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and angiotensin II receptor antagonists &#40;ARA II&#41; in diabetic nephropathy&#46;<span class="elsevierStyleSup">4</span> However&#44; despite these advances&#44; diabetic nephropathy is still the most frequent cause of end-stage renal disease in developed countries&#46; Only a complete understanding of the pathogenic processes that initiate and maintain renal injury will allow the design of novel&#44; successful therapeutic strategies&#46;</p><p class="elsevierStylePara"><span class="elsevierStyleBold">HIGH THROUGHPUT TECHNIQUES FOR IDENTIFYING BIOMARKERS AND THERAPEUTIC TARGETS</span></p><p class="elsevierStylePara">Traditionally the search for mediators of tissue injury entailed the careful scanning of the literature for newly described molecules&#44; which had properties that could make them relevant for renal injury&#46; Once a molecule of potential interest was identified&#44; its expression in renal injury was studied in a one-by-one basis&#46; If protein expression differed between normal and diseased tissue&#44; the actions of the molecule on cultured cells and animal models were explored&#46; This is an inefficient&#44; time-consuming approach&#46; The novel availability of high throughput techniques such as transcriptomics &#40;the simultaneous study of the mRNA expression levels of thousands of genes&#41; or proteomics &#40;the simultaneous study of the expression levels of multiple proteins&#41; allows the identification of hundreds of differentially expressed candidate genes or proteins&#46; Such patterns of expression may themselves be used for diagnostic or prognostic purposes&#46; Bioinformatics algorithms allow to manage the huge amount of data and to search for statistical associations with the presence of disease or with disease progression&#46; Thus&#44; a panel of 65 urine proteomics biomarkers correctly identified diabetic nephropathy with 97&#37; sensitivity and specificity&#46;<span class="elsevierStyleSup">5</span> Furthermore&#44; this panel of biomarkers identified patients with microalbuminuria and diabetes that progressed toward overt diabetic nephropathy over 3 years&#46;<span class="elsevierStyleSup">5</span> For biomarker identification a pathogenic function of the candidate is not required&#46; In addition&#44; novel therapeutic targets may be uncovered&#46; For this&#44; bioinformatics and focused data analysis help to prioritize molecules with highest or lowest level of expression&#44; to identify molecules related to processes that participate in the pathogenesis of the disease&#44; and to identify relationships between differentially regulated molecules&#46; This reduces the field of candidate therapeutic targets&#46; Then&#44; the differential expression of these candidates can be confirmed by RT-PCR at the mRNA level and by immunohistochemistry at the protein level &#40;Figure 1&#46;&#41; Immunohistochemistry localizes the cell types expressing the protein&#44; thus guiding the choice of cell culture models&#46; Additional criteria to choose a molecule for further studies may be the simultaneous differential expression of several molecules that belong to the same functional pathway&#46; This was the case for cell death related genes of the TNF-related apoptosis-inducing ligand &#40;TRAIL&#41; pathway expressed in human diabetic nephropathy&#46;<span class="elsevierStyleSup">6</span></p><p class="elsevierStylePara"><span class="elsevierStyleBold">TRANSCRIPTOMICS OF DIABETIC KIDNEYS</span></p><p class="elsevierStylePara">The European Renal cDNA Bank &#40;ERCB&#41; was initially funded by the European Union and is now located at the University of Zurich &#40;Nephrology Clinic and Institute of Physiology&#41; &#40;http&#58;&#47;&#47;www&#46;portailderecherche&#46;ch&#47;unizh&#47;p9291&#46;htm&#46;&#41; Fragments of renal biopsies were collected from all over Europe and classified by pathological diagnosis&#46; Tubulointerstitial and glomerular compartments were manually microdissected from cortical tissue segments and mRNA expression was assessed by microarray chips displaying 22&#44;283 probe sets&#46; The resulting huge amount of gene expression data was used to further unravel the pathogenesis of diabetic kidney injury&#46; As an example&#44; the activation of the NFkB pathway was tested in human diabetic nephropathy&#46; The focused analysis of this master transcriptional switch&#44; involved in multiple processes&#44; segregated progressive diabetic nephropathy from mild diabetic nephropathy and controls by showing upregulation of 54 of 138 known NF-kB targets&#46;<span class="elsevierStyleSup">7</span></p><p class="elsevierStylePara"><span class="elsevierStyleBold">APOPTOSIS-RELATED GENE EXPRESSION IN HUMAN DIABETIC NEPHROPATHY</span></p><p class="elsevierStylePara">Apoptotic cell death may contribute to the gradual loss of renal mass in diabetic nephropathy&#46;<span class="elsevierStyleSup">1&#44;8</span> Indeed&#44; 25&#37; of apoptosis related genes were differentially regulated in the tubulointerstitium of renal biopsies from diabetic nephropathy patients<span class="elsevierStyleSup">6</span>&#46; Those with a higher than 1&#46;5 fold change are presented in figure 2&#46; Differentially expressed apoptosisrelated genes included those encoding proteins involved in death receptor interactions&#44; such as Fas&#44; TRAIL and osteoprotegerin &#40;OPG&#46;&#41; These data are consistent with the already described upregulation of Fas in diabetic nephropathy&#46;<span class="elsevierStyleSup">9</span> Cytokines belonging to the TNF superfamily are key regulators of cell survival&#44; inflammation and fibrosis&#46; Among them&#44; Fas ligand and TWEAK participate in the pathogenesis of renal injury and TNF has an important role in diabetic nephropathy&#46;<span class="elsevierStyleSup">10-15</span> TNF may promote synthesis and release of chemokines and inflammatory and hemodynamic mediators&#44; proliferation&#44; cytotoxicity and regulation of cell death related genes&#46;<span class="elsevierStyleSup">15</span> However&#44; the role of TRAIL and OPG in kidney disease was unexplored&#46;</p><p class="elsevierStylePara"><span class="elsevierStyleBold">TRAIL</span></p><p class="elsevierStylePara">TRAIL &#40;APO2L&#47;TNFSF10&#41; is a TNF superfamily cytokine that binds to a complex system of receptors&#46;<span class="elsevierStyleSup">16-18</span> Depending on the relative levels of the TRAIL receptors and on the cellular system&#44; TRAIL can exert different functions that&#44; in addition to cell death&#44; also include survival&#44; proliferation&#44; and maturation&#46;<span class="elsevierStyleSup">19</span> TRAIL is a type II trans-membrane protein with a molecular mass of 33-35 kDa&#46; Membrane-bound TRAIL can be cleaved from the cell surface to form a soluble trimeric ligand that retains the proapoptotic activity&#46; TRAIL induces apoptosis in human cancer cells and primary tumors&#44; showing minimal or absent toxicity on normal cells&#46; TRAIL and TRAIL-receptor &#40;TRAIL-R&#41; agonists are in clinical trials as anti-cancer agents&#46;<span class="elsevierStyleSup">20</span> TRAIL is normally expressed in many human tissues including liver&#44; colon&#44; heart&#44; kidney&#44; lung and testis&#44; which is consistent to the low cytotoxicity to most healthy tissues&#46;<span class="elsevierStyleSup">21</span> However&#44; data from knockout mice suggest that TRAIL may induce apoptosis in non-tumoral parenchymal cells immersed in an inflammatory environment&#46;<span class="elsevierStyleSup">22</span> Available studies on TRAIL and diabetes have emphasized its role in immune response regulation&#46;<span class="elsevierStyleSup">23</span></p><p class="elsevierStylePara"><span class="elsevierStyleBold">TRAIL RECEPTORS</span></p><p class="elsevierStylePara">TRAIL has a complex system of receptors&#46; In humans&#44; it consists in 4 membrane-bound and a soluble receptor&#46; All TRAIL receptors belong to the TNF receptor superfamily&#46; Mice have only one receptor for TRAIL with a functional DD&#44; but the system is very similar<span class="elsevierStyleSup">24</span> Human TRAIL-R1 &#40;DR4&#47;TNFRSF10A&#41; and TRAIL-R2 &#40;DR5&#47;TRICK2&#47;KILLER&#47;TNFSFR10B&#41; contain a cytoplasmic death domain and activate caspases&#44; promoting apoptosis&#46;<span class="elsevierStyleSup">18</span> By contrast&#44; human TRAIL-R3 &#40;TRID&#47;DcR1&#47; LIT&#47;TNFRSF10C&#41; and TRAIL-R4 &#40;DcR2&#47;TRUNDDTNFRSF10D&#41; bind TRAIL without activation of the apoptotic machinery and are considered decoy receptors&#46;25 TRAIL-R3 has a glycosylphosphatidylinositol membrane anchor and lacks an intracellular domain and TRAIL-R4 contains a truncated DD&#46; OPG &#40;TNFRSF11B&#41; is a soluble decoy receptor for TRAIL&#46;<span class="elsevierStyleSup">26</span> In addition OPG binds to and antagonizes the TNF superfamily member receptor activator of NF-kB ligand &#40;RANKL&#41;&#46;<span class="elsevierStyleSup">27</span> As OPG is a decoy for both TRAIL and RANKL potential cross-regulatory mechanisms involving the balance among TRAIL&#44; OPG and RANKL may exist&#46; Indeed&#44; OPG binding to TRAIL inhibits its interaction with TRAIL-Rs and consequently TRAIL-induced apoptosis&#46; Conversely&#44; TRAIL can block the inhibitory activity of OPG on osteoclastogenesis&#46;<span class="elsevierStyleSup">17</span> The affinity of TRAIL for OPG is weaker than that for its lethal receptors&#44; but recent studies support the biological relevance of the OPG&#47;TRAIL interaction&#46;<span class="elsevierStyleSup">20</span> OPG is increased in serum of patients with renal dysfunction&#44; including diabetic nephropathy&#46;<span class="elsevierStyleSup">28-30</span> However&#44; the source of serum OPG is unclear&#46; Increased serum OPG levels are also associated to increased coronary artery and aorta calcification&#46;<span class="elsevierStyleSup">30</span> OPG deficient mice display calcification of the aorta and renal arteries&#44; suggesting that OPG plays a role in vascular calcification&#46;<span class="elsevierStyleSup">26</span></p><p class="elsevierStylePara"><span class="elsevierStyleBold">TRAIL AND ITS RECEPTORS IN THE KIDNEY</span></p><p class="elsevierStylePara">TRAIL&#44; TRAIL-R1 and -R2 mRNA are expressed in the normal kidney&#46; TRAIL is expressed in tubules but not in normal glomeruli&#46; TRAIL-R1 has a similar pattern of expression&#44; while TRAIL-R2 is additionally expressed in Henle&#180;s loop&#46; TRAIL-R3 and R4 are absent from or not studied in normal kidney&#46;<span class="elsevierStyleSup">31</span> TRAIL knock-out mice did not have renal pathology&#44; suggesting that TRAIL is not essential for normal kidney physiology and development&#46;</p><p class="elsevierStylePara"><span class="elsevierStyleBold">INTERPLAY OF HIGH GLUCOSE LEVELS AND INFLAMMATION IN DIABETIC KIDNEY INJURY</span></p><p class="elsevierStylePara">The transcriptomic finding of increased expression of TRAIL and OPG in human diabetic kidneys was confirmed by RT-PCR and found to correlate to clinical severity of renal disease&#46;<span class="elsevierStyleSup">6</span> In an independent cohort of diabetic nephropathy patients TRAIL protein was increased as assessed by immunohistochemistry&#46; In diabetes tubular epithelium was the main site of TRAIL expression&#44; and there also was de novo podocyte expression&#46;<span class="elsevierStyleSup">6&#44;32</span> Furthermore TRAIL staining correlated with tubular atrophy&#44; interstitial fibrosis and interstitial inflammation&#44; suggesting a pathogenic role for TRAIL in diabetic kidney injury&#46; Both TRAIL and OPG&#44; two potentially antagonic molecules&#44; were upregulated&#44; and their relationship was dissected in cultured human tubular cells &#40;Figure 3&#46;&#41; First&#44; factors contributing to increased TRAIL expression were studied&#46; High glucose per se did not modulate TRAIL expression&#46; However&#44; proinflammatory cytokines present in chronic kidney injury&#44; such as IFNg and TNFa&#44;<span class="elsevierStyleSup">15&#44;33</span> increased TRAIL expression&#46; CD74 is a receptor for MIF overexpressed in human diabetic nephropathy &#40;Figure 2&#46;&#41; Its engagement by MIF increased TRAIL expression in cultured human podocytes and tubular cells&#46;<span class="elsevierStyleSup">32</span> Next we approached possible functions of TRAIL in tubular cells&#46; TRAIL weakly induced tubular cell death in a dose-dependent manner<span class="elsevierStyleSup">6</span>&#46; This is consistent with a role in a nephropathy that progresses over years&#44; such as diabetic nephropathy&#46; The environment modulated the sensitivity of tubular cells to TRAIL-induced cell death&#46; The combination of high glucose and proinflammatory cytokines further increased the susceptibility of tubular cells to TRAIL-induced apoptosis&#46; Hyperglycemia is among the microenvironmental factors that may induce or facilitate apoptosis&#46;<span class="elsevierStyleSup">8&#44;34&#44;35</span> Several factors contribute to the higher sensitivity of tubular cells in a diabetic or inflammatory milieu to apoptosis&#46; High expression of death receptors &#40;Fas&#44; Fn14&#41; and intracellular lethal molecules &#40;Bax&#44; Smac&#47;Diablo&#44; FADD&#41;&#44; as well as decreased expression of antiapoptotic molecules &#40;Bcl2&#44; BclxL&#41; have been observed&#46;<span class="elsevierStyleSup">11&#44;14&#44;36-38</span> We are currently characterizing the role of additional molecules&#44; not previously suspected to be involved in cell death&#44; that have been identified by transcriptomics and functional genomics&#46;<span class="elsevierStyleSup">32&#44;39</span></p><p class="elsevierStylePara">NFkB activation by TRAIL also protected cells from lethality induced by TRAIL&#46;6 In this regard&#44; TRAIL resembles TNF in that it activates simultaneously death and survival signals&#46; If NFkB-mediated survival signals are blocked&#44; cell death increases&#46; Finally OPG protected from TRAIL-induced cell death by behaving as a decoy receptor&#46; We hypothesize that the end result of the increased expression of TRAIL and OPG in a particular patient may depend on the relative balance between them &#40;Figure 3&#46;&#41; If TRAIL prevails&#44; tissue injury results&#46; If OPG prevails&#44; the cells are protected from TRAIL&#46; Nevertheless&#44; OPG may have additional functions in diabetic nephropathy&#46;</p><p class="elsevierStylePara">The expression of TRAIL&#44; TRAIL-R1 and -R2 increases in renal proximal and distal convoluted tubules of rejected kidney tissue&#46;<span class="elsevierStyleSup">40</span> However&#44; there is insufficient information on the expression of TRAIL and its receptors in other inflammatory renal diseases&#46;</p><p class="elsevierStylePara"><span class="elsevierStyleBold">FOLLOWING THE TRAIL</span></p><p class="elsevierStylePara">In medicine every answer brings new questions&#46; TRAIL is the most upregulated gene encoding proapoptotic proteins in human diabetic kidneys&#46; We now have to explore what additional factors regulate its expression in tubular cells and podocytes&#44; how does glucose sensitize to the proapoptotic effect of TRAIL and whether TRAIL therapeutic modulation protects from the development or progression of diabetic nephropathy in preclinical studies&#46; In addition&#44; the biomarker potential of molecules in this pathway should be explored&#46;</p><p class="elsevierStylePara"><a href="grande&#47;22618078&#95;f1&#95;p14&#46;jpg" class="elsevierStyleCrossRefs"><img src="22618078_f1_p14.jpg"></img></a></p><p class="elsevierStylePara">Figure 1&#46; </p><p class="elsevierStylePara"><a href="grande&#47;22618078&#95;f2&#95;p15&#46;jpg" class="elsevierStyleCrossRefs"><img src="22618078_f2_p15.jpg"></img></a></p><p class="elsevierStylePara">Figure 2&#46; </p><p class="elsevierStylePara"><a href="grande&#47;22618078&#95;f3&#95;p16&#46;jpg" class="elsevierStyleCrossRefs"><img src="22618078_f3_p16.jpg"></img></a></p><p class="elsevierStylePara">Figure 3&#46; </p>"
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        "resumen" => "<p class="elsevierStylePara">La nefropat&#237;a diab&#233;tica es la causa m&#225;s com&#250;n de enfermedad renal cr&#243;nica terminal&#46; La modulaci&#243;n terap&#233;utica de la angiotensina II retarda&#44; pero no evita&#44; su progresi&#243;n&#46; La muerte celular contribuye a la p&#233;rdida de masa renal en las nefropat&#237;as cr&#243;nicas&#46; Un consorcio europeo emple&#243; la transcript&#243;mica en biopsias renales para identificar nuevos mediadores implicados en la muerte de la c&#233;lula renal durante la nefropat&#237;a diab&#233;tica&#46; Un 25&#37; de los genes relacionados con la muerte celular estaban expresados diferencialmente en la nefropat&#237;a diab&#233;tica&#46; TRAIL y osteoprotegerina fueron los genes m&#225;s sobreexpresados&#44; y tambi&#233;n estaba aumentado CD74&#46; Las c&#233;lulas tubulares y podocitos expresan TRAIL bajo la regulaci&#243;n de citocinas proinflamatorias &#40;MIF v&#237;a CD74&#44; TNF&#41;&#46; La hiperglucemia sensibiliza a las c&#233;lulas renales a la apoptosis inducida por TRAIL&#44; mientras que la osteoprotegerina protege&#46; Estos resultados sugieren que&#44; adem&#225;s de la glucemia&#44; la inflamaci&#243;n y TRAIL pueden ser objetivos terap&#233;uticos en la nefropat&#237;a diab&#233;tica&#46;</p>"
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        "resumen" => "<p class="elsevierStylePara">Diabetic nephropathy is the most common cause of endstage renal disease&#46; Approaches targeting angiotensin II significantly delay its progression&#46; However&#44; many patients still need renal replacement therapy&#46; High throughput techniques such as unbiased gene expression profiling and proteomics may identify new therapeutic targets&#46; Cell death is thought to contribute to progressive renal cell depletion in chronic nephropathies&#46; A European collaborative effort recently applied renal biopsy transcriptomics to identify novel mediators of renal cell death in diabetic nephropathy&#46; Twenty-five percent of cell death regulatory genes were upor downregulated in diabetic kidneys&#46; TNF-related apoptosisinducing ligand &#40;TRAIL&#41; and osteoprotegerin had the highest level of expression&#46; In diabetic nephropathy&#44; tubular cells and podocytes express TRAIL&#46; Inflammatory cytokines&#44; including MIF via CD74&#44; upregulate TRAIL&#46; A high glucose environment sensitized renal cells to the lethal effect of TRAIL&#44; while osteoprotegerin is protective&#46; These results suggest that&#44; in addition to glucose levels&#44; inflammation and TRAIL are therapeutic targets in diabetic nephropathy&#46;</p>"
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                  "referenciaCompleta" => "1- Kumar D, Robertson S, Burns KD: Evidence of apoptosis in human diabetic kidney. Mol Cell Biochem. 2004, 259:67-70."
                  "contribucion" => array:1 [
                    0 => null
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                  "referenciaCompleta" => "2- Sanz AB, Santamaria B, Ruiz Ortega M, Egido J, Ortiz A. Mechanisms of renal apoptosis in health and disease. J Am Soc Nephrol. 2008;19:1634-42"
                  "contribucion" => array:1 [
                    0 => null
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                  "referenciaCompleta" => "3- Ruiz Ortega M, Gonzalez S, Serón D, Condom E, Bustos C, Largo R,y cols. ACE inhibition reduces proteinuria, glomerular lesions and extracellular matrix production in a normotensive rat model of immune complex nephritis. Kidney Int 1995;48:1778-91."
                  "contribucion" => array:1 [
                    0 => null
                  ]
                  "host" => array:1 [
                    0 => null
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                0 => array:3 [
                  "referenciaCompleta" => "4- Parving HH, de Zeeuw D, Cooper ME, Remuzzi G, Liu N, Lunceford y cols. ACE gene polymorphism and losartan treatment in type 2 diabetic patients with nephropathy. J Am Soc Nephrol. 2008; 19: 771¿79."
                  "contribucion" => array:1 [
                    0 => null
                  ]
                  "host" => array:1 [
                    0 => null
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                0 => array:3 [
                  "referenciaCompleta" => "5- Rossing K, Mischak H, Dakna M, Zürbig P, Novak J, Julian BA y cols; on behalf of the PREDICTIONS Network. Urinary Proteomics in Diabetes and CKD. J Am Soc Nephrol. 2008; 19:1283-90"
                  "contribucion" => array:1 [
                    0 => null
                  ]
                  "host" => array:1 [
                    0 => null
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                0 => array:3 [
                  "referenciaCompleta" => "6- Lorz C, Benito-Martín A, Boucherot A, Ucero AC, Rastaldi MP, Henger A, y cols. The death ligand TRAIL in diabetic nephropathy. J Am Soc Nephrol. 2008, 19;904-14."
                  "contribucion" => array:1 [
                    0 => null
                  ]
                  "host" => array:1 [
                    0 => null
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                0 => array:3 [
                  "referenciaCompleta" => "7- Schmid H, Boucherot A, Yasuda Y, Henger A, Brunner B, Eichinger F y cols. Modular activation of nuclear factor-kappaB transcriptional programs in human diabetic nephropathy. Diabetes 2006;11,2993-3003"
                  "contribucion" => array:1 [
                    0 => null
                  ]
                  "host" => array:1 [
                    0 => null
                  ]
                ]
              ]
            ]
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                0 => array:3 [
                  "referenciaCompleta" => "8- Ortiz A, Ziyadeh FN, Neilson EG: Expression of apoptosis-regulatory genes in renal proximal tubular epithelial cells exposed to high ambient glucose and in diabetic kidneys. J Investig Med . 1997; 45:50-56."
                  "contribucion" => array:1 [
                    0 => null
                  ]
                  "host" => array:1 [
                    0 => null
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                ]
              ]
            ]
            8 => array:3 [
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              "referencia" => array:1 [
                0 => array:3 [
                  "referenciaCompleta" => "9- Kelly DJ, Stein-Oakley A, Zhang Y, Wassef L, Maguire J, Koji T,y cols. Fas-induced apoptosis is a feature of progressive diabetic nephropathy in transgenic (mRen-2)27 rats: attenuation with renin-angiotensin blockade. Nephrology (Carlton) 2004; 9:7-13."
                  "contribucion" => array:1 [
                    0 => null
                  ]
                  "host" => array:1 [
                    0 => null
                  ]
                ]
              ]
            ]
            9 => array:3 [
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              "etiqueta" => "10"
              "referencia" => array:1 [
                0 => array:3 [
                  "referenciaCompleta" => "10- Gonzalez-Cuadrado S, Lorz C, Garcia del Moral R, O'Valle F, Alonso C, Ramiro F,y cols. Agonistic anti-Fas antibodies induce glomerular cell apoptosis in mice in vivo. Kidney Int 1997; 51:1739-46."
                  "contribucion" => array:1 [
                    0 => null
                  ]
                  "host" => array:1 [
                    0 => null
                  ]
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              ]
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            10 => array:3 [
              "identificador" => "bib11"
              "etiqueta" => "11"
              "referencia" => array:1 [
                0 => array:3 [
                  "referenciaCompleta" => "11- Justo P, Sanz AB, Sanchez-Niño MD, Winkles JA, Lorz C, Egido J y cols. Cytokine cooperation in renal tubular cell injury: the role of TWEAK. Kidney Int 2006;70:1750-8."
                  "contribucion" => array:1 [
                    0 => null
                  ]
                  "host" => array:1 [
                    0 => null
                  ]
                ]
              ]
            ]
            11 => array:3 [
              "identificador" => "bib12"
              "etiqueta" => "12"
              "referencia" => array:1 [
                0 => array:3 [
                  "referenciaCompleta" => "12- Sanz AB, Justo P, Sanchez-Niño MD, Blanco-Colio LM, Winkles JA, Kreztler M y cols. The Cytokine TWEAK Modulates Renal Tubulointerstitial Inflammation. J Am Soc Nephrol 2008;19:695-703"
                  "contribucion" => array:1 [
                    0 => null
                  ]
                  "host" => array:1 [
                    0 => null
                  ]
                ]
              ]
            ]
            12 => array:3 [
              "identificador" => "bib13"
              "etiqueta" => "13"
              "referencia" => array:1 [
                0 => array:3 [
                  "referenciaCompleta" => "13- Ortiz A, Lorz C, Egido J: The Fas ligand/Fas system in renal injury. Nephrol Dial Transplant. 1999;14:1831-34."
                  "contribucion" => array:1 [
                    0 => null
                  ]
                  "host" => array:1 [
                    0 => null
                  ]
                ]
              ]
            ]
            13 => array:3 [
              "identificador" => "bib14"
              "etiqueta" => "14"
              "referencia" => array:1 [
                0 => array:3 [
                  "referenciaCompleta" => "14- Lorz C, Ortiz A, Justo P, Gonzalez-Cuadrado S, Duque N, Gomez-Guerrero C y cols. Proapoptotic Fas ligand is expressed by normal kidney tubular epithelium and injured glomeruli. J Am Soc Nephrol. 2000; 11:1266-77."
                  "contribucion" => array:1 [
                    0 => null
                  ]
                  "host" => array:1 [
                    0 => null
                  ]
                ]
              ]
            ]
            14 => array:3 [
              "identificador" => "bib15"
              "etiqueta" => "15"
              "referencia" => array:1 [
                0 => array:3 [
                  "referenciaCompleta" => "15- Navarro JF, Mora-Fernández C. The role of TNF-alpha in diabetic nephropathy: pathogenic and therapeutic implications. Cytokine Growth Factor Rev. 2006;17: 441-50."
                  "contribucion" => array:1 [
                    0 => null
                  ]
                  "host" => array:1 [
                    0 => null
                  ]
                ]
              ]
            ]
            15 => array:3 [
              "identificador" => "bib16"
              "etiqueta" => "16"
              "referencia" => array:1 [
                0 => array:3 [
                  "referenciaCompleta" => "16- Wiley SR, Schooley K, Smolak PJ, Din WS, Huang CP, Nicholl JK,y cols. Identification and characterization of a new member of the TNF family that induces apoptosis. Immunity.1995; 3: 673¿82."
                  "contribucion" => array:1 [
                    0 => null
                  ]
                  "host" => array:1 [
                    0 => null
                  ]
                ]
              ]
            ]
            16 => array:3 [
              "identificador" => "bib17"
              "etiqueta" => "17"
              "referencia" => array:1 [
                0 => array:3 [
                  "referenciaCompleta" => "17- Emery JG, McDonnell P, Burke MB, Deen KC, Lyn S, Silverman C, y cols. Osteoprotegerin is a receptor for the cytotoxic ligand TRAIL. J Biol Chem 1998; 273: 14363¿67."
                  "contribucion" => array:1 [
                    0 => null
                  ]
                  "host" => array:1 [
                    0 => null
                  ]
                ]
              ]
            ]
            17 => array:3 [
              "identificador" => "bib18"
              "etiqueta" => "18"
              "referencia" => array:1 [
                0 => array:3 [
                  "referenciaCompleta" => "18- Schneider P, Bodmer JL, Thome M, Hofmann K, Holler N, Tschopp J: Characterization of two receptors for TRAIL. FEBS Lett .1997; 416: 329¿34."
                  "contribucion" => array:1 [
                    0 => null
                  ]
                  "host" => array:1 [
                    0 => null
                  ]
                ]
              ]
            ]
            18 => array:3 [
              "identificador" => "bib19"
              "etiqueta" => "19"
              "referencia" => array:1 [
                0 => array:3 [
                  "referenciaCompleta" => "19- Schneider P, Thome M, Burns K, Bodmer JL, Hofmann K, Kataoka T, y cols. TRAIL receptors 1 (DR4) and 2 (DR5) signal FADD-dependent apoptosis and activate NF-kappaB. Immunity 1997;7:831-36"
                  "contribucion" => array:1 [
                    0 => null
                  ]
                  "host" => array:1 [
                    0 => null
                  ]
                ]
              ]
            ]
            19 => array:3 [
              "identificador" => "bib20"
              "etiqueta" => "20"
              "referencia" => array:1 [
                0 => array:3 [
                  "referenciaCompleta" => "20- Corallini F, Rimondi E, Secchiero P. TRAIL and osteoprotegerin: a role in endothelial physiopathology? Front Biosci. 2008;13:135-47."
                  "contribucion" => array:1 [
                    0 => null
                  ]
                  "host" => array:1 [
                    0 => null
                  ]
                ]
              ]
            ]
            20 => array:3 [
              "identificador" => "bib21"
              "etiqueta" => "21"
              "referencia" => array:1 [
                0 => array:3 [
                  "referenciaCompleta" => "21- Kruyt FA. TRAIL and cancer therapy. Cancer Lett. 2008;263:14-25."
                  "contribucion" => array:1 [
                    0 => null
                  ]
                  "host" => array:1 [
                    0 => null
                  ]
                ]
              ]
            ]
            21 => array:3 [
              "identificador" => "bib22"
              "etiqueta" => "22"
              "referencia" => array:1 [
                0 => array:3 [
                  "referenciaCompleta" => "22- Zheng SJ, Wang P, Tsabary G, Chen YH. Critical roles of TRAIL in hepatic cell death and hepatic inflammation. J Clin Invest, 12004;13, 58-64"
                  "contribucion" => array:1 [
                    0 => null
                  ]
                  "host" => array:1 [
                    0 => null
                  ]
                ]
              ]
            ]
            22 => array:3 [
              "identificador" => "bib23"
              "etiqueta" => "23"
              "referencia" => array:1 [
                0 => array:3 [
                  "referenciaCompleta" => "23- Mi QS, Ly D, Lamhamedi-Cherradi SE, Salojin KV, Zhou L, Grattan M,y cols. Blockade of tumor necrosis factor-related apoptosis-inducing ligand exacerbates type 1 diabetes in NOD mice. Diabetes. 2003 52: 1967¿75."
                  "contribucion" => array:1 [
                    0 => null
                  ]
                  "host" => array:1 [
                    0 => null
                  ]
                ]
              ]
            ]
            23 => array:3 [
              "identificador" => "bib24"
              "etiqueta" => "24"
              "referencia" => array:1 [
                0 => array:3 [
                  "referenciaCompleta" => "24- Lorz C, Benito A, Ucero AC, Santamaría B, Ortiz A. TRAIL andkidney disease. Front Biosci 2008; (in press)"
                  "contribucion" => array:1 [
                    0 => null
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:1 [
                        "itemHostRev" => array:3 [
                          "pii" => "S0021915013007636"
                          "estado" => "S300"
                          "issn" => "00219150"
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            24 => array:3 [
              "identificador" => "bib25"
              "etiqueta" => "25"
              "referencia" => array:1 [
                0 => array:3 [
                  "referenciaCompleta" => "25- Sheridan JP, Marsters SA, Pitti RM, Gurney A, Skubatch M, Baldwin D,y cols. Control of TRAIL-induced apoptosis by a family of signaling and decoy receptors. Science. 1997;277: 818¿21."
                  "contribucion" => array:1 [
                    0 => null
                  ]
                  "host" => array:1 [
                    0 => null
                  ]
                ]
              ]
            ]
            25 => array:3 [
              "identificador" => "bib26"
              "etiqueta" => "26"
              "referencia" => array:1 [
                0 => array:3 [
                  "referenciaCompleta" => "26- Simonet WS, Lacey DL, Dunstan CR, Kelley M, Chang MS, Luthy R,y cols. Osteoprotegerin: A novel secreted protein involved in the regulation of bone density. Cell. 1997;89: 309¿19."
                  "contribucion" => array:1 [
                    0 => null
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:1 [
                        "itemHostRev" => array:3 [
                          "pii" => "S0735109710002809"
                          "estado" => "S300"
                          "issn" => "07351097"
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            26 => array:3 [
              "identificador" => "bib27"
              "etiqueta" => "27"
              "referencia" => array:1 [
                0 => array:3 [
                  "referenciaCompleta" => "27- Zauli G, Rimondi E, Nicolin V, Melloni E, Celeghini C, Secchiero P: TNF-related apoptosis-inducing ligand (TRAIL) blocks osteoclastic differentiation induced by RANKL plus M-CSF. Blood.2004;104: 2044-50."
                  "contribucion" => array:1 [
                    0 => null
                  ]
                  "host" => array:1 [
                    0 => null
                  ]
                ]
              ]
            ]
            27 => array:3 [
              "identificador" => "bib28"
              "etiqueta" => "28"
              "referencia" => array:1 [
                0 => array:3 [
                  "referenciaCompleta" => "28- Nitta K, Akiba T, Uchida K, Kawashima A, Yumura W, Kabaya T,y cols. The progression of vascular calcification and serum osteoprotegerin levels in patients on long-term hemodialysis. Am J Kidney Dis. 2003; 42:303-09."
                  "contribucion" => array:1 [
                    0 => null
                  ]
                  "host" => array:1 [
                    0 => null
                  ]
                ]
              ]
            ]
            28 => array:3 [
              "identificador" => "bib29"
              "etiqueta" => "29"
              "referencia" => array:1 [
                0 => array:3 [
                  "referenciaCompleta" => "29- Rasmussen LM, Tarnow L, Hansen TK, Parving HH, Flyvbjerg A: Plasma osteoprotegerin levels are associated with glycaemic status, systolic blood pressure, kidney function and cardiovascular morbidity in type 1 diabetic patients. Eur J Endocrinol 2006; 154:75-81."
                  "contribucion" => array:1 [
                    0 => null
                  ]
                  "host" => array:1 [
                    0 => null
                  ]
                ]
              ]
            ]
            29 => array:3 [
              "identificador" => "bib30"
              "etiqueta" => "30"
              "referencia" => array:1 [
                0 => array:3 [
                  "referenciaCompleta" => "30- Jono S, Ikari Y, Shioi A, Mori K, Miki T, Hara K, y cols. Serum osteoprotegerin levels are associated with the presence and severity of coronary artery disease. Circulation 2002; 106:1192-94."
                  "contribucion" => array:1 [
                    0 => null
                  ]
                  "host" => array:1 [
                    0 => null
                  ]
                ]
              ]
            ]
            30 => array:3 [
              "identificador" => "bib31"
              "etiqueta" => "31"
              "referencia" => array:1 [
                0 => array:3 [
                  "referenciaCompleta" => "31- Spierings DC, de Vries EG, Vellenga E, van den Heuvel FA, Koornstra JJ, Wesseling J, y cols: Tissue distribution of the death ligand TRAIL and its receptors. J Histochem Cytochem 2004; 52: 821-31"
                  "contribucion" => array:1 [
                    0 => null
                  ]
                  "host" => array:1 [
                    0 => null
                  ]
                ]
              ]
            ]
            31 => array:3 [
              "identificador" => "bib32"
              "etiqueta" => "32"
              "referencia" => array:1 [
                0 => array:3 [
                  "referenciaCompleta" => "32- Sanchez-Niño MD, Sanz AB, Ihalmo P, Lassila M, Holthofer H, Mezzano S,y cols. The MIF receptor CD74 in diabetic podocyte injury. J Am Soc Nephrol 2009 (in press)"
                  "contribucion" => array:1 [
                    0 => null
                  ]
                  "host" => array:1 [
                    0 => null
                  ]
                ]
              ]
            ]
            32 => array:3 [
              "identificador" => "bib33"
              "etiqueta" => "33"
              "referencia" => array:1 [
                0 => array:3 [
                  "referenciaCompleta" => "33- Mensah-Brown EP, Obineche EN, Galadari S, Chandranath E, Shahin A, Ahmed I, y cols: Streptozotocin-induced diabetic nephropathy in rats: The role of inflammatory cytokines. Cytokine 2005; 31: 180¿190."
                  "contribucion" => array:1 [
                    0 => null
                  ]
                  "host" => array:1 [
                    0 => null
                  ]
                ]
              ]
            ]
            33 => array:3 [
              "identificador" => "bib34"
              "etiqueta" => "34"
              "referencia" => array:1 [
                0 => array:3 [
                  "referenciaCompleta" => "34- Baumgartner-Parzer SM, Wagner L, Pettermann M, Grillari J, Gessl A, Waldhausl W: High-glucose¿triggered apoptosis in cultured endothelial cells. Diabetes 1995; 44: 1323¿27."
                  "contribucion" => array:1 [
                    0 => null
                  ]
                  "host" => array:1 [
                    0 => null
                  ]
                ]
              ]
            ]
            34 => array:3 [
              "identificador" => "bib35"
              "etiqueta" => "35"
              "referencia" => array:1 [
                0 => array:3 [
                  "referenciaCompleta" => "35- Moley KH, Chi MM, Knudson CM, Korsmeyer SJ, Mueckler MM: Hyperglycemia induces apoptosis in pre-implantation embryos through cell death effector pathways. Nat Med .1998; 4: 1421¿24."
                  "contribucion" => array:1 [
                    0 => null
                  ]
                  "host" => array:1 [
                    0 => null
                  ]
                ]
              ]
            ]
            35 => array:3 [
              "identificador" => "bib36"
              "etiqueta" => "36"
              "referencia" => array:1 [
                0 => array:3 [
                  "referenciaCompleta" => "36- Ortiz A, Lorz C, Catalán MP, Danoff TM, Yamasaki Y, Egido J, y cols. Expression of apoptosis regulatory proteins in tubular epithelium stressed in culture or following acute renal failure. Kidney Int. 2000;57:969-81."
                  "contribucion" => array:1 [
                    0 => null
                  ]
                  "host" => array:1 [
                    0 => null
                  ]
                ]
              ]
            ]
            36 => array:3 [
              "identificador" => "bib37"
              "etiqueta" => "37"
              "referencia" => array:1 [
                0 => array:3 [
                  "referenciaCompleta" => "37- Justo P, Sanz A, Lorz C, Egido J, Ortiz A. Expression of Smac/Diablo in tubular epithelial cells and during acute renal failure. Kidney Int. 2003; 64: 52-56."
                  "contribucion" => array:1 [
                    0 => null
                  ]
                  "host" => array:1 [
                    0 => null
                  ]
                ]
              ]
            ]
            37 => array:3 [
              "identificador" => "bib38"
              "etiqueta" => "38"
              "referencia" => array:1 [
                0 => array:3 [
                  "referenciaCompleta" => "38- Justo J, Sanz AB, Lorz C, Egido J, Ortiz A. Lethal activity of FADD death domain in renal tubular epithelial cells. Kidney Int 2006; 69, 2205-11."
                  "contribucion" => array:1 [
                    0 => null
                  ]
                  "host" => array:1 [
                    0 => null
                  ]
                ]
              ]
            ]
            38 => array:3 [
              "identificador" => "bib39"
              "etiqueta" => "39"
              "referencia" => array:1 [
                0 => array:3 [
                  "referenciaCompleta" => "39- Koenig-Hoffmann K, Bonin-Debs AL, Boche I, Gawin B, Gnirke A, Hergersberg C,y cols. High throughput functional genomics: identification of novel genes with tumor suppressor phenotypes. Int J Cancer. 2005; 113:434-9."
                  "contribucion" => array:1 [
                    0 => null
                  ]
                  "host" => array:1 [
                    0 => null
                  ]
                ]
              ]
            ]
            39 => array:3 [
              "identificador" => "bib40"
              "etiqueta" => "40"
              "referencia" => array:1 [
                0 => array:3 [
                  "referenciaCompleta" => "40- Song CJ, Liu XS, Zhu Y, Chen LH, Jia W, Li YN, y cols: Expression of TRAIL, DR4, and DR5 in kidney and serum from patients receiving renal transplantation. Transplant Proc. 2004; 36:1340-3"
                  "contribucion" => array:1 [
                    0 => null
                  ]
                  "host" => array:1 [
                    0 => null
                  ]
                ]
              ]
            ]
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