44;97</span></span>&#160;and the time course of Klotho mRNA downregulation&#44; that is already observed at 3h&#44; suggest activation of the canonical NF&#954;B pathway&#46; Indeed&#44; RelA was necessary for TWEAK- and TNF-induced Klotho repression&#46; For the first time it was observed TWEAK downregulates NF&#954;B-mediated gene expression&#46; Regulation of NF&#954;B activation function is controlled through different mechanism&#44; such as interaction of the p65&#47;RelA subunit with histone deacetylase &#40;HDAC&#41; corepresor proteins<span class="elsevierStyleSup">&#46;<span class="elsevierStyleSup">101-103</span></span> In this regard&#44; HDAC inhibitors prevented repression of Klotho induced by TWEAK or TNF&#46; In addition&#44; recruitment of NFkB to chromatin is regulated in a promoter-specific manner&#46; TWEAK induced histone H3 and H4 deacetylation at the murine Klotho promoter in renal tubular cells&#46;&#160;</p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara"><span class="elsevierStyleBold"><span class="elsevierStyleBold">INTERACTION BETWEEN INFLAMMATION AND AGEING&#58; NF</span><span class="elsevierStyleBold">&#954;</span><span class="elsevierStyleBold">B</span></span></p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara">From the above mentioned studies the NF&#954;B emerges as a family of pleiotropic transcription factors with a key role at the interface between inflammation and ageing&#46;<span class="elsevierStyleSup">52&#44;104-107</span> This notion had been advanced before by proponents of the inflamma-aging concept&#46;<span class="elsevierStyleSup">108</span> The term inflamm-aging has been used to describe the age-related increase in the systemic pro-inflammatory status of humans&#46;<span class="elsevierStyleSup">109</span><span class="elsevierStyleBold">&#160;</span></p><p class="elsevierStylePara">A wide range of stimuli relevant to tissue injury activate NF&#954;B&#44; including cytokines&#44; growth factors&#44; immune mediators&#44; proteinuria and genotoxic or mechanical stretch<span class="elsevierStyleSup">&#46;<span class="elsevierStyleSup">110&#44;111</span></span> Activation of NF&#954;B can proceed through classical&#47;canonical&#44; alternative&#47;non-canonical NF&#954;B and hybrid pathways<span class="elsevierStyleSup">&#46;<span class="elsevierStyleSup">104&#44;106&#44;112</span></span> Classical NF&#954;B activation<span class="elsevierStyleBold"><span class="elsevierStyleBold">&#160;</span></span>is usually a rapid and transient response to a wide range of stimuli&#46; Under basal conditions NF&#954;B is inactive in the cytosol because it is bound to inhibitory I&#954;B proteins&#46; Activating stimuli activate the inhibitor of &#954;B kinases &#40;IKK&#41;&#44; which phosphorylate I&#954;Bs&#44; marking them for degradation by the proteasome&#46; Degradation of I&#954;B releases and activates NF&#954;B dimers&#44; such as those containing RelA&#46; RelA containing dimers then migrate to the nucleus where they bind to &#954;B DNA sequences in promoters and enhancers of target genes&#46; In general canonical NF&#954;B promote the transcription and expression of proinflammatory genes&#44; as observed for CXCL16 in TWEAK-stimulated tubular cells&#46; There are several negative feed-back mechanisms&#46; Thus&#44; suppressors of cytokine signaling &#40;SOCS&#41;-1 promotes the ubiquitination and proteasomal degradation of RelA-containing dimers&#44; thus quenching the NF&#954;B response&#46;<span class="elsevierStyleSup">113</span> The SOCS1 overexpression decreases inflammation in experimental DN<span class="elsevierStyleSup">&#46;<span class="elsevierStyleSup">114</span></span></p><p class="elsevierStylePara">As a result of NF&#954;B integration of stimulus information it may both induce or repress individual gene transcription&#46;<span class="elsevierStyleSup">115</span> However&#44; the fact that NF&#954;B can function as a repressor of gene expression is less well-known&#46; Gene expression repression by NF&#954;B may suppress the inflammatory response by recruiting inhibitory components of the NF&#954;B system&#46; Thus&#44; antiinflammatory cytokines&#44; such as IL-10 promote synthesis of nuclear located atypical I&#954;B proteins B-cell lymphoma 3 &#40;BCL-3&#41;&#44; I&#954;B&#950; and I&#954;BNS&#44; which bind to DNA-bound NF&#954;B dimers and may repress transcription of inflammatory genes&#46;<span class="elsevierStyleSup">113</span> In addition repression of gene expression by NF&#954;B has been implicated in sepsis-induced downregulation of kidney aquaporin&#47;V2 receptor and may have a role in resolution of inflammation&#46;<span class="elsevierStyleSup">116&#44;117</span> However&#44; classical NF&#954;B dimers containing RelA may also downregulate Klotho mRNA and Klotho-dependent anti-inflammatory and ageing pathways&#44; as observed for TWEAK and TNF&#44; and&#44; thus&#44; promote further injury in and outside the kidney&#46;</p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara"><span class="elsevierStyleBold"><span class="elsevierStyleBold">CONCLUSIONS</span></span></p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara">In summary&#44; transcriptomics of AKI tissue has identified TWEAK as a novel regulator of CXCL16 expression in renal tubular cells through activation of the RelA NF&#954;B transcription factor&#46; In addition&#44; TWEAK&#44; like TNF&#945;&#44; downregulated Klotho in renal tubular cells through a similar NF&#954;B RelA-dependent mechanism&#46; Since Klotho has anti-ageing and anti-inflammatory properties&#44; these findings may have therapeutic implications in kidney injury and also for inflammation-associated premature aging&#46; Thus targeting either TWEAK&#44; through neutralizing anti-TWEAK antibodies currently undergoing clinical trials in lupus nephritis&#44; or targeting NF&#954;B&#44; may potentially limit inflammation and the adverse consequences of inflammation on ageing&#46;</p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara"><span class="elsevierStyleBold"><span class="elsevierStyleBold">Acknowledgments</span></span></p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara">This work has been supported by Sociedad Espa&#241;ola de Nefrolog&#237;a&#46; Additional funding for the group&#58; FIS PS09&#47;00447&#44; CP07&#47;0020&#44; PI08&#47;1083&#44; PI081564&#44; ISCIII-RETIC REDinREN&#47;RD06&#47;0016&#44; Comunidad de Madrid S2010&#47;BMD-2378&#44; SAF 2007-60896&#44; Ministerio de Ciencia y Tecnolog&#237;a PI10&#47;00072&#46; Salary&#58; FIS to MCI and FIS Sara Borrel to ABS&#44; MDSN&#44; Programa Intensificaci&#243;n Actividad Investigadora &#40;ISCIII&#47;Agencia La&#237;n-Entralgo&#47;CM&#41; to AO&#46;</p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara"><span class="elsevierStyleBold">Conflict of interest<br></br>&#160;<br></br><br></br></span></p><p class="elsevierStylePara">The authors declare that there is no conflict of interest associated with this manuscript&#46;</p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara"><span class="elsevierStyleBold">Key concepts</span></p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara">1&#46; Tissue transcriptomics allows the non-biased analysis of gene expression and identification of potential novel therapeutic targets in tissue injury&#46;</p><p class="elsevierStylePara">2&#46; Acute kidney injury transcriptomics identified the simultaneous upregulation of inflammatory genes such as the TWEAK receptor FN14 and chemokines like CXCL16 and the downregulation of anti-inflammatory&#47;anti-ageing genes such as Klotho&#46;</p><p class="elsevierStylePara">3&#46; TWEAK stimulation of tubular cells in culture reproduced the findings in AKI&#46;</p><p class="elsevierStylePara">4&#46; The transcription factor NF&#954;B appears to be the key to both upregulation of proinflammatory genes and downregulation of Klotho in response to TWEAK&#46;</p><p class="elsevierStylePara">5&#46; Thus either targeting TWEAK&#44; through neutralizing anti-TWEAK antibodies currently undergoing clinical trials in lupus nephritis&#44; or targeting NF&#954;B&#44; may potentially limit inflammation and the adverse consequences of inflammation on ageing&#46;</p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara"><a href="grande&#47;11667&#95;16025&#95;34732&#95;en&#95;f111667&#95;copia&#46;jpg" class="elsevierStyleCrossRefs"><img src="11667_16025_34732_en_f111667_copia.jpg" alt="Gene expression for representative mediators of inflammation and ageing in experimental acute kidney injury &#40;AKI&#41;&#58; Transcriptomics results of kidney tissue"></img></a></p><p class="elsevierStylePara">Figure 1&#46; Gene expression for representative mediators of inflammation and ageing in experimental acute kidney injury &#40;AKI&#41;&#58; Transcriptomics results of kidney tissue</p>"
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        "resumen" => "<p class="elsevierStylePara">No existen estrategias terap&#233;uticas y fisiopatol&#243;gicas para el fracaso renal agudo &#40;FRA&#41;&#44; por lo que los niveles de mortalidad contin&#250;an siendo elevados&#46; Adem&#225;s&#44; la enfermedad renal cr&#243;nica &#40;ERC&#41; predispone a sufrir FRA y el FRA&#44; a su vez&#44; contribuye a que la ERC avance&#46; Recientemente&#44; una estrategia transcript&#243;mica revel&#243; una relaci&#243;n entre el FRA&#44; la inflamaci&#243;n y la regulaci&#243;n del envejecimiento&#46; Un an&#225;lisis transcript&#243;mico de modelos experimentales de FRA revel&#243; un aumento de la expresi&#243;n renal de Fn14 y la quimiocina transmembrana CXCL16&#44; as&#237; como un descenso en la expresi&#243;n de la hormona Klotho antienvejecimiento secretada por el ri&#241;&#243;n&#46; Fn14 es el receptor de la citoquina tumor necrosis factor-like weak inducer of apoptosis &#40;TWEAK&#41;&#44; miembro de la superfamilia de factor de necrosis tumoral&#46; En los ri&#241;ones con FRA&#44; exist&#237;a una correlaci&#243;n positiva entre Fn14 y la expresi&#243;n de ARNm de CXCL16 y una correlaci&#243;n inversa entre Fn14 y el ARNm de Klotho&#46; El lugar donde se da la expresi&#243;n in vivo de Fn14&#44; CXCL16 y Klotho es las c&#233;lulas tubulares&#46; La investigaci&#243;n en las relaciones entre estas tres mol&#233;culas revel&#243; que la activaci&#243;n de Fn14 por TWEAK provoc&#243; la inflamaci&#243;n mediante la secreci&#243;n de quimiocinas como la CXCL16 en c&#233;lulas tubulares&#44; tanto en cultivo como in vivo&#46; Adem&#225;s&#44; la activaci&#243;n de Fn14 por TWEAK disminuy&#243; la expresi&#243;n de ARNm de Klotho y de prote&#237;na&#44; en cultivo y in vivo&#46; Curiosamente&#44; tanto la activaci&#243;n TWEAK de la trascripci&#243;n de ARNm de CXCL16 y la supresi&#243;n de la trascripci&#243;n de ARNm de Klotho estuvieron mediadas por el factor de transcripci&#243;n NF-kB&#46; Como conclusi&#243;n&#44; la uni&#243;n de TWEAK y Fn14 es un elemento clave en promover de la activaci&#243;n mediada por NF-kB de las v&#237;as de inflamaci&#243;n y en la supresi&#243;n de las v&#237;as antiinflamatorias y antienvejecimiento&#46; Esta informaci&#243;n puede influir en las futuras estrategias terap&#233;uticas para el FRA y la inflamaci&#243;n&#47;envejecimiento&#46;</p>"
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        "resumen" => "<p class="elsevierStylePara">There are no pathophysiolgical therapeutic approaches to acute kidney injury &#40;AKI&#41; and the mortality remains high&#46; In addition chronic kidney disease &#40;CKD&#41; predisposes to AKI and AKI contributes to progression of CKD&#46; Recently a transcriptomics approach unveiled a relationship between AKI&#44; inflammation and the regulation of ageing&#46; A transcriptomics analysis of experimental AKI revealed increased kidney expression of Fn14 and transmembrane chemokine CXCL16&#44; as well as a decreased expression of the kidney-secreted anti-ageing hormone Klotho&#46; Fn14 is the receptor for tumor necrosis factor-like weak inducer of apoptosis &#40;TWEAK&#41;&#44; a member of the TNF superfamily&#46; In AKI kidneys there was a positive correlation between Fn14 and CXCL16 mRNA expression and an inverse correlation between Fn14 and Klotho mRNA&#46; Tubular cells were the site of Fn14&#44; CXCL16 and Klotho expression in vivo&#46; Research on the relationships between these three molecules disclosed that TWEAK activation of Fn14 promoted inflammation through secretion of chemokines such as CXL16 in tubular cells in culture and in vivo&#46; Furthermore&#44; TWEAK activation of Fn14 decreased expression of Klotho mRNA and protein in culture and in vivo&#46; Interestingly&#44; both TWEAK activation of CXCL16 mRNA transcription and suppression of Klotho mRNA transcription were mediated by the NF&#954;B transcription factor&#46; In conclusion&#44; TWEAK engagement of Fn14 is a central event promoting NF&#954;B-mediated activation of inflammation pathways and suppression of anti-inflammatory&#47;anti-ageing pathways&#46; This information may influence future therapeutic approaches to AKI and inflammation&#47;aging&#46;</p>"
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                  "referenciaCompleta" => "Chawla LS, Kimmel PL. Acute kidney injury and chronic kidney disease: an integrated clinical syndrome. Kidney Int 2012;82(5):516-24. <a href="http://www.ncbi.nlm.nih.gov/pubmed/22673882" target="_blank">[Pubmed]</a>"
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