Connective tissue growth factor (CTGF): a key factor in the onset and progression of kidney damage
El factor de crecimiento de tejido conectivo (CTGF): factor clave en el inicio y la progresión del daño renal
E.. Sánchez-Lópeza, R.. Rodríguez Díeza, J.. Rodríguez Vitaa, S.. Rayego Mateosa, R. R.. Rodríguez Díeza, E.. Rodríguez Garcíaa, C.. Lavoz Barriaa, S.. Mezzanob, R.. Selgasc, J.. Egidod, A.. Ortize, Marta Ruiz Ortegaa
a Laboratorio de Biología celular en Enfermedades Renales, Universidad Autónoma de Madrid, Madrid,
b División de Nefrología, Escuela de Medicina. Universidad Austral, Valdivia, Chile,
c Servicio Nefrología, Hospital La Paz, Madrid,
d Laboratorio de Investigación Renal, Fundación Jiménez Díaz. Universidad Autónoma de Madrid, Madrid,
e Unidad de Diálisis, Fundación Jiménez Díaz, Madrid,
Read
12699
Timeswas read the article
3163
Total PDF
9536
Total HTML
Share statistics
array:21 [ "pii" => "X2013251409003613" "issn" => "20132514" "doi" => "10.3265/Nefrologia.2009.29.5.5429.en.full" "estado" => "S300" "fechaPublicacion" => "2009-10-01" "documento" => "article" "licencia" => "http://www.elsevier.com/open-access/userlicense/1.0/" "subdocumento" => "fla" "cita" => "Nefrologia (English Version). 2009;29:382-91" "abierto" => array:3 [ "ES" => true "ES2" => true "LATM" => true ] "gratuito" => true "lecturas" => array:2 [ "total" => 6634 "formatos" => array:3 [ "EPUB" => 317 "HTML" => 5597 "PDF" => 720 ] ] "Traduccion" => array:1 [ "es" => array:17 [ "pii" => "X0211699509003616" "issn" => "02116995" "doi" => "10.3265/Nefrologia.2009.29.5.5429.en.full" "estado" => "S300" "fechaPublicacion" => "2009-10-01" "documento" => "article" "licencia" => "http://www.elsevier.com/open-access/userlicense/1.0/" "subdocumento" => "fla" "cita" => "Nefrologia. 2009;29:382-91" "abierto" => array:3 [ "ES" => true "ES2" => true "LATM" => true ] "gratuito" => true "lecturas" => array:2 [ "total" => 10782 "formatos" => array:3 [ "EPUB" => 269 "HTML" => 9928 "PDF" => 585 ] ] "es" => array:12 [ "idiomaDefecto" => true "titulo" => "El factor de crecimiento de tejido conectivo (CTGF): factor clave en el inicio y la progresión del daño renal" "tienePdf" => "es" "tieneTextoCompleto" => "es" "tieneResumen" => array:2 [ 0 => "es" 1 => "en" ] "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "382" "paginaFinal" => "391" ] ] "titulosAlternativos" => array:1 [ "en" => array:1 [ "titulo" => "Connective tissue growth factor (CTGF): a key factor in the onset and progression of kidney damage" ] ] "contieneResumen" => array:2 [ "es" => true "en" => true ] "contieneTextoCompleto" => array:1 [ "es" => true ] "contienePdf" => array:1 [ "es" => true ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig1" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "copyright" => "Elsevier España" "figura" => array:1 [ 0 => array:4 [ "imagen" => "407527_fig1.jpg" "Alto" => 522 "Ancho" => 518 "Tamanyo" => 36731 ] ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "E. Sánchez-López, R. Rodríguez Díez, J. Rodríguez Vita, S. Rayego Mateos, R. R. Rodríguez Díez, E. Rodríguez García, C. Lavoz Barria, S. Mezzano, R. Selgas, J. Egido, A. Ortiz, Marta Ruiz Ortega" "autores" => array:12 [ 0 => array:2 [ "Iniciales" => "E." "apellidos" => "Sánchez-López" ] 1 => array:2 [ "Iniciales" => "R." "apellidos" => "Rodríguez Díez" ] 2 => array:2 [ "Iniciales" => "J." "apellidos" => "Rodríguez Vita" ] 3 => array:2 [ "Iniciales" => "S." "apellidos" => "Rayego Mateos" ] 4 => array:2 [ "Iniciales" => "R. R." "apellidos" => "Rodríguez Díez" ] 5 => array:2 [ "Iniciales" => "E." "apellidos" => "Rodríguez García" ] 6 => array:2 [ "Iniciales" => "C." "apellidos" => "Lavoz Barria" ] 7 => array:2 [ "Iniciales" => "S." "apellidos" => "Mezzano" ] 8 => array:2 [ "Iniciales" => "R." "apellidos" => "Selgas" ] 9 => array:2 [ "Iniciales" => "J." "apellidos" => "Egido" ] 10 => array:2 [ "Iniciales" => "A." "apellidos" => "Ortiz" ] 11 => array:2 [ "nombre" => "Marta" "apellidos" => "Ruiz Ortega" ] ] ] ] ] "idiomaDefecto" => "es" "Traduccion" => array:1 [ "en" => array:9 [ "pii" => "X2013251409003613" "doi" => "10.3265/Nefrologia.2009.29.5.5429.en.full" "estado" => "S300" "subdocumento" => "" "abierto" => array:3 [ "ES" => true "ES2" => true "LATM" => true ] "gratuito" => true "lecturas" => array:1 [ "total" => 0 ] "idiomaDefecto" => "en" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/X2013251409003613?idApp=UINPBA000064" ] ] "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/X0211699509003616?idApp=UINPBA000064" "url" => "/02116995/0000002900000005/v0_201502091404/X0211699509003616/v0_201502091404/es/main.assets" ] ] "itemSiguiente" => array:17 [ "pii" => "X2013251409003605" "issn" => "20132514" "doi" => "10.3265/Nefrologia.2009.29.5.5400.en.full" "estado" => "S300" "fechaPublicacion" => "2009-10-01" "documento" => "article" "licencia" => "http://www.elsevier.com/open-access/userlicense/1.0/" "subdocumento" => "fla" "cita" => "Nefrologia (English Version). 2009;29:392-6" "abierto" => array:3 [ "ES" => true "ES2" => true "LATM" => true ] "gratuito" => true "lecturas" => array:2 [ "total" => 4959 "formatos" => array:3 [ "EPUB" => 251 "HTML" => 4060 "PDF" => 648 ] ] "en" => array:11 [ "idiomaDefecto" => true "titulo" => "FGF23: a key player in mineral and bone disorder in CKD" "tienePdf" => "en" "tieneTextoCompleto" => "en" "tieneResumen" => array:2 [ 0 => "es" 1 => "en" ] "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "392" "paginaFinal" => "396" ] ] "contieneResumen" => array:2 [ "es" => true "en" => true ] "contieneTextoCompleto" => array:1 [ "en" => true ] "contienePdf" => array:1 [ "en" => true ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig1" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "copyright" => "Elsevier España" "figura" => array:1 [ 0 => array:4 [ "imagen" => "40818078_f1_pag394.jpg" "Alto" => 579 "Ancho" => 825 "Tamanyo" => 39056 ] ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "H. Komaba, M. Fukagawa" "autores" => array:2 [ 0 => array:2 [ "Iniciales" => "H." "apellidos" => "Komaba" ] 1 => array:2 [ "Iniciales" => "M." "apellidos" => "Fukagawa" ] ] ] ] ] "idiomaDefecto" => "en" "Traduccion" => array:1 [ "en" => array:9 [ "pii" => "X0211699509003608" "doi" => "10.3265/Nefrologia.2009.29.5.5400.en.full" "estado" => "S300" "subdocumento" => "" "abierto" => array:3 [ "ES" => true "ES2" => true "LATM" => true ] "gratuito" => true "lecturas" => array:1 [ "total" => 0 ] "idiomaDefecto" => "en" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/X0211699509003608?idApp=UINPBA000064" ] ] "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/X2013251409003605?idApp=UINPBA000064" "url" => "/20132514/0000002900000005/v0_201502091625/X2013251409003605/v0_201502091625/en/main.assets" ] "itemAnterior" => array:17 [ "pii" => "X2013251409003590" "issn" => "20132514" "doi" => "10.3265/Nefrologia.2009.29.5.5663.en.full" "estado" => "S300" "fechaPublicacion" => "2009-10-01" "documento" => "article" "licencia" => "http://www.elsevier.com/open-access/userlicense/1.0/" "subdocumento" => "fla" "cita" => "Nefrologia (English Version). 2009;29:379-81" "abierto" => array:3 [ "ES" => true "ES2" => true "LATM" => true ] "gratuito" => true "lecturas" => array:2 [ "total" => 3387 "formatos" => array:3 [ "EPUB" => 246 "HTML" => 2704 "PDF" => 437 ] ] "en" => array:9 [ "idiomaDefecto" => true "titulo" => "The failure to propose live-donor transplants is bad practice" "tienePdf" => "en" "tieneTextoCompleto" => "en" "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "379" "paginaFinal" => "381" ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "No indicar el trasplante de vivo es una mala práctica" ] ] "contieneTextoCompleto" => array:1 [ "en" => true ] "contienePdf" => array:1 [ "en" => true ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => " Organización Nacional de Trasplantes, M.O. Valentín, B. Domínguez-Gil, E. Martín Escobar, R. Matesanz" "autores" => array:5 [ 0 => array:1 [ "apellidos" => "Organización Nacional de Trasplantes" ] 1 => array:2 [ "Iniciales" => "M.O." "apellidos" => "Valentín" ] 2 => array:2 [ "Iniciales" => "B." "apellidos" => "Domínguez-Gil" ] 3 => array:2 [ "Iniciales" => "E." "apellidos" => "Martín Escobar" ] 4 => array:2 [ "Iniciales" => "R." "apellidos" => "Matesanz" ] ] ] ] ] "idiomaDefecto" => "en" "Traduccion" => array:1 [ "es" => array:9 [ "pii" => "X0211699509003593" "doi" => "10.3265/Nefrologia.2009.29.5.5663.en.full" "estado" => "S300" "subdocumento" => "" "abierto" => array:3 [ "ES" => true "ES2" => true "LATM" => true ] "gratuito" => true "lecturas" => array:1 [ "total" => 0 ] "idiomaDefecto" => "es" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/X0211699509003593?idApp=UINPBA000064" ] ] "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/X2013251409003590?idApp=UINPBA000064" "url" => "/20132514/0000002900000005/v0_201502091625/X2013251409003590/v0_201502091625/en/main.assets" ] "en" => array:15 [ "idiomaDefecto" => true "titulo" => "Connective tissue growth factor (CTGF): a key factor in the onset and progression of kidney damage" "tieneTextoCompleto" => true "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "382" "paginaFinal" => "391" ] ] "autores" => array:1 [ 0 => array:3 [ "autoresLista" => "E. Sánchez-López, R. Rodríguez Díez, J. Rodríguez Vita, S. Rayego Mateos, R. R. Rodríguez Díez, E. Rodríguez García, C. Lavoz Barria, S. Mezzano, R. Selgas, J. Egido, A. Ortiz, Marta Ruiz Ortega" "autores" => array:12 [ 0 => array:3 [ "Iniciales" => "E." "apellidos" => "Sánchez-López" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "affa" ] ] ] 1 => array:3 [ "Iniciales" => "R." "apellidos" => "Rodríguez Díez" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "affa" ] ] ] 2 => array:3 [ "Iniciales" => "J." "apellidos" => "Rodríguez Vita" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "affa" ] ] ] 3 => array:3 [ "Iniciales" => "S." "apellidos" => "Rayego Mateos" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "affa" ] ] ] 4 => array:3 [ "Iniciales" => "R. R." "apellidos" => "Rodríguez Díez" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "affa" ] ] ] 5 => array:3 [ "Iniciales" => "E." "apellidos" => "Rodríguez García" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "affa" ] ] ] 6 => array:3 [ "Iniciales" => "C." "apellidos" => "Lavoz Barria" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "affa" ] ] ] 7 => array:3 [ "Iniciales" => "S." "apellidos" => "Mezzano" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">b</span>" "identificador" => "affb" ] ] ] 8 => array:3 [ "Iniciales" => "R." "apellidos" => "Selgas" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">c</span>" "identificador" => "affc" ] ] ] 9 => array:3 [ "Iniciales" => "J." "apellidos" => "Egido" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">d</span>" "identificador" => "affd" ] ] ] 10 => array:3 [ "Iniciales" => "A." "apellidos" => "Ortiz" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">e</span>" "identificador" => "affe" ] ] ] 11 => array:4 [ "nombre" => "Marta" "apellidos" => "Ruiz Ortega" "email" => array:1 [ 0 => "mruizo@fjd.es" ] "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "affa" ] ] ] ] "afiliaciones" => array:5 [ 0 => array:3 [ "entidad" => "Laboratorio de Biología celular en Enfermedades Renales, Universidad Autónoma de Madrid, Madrid, " "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "affa" ] 1 => array:3 [ "entidad" => "División de Nefrología, Escuela de Medicina. Universidad Austral, Valdivia, Chile, " "etiqueta" => "<span class="elsevierStyleSup">b</span>" "identificador" => "affb" ] 2 => array:3 [ "entidad" => "Servicio Nefrología, Hospital La Paz, Madrid, " "etiqueta" => "<span class="elsevierStyleSup">c</span>" "identificador" => "affc" ] 3 => array:3 [ "entidad" => "Laboratorio de Investigación Renal, Fundación Jiménez Díaz. Universidad Autónoma de Madrid, Madrid, " "etiqueta" => "<span class="elsevierStyleSup">d</span>" "identificador" => "affd" ] 4 => array:3 [ "entidad" => "Unidad de Diálisis, Fundación Jiménez Díaz, Madrid, " "etiqueta" => "<span class="elsevierStyleSup">e</span>" "identificador" => "affe" ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "El factor de crecimiento de tejido conectivo (CTGF): factor clave en el inicio y la progresión del daño renal" ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig1" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "copyright" => "Elsevier España" "figura" => array:1 [ 0 => array:4 [ "imagen" => "40718078_f1_pag384.jpg" "Alto" => 856 "Ancho" => 822 "Tamanyo" => 67327 ] ] ] ] "textoCompleto" => "INTRODUCTION <br></br><br></br>Numerous diseases, such as proliferative disorders and fibrotic lesions, skin conditions, atherosclerosis, pulmonary fibrosis and multiple renal pathologies present high CTGF levels in tissue, mainly in fibrotic areas. <span class="elsevierStyleSup">1-5</span> Although CTGF has traditionally been considered a profibrotic factor, it is a multi-function factor with biological activities that vary depending on the cell type. These activities include regulating cellular apoptosis/proliferation, angiogenesis, migration, adhesion and fibrosis. <span class="elsevierStyleSup">2,3</span> In this study, we reviewed CTGF¿s role focusing on its importance in renal disease. <br></br><br></br>STRUCTURE <br></br><br></br>CTGF is a secretable cysteine-rich protein with a molecular weight of 38kDa, which was identified in cultured endothelial cells from the umbilical cord vein. <span class="elsevierStyleSup">6</span> CTGF, also known as CCN2, belongs to the CCN family of early response genes, which is made up of five members: Cyr61 (cysteine-61 rich protein), Nov (nephroblastoma overexpressed gene), WISP-1 (Wnt-1 induced secreted protein 1), WISP-2 and WISP-3. <span class="elsevierStyleSup">1,2,7,8</span> All members of this family are characterised by a high percentage of homology in their amino acid sequence, which ranges between 50 and 90%, and they present 38 cysteine residues that are grouped in two segments (22 in the N-terminal and 16 in the C-terminal regions). This is typical of other growth factors such as the plateletderived growth factor (PDGF), the nerve growth factor and the transforming growth factor-β (TGF-β). <span class="elsevierStyleSup">3,9</span><br></br><br></br>Proteins in this family carry a secretory signal peptide in the NH <span class="elsevierStyleInf">2</span>-terminal end and four preserved secretion domains or modules. <span class="elsevierStyleSup">9</span> These domains are as follows: 1) insulin-like growth factor (IGF) binding domain with the <br></br>conserved binding sequence Gly-Cys-Gly-Cys-Cys-X-XCys located within the amino-terminal region for all  GFbinding proteins; <span class="elsevierStyleSup">10-12</span> Von Willebrand type C domain, which participates in protein oligomerisation and <br></br>formation; <span class="elsevierStyleSup">13</span> 3) thrombospondin-1 domain, implicated in binding soluble macromolecules to a matrix; <span class="elsevierStyleSup">14</span> and 4) Cterminal domain, a dimerisation domain implicated in cell-surface binding, which has mitogenic activity for <br></br>fibroblasts and is responsible for interaction with fibronectin. <span class="elsevierStyleSup">15</span><br></br><br></br>REGULATION <br></br><br></br>Depending on the cell type, a wide variety of factors and molecules is involved in regulating CTGF expression. G-protein-coupled receptor agonists, growth factors such as TGF-β, angiotensin II (AngII), bone morphogenetic protein (BMP), vascular endothelial growth factor (VEGF), IGF, granulocyte/macrophage colony stimulation factor (GM-CSF), interleukin-4 (IL-4), high levels of glucose, hypoxia, mechanical stress and oxidative stress cause a rapid increase in CTGF expression (figure 1). <span class="elsevierStyleSup">16-24</span> However, other factors such as the tumour necrosis factor alpha (TNF-α), interleukin-1¿ (IL-1β), cAMP and treatment with peroxysome proliferative activated receptor-γ (PPAR-γ) inhibit CTGF expression induced by TGF-β and AngII in some cell types. <span class="elsevierStyleSup">25-29</span> Various signal mechanisms have been related to increased CTGF. These include the SMAD protein signalling pathway, the reactive oxygen species, <br></br>the small G protein RhoA, protein kinase C, Janus kinase (JAK), phosphatydilinosotol-3 kinase (PI3K) and the mitogen-activated protein kinase (MAPK) cascades. <span class="elsevierStyleSup">30-33</span><br></br><br></br>Most of the studies that have been carried out have focussed on investigating TGF-β-induced CTGF regulation. A SMAD-binding element has been described in the CTGF promoter, which is necessary for its induction by TGF-β. <span class="elsevierStyleSup">34</span> In proximal tubular epithelial cells and mesangial cells, TGF-β increases CTGF production in a process that is regulated by SMAD proteins and the Ras/MEK/ERK signalling cascade. <span class="elsevierStyleSup">36,37</span> However, this process is mediated by Rho activation <span class="elsevierStyleSup">35</span> in renal fibroblasts. The MAPK signalling cascade also plays an important role in regulating CTGF. In hepatocytes, TGF-β induces CTGF expression and production by means of ERK1/2, <span class="elsevierStyleSup">38</span> while in lung fibroblasts the process is mainly mediated by the kinase JNK1/2. <span class="elsevierStyleSup">39</span> Studies performed by our group have focussed on the regulation caused by AngII. In human tubular epithelial cells, AngII induces CTGF production by activating MAPK (ERK, p38 and JNK) and Rhoassociated protein kinase, ROCK. <span class="elsevierStyleSup">39</span> Rho involvement in CTGF regulation has been described for many cell types, including lung fibroblasts and vascular smooth muscle cells. <span class="elsevierStyleSup">34,41</span> In the latter, CTGF increases in response to AngII through other pathways such as ROS, SMAD proteins and the kinases p38, JNK1/2, ROCK, PKC and PTK. <span class="elsevierStyleSup">34,42</span> In fibroblasts, ERK1/2 and JNK1/2 inhibitors, but not p38 inhibitors, decrease AngII-stimulated CTGF expression <span class="elsevierStyleSup">43</span>. Nevertheless, in rat mesangial cells, we find ROS and p38 production among the pathways that are involved in AngII-induced CTGF production. <span class="elsevierStyleSup">29</span> Recent molecular studies have revealed the presence of a highly conserved NF-κB binding sites in the proximal region of the CTGF promoter. <span class="elsevierStyleSup">44</span> In mesangial cells, we have observed that blocking NF-κB decreases AngIIinduced CTGF production (unpublished data), which <br></br>suggests that activation of the NF-κB transcription factor is involved in CTGF regulation in the kidney. <br></br><br></br>SIGNAL TRANSDUCTION AND BIOLOGICAL FUNCTIONS OF CTGF <br></br><br></br>There is still no known receptor that is specific to CTGF. However, it has been stated that it interacts with various <br></br>proteins, such as tyrosine-kinase and integrin, which activate multiple signalling systems. The first interaction studies revealed that there are CTGF-receptor complexes with a molecular weight of about 280kDa located in chondrocytes, osteoblasts and endothelial cells. <span class="elsevierStyleSup">45</span> In various cell types, CTGF acts by binding different integrins, such as integrin α5β1 or αIIbβ3, to heparan sulphate proteoglycan receptors -which activates various kinases, such as focal adhesion kinase (FAK), ERK and Rac <span class="elsevierStyleSup">16,47-49</span>- and to the macroglobulin receptor for the low-density lipoprotein receptor-related protein <span class="elsevierStyleSup">46</span> (LPR) (figure 1). It binds directly to BMP-4 and TGF-β <span class="elsevierStyleSup">50</span> at its cysteine-rich domain, interacts with fibronectin at its carboxyl-terminal domain, and binds with IGF <span class="elsevierStyleSup">52</span> at its amino-terminal domain. In human mesangial cells, CTGF interacts with the dual receptor tyrosine-kinase system A (RTK-A) and p75 <span class="elsevierStyleInf">NTR</span> that participates in neurotrophin signal transduction in the nervous system (figure 1). Receptor tyrosine kinases bind numerous adapter proteins and activate multiple intracellular signalling pathways, which would be in keeping with CTGF¿s multi-functional properties <span class="elsevierStyleSup">66</span> that include regulating and synthesising extracellular matrix <br></br>(ECM), <span class="elsevierStyleSup">4,53,54</span> endothelial cell migration and angiogenesis, regulation of extracellular matrix, mesothelial cell apoptosis, <span class="elsevierStyleSup">56</span> survival of hepatic and mesangial cells <span class="elsevierStyleSup">57,58</span> and fibroblast and chondrocyte proliferation and differentiation. <span class="elsevierStyleSup">59,60</span> In the kidney, CTGF actively participates in fibrosis and epithelial mesenchymal transition (EMT) and, as we described above, in the inflammatory response. We will presently give a more in-depth review of this topic. <br></br><br></br>RELATION BETWEEN CTGF AND TGF-β <br></br><br></br>Numerous in vivo examples demonstrate that TGF-β participates in fibrotic processes. It has been stated that CTGF and TGF-β act in synergy to promote chronic fibrosis (figure 2). Subcutaneous co-injection of the two agents produces sustained and persistent fibrosis in mice. Various experimental models, such as those for unilateral ureter <br></br>obstruction, nephritis due to anti-Thy1 antibodies, diabetic glomerulosclerosis and AngII infusion <span class="elsevierStyleSup">61-63</span> show high levels of TGF-β and CTGF during advanced stages of fibrosis, indicating that these factors may contribute to the progression of kidney damage (figure 3). As stated previously, CTGF binds directly to TGF-β and increases its responses. The mechanism is based on CTGF¿s chaperone function that increases TGF-β¿s affinity for its different receptors, creating more intense and prolonged responses. <span class="elsevierStyleSup">64</span> This is not the only manner by which CTGF participates in TGF-β responses. Endogenous production of CTGF by TGF-β involves a transcriptional suppression of SMAD-7 through induction of the TGF-ß-inducible early gene (TIEG-1) transcription factor. By means of this mechanism, TGF-β blocks feedback regulation through SMAD-7, perpetuating the activation of TGF-β signalling. <span class="elsevierStyleSup">32</span> This may be relevant for pathological conditions in which there is increased CTGF expression. <br></br><br></br>Blocking TGF-β activity with neutralising antibodies and/or decorin, which captures its active form, has been shown to reduce fibrosis in experimental models for kidney damage. However, TGF-β deficiency is lethal in the mouse; it <br></br>develops a lesion repair defect, with collagen deposit problems, and presents a hyperinflammatory phenotype. <span class="elsevierStyleSup">65</span><br></br>This suggests that it would be better to find a more specific therapeutic target for fibrotic diseases. Mice that are <br></br>heterozygous for CTGF gene deletion have matrix organisation and synthesis defects during osteogenesis, which results in seriously defective development of the skeletal component of the thoracic cage; they die immediately after birth. <span class="elsevierStyleSup">66</span> In addition, CTGF is a mediator of fibrosis caused by TGF-β and other factors that are involved in tissue damage, and for that reason, it may be a new, more useful target for antifibrotic therapy. <br></br><br></br>CTGF AS A MEDIATOR OF RENAL FIBROSIS AND EPITHELIAL-MESENCHYMAL TRANSITION <br></br><br></br>CTGF is not expressed in the healthy kidney, but its expression is induced by human renal diseases, including <br></br>glomerulonephritis, glomerulosclerosis and diabetic nephropathy; its expression levels are correlated with the <br></br>severity and progression of renal fibrosis. <span class="elsevierStyleSup">5,67-69</span> Our group used the model of kidney damage caused by the systemic infusion of AngII in rats to study the role CTGF plays in the onset and progression of in vivo kidney  damage. <br></br><br></br>The infusion of AngII rapidly induces the expression of CTGF, which appears after three days and remains high for two weeks, which was the end point of the study (figure 3). The appearance of CTGF, which was observed in tubular epithelial and glomerular cells three days after infusion, precedes the accumulation of ECM (characterised by an increase in the fibronectin deposit) which is seen after one week. This indicates that CTGF may act as a mediator of renal fibrosis caused by AngII in vivo. <span class="elsevierStyleSup">70</span> Through in vitro studies of rat mesangial cells, we observed that blocking endogenous CTGF synthesis by using antisense oligonucleotides prevents AngII-induced fibronectin and collagen IV production. <span class="elsevierStyleSup">43</span> These data show that CTGF is a mediator of AngII¿s fibrotic response in the kidney. <br></br><br></br>Infusion of AngII also increases expression of TGF-β in the kidney. This factor is synthesised as an inactive protein <br></br>which is anchored to the membrane before being activated. <span class="elsevierStyleSup">71</span> In cell cultures, AngII increases mRNA expression of TGF-β, protein production and latent TGF-β activation in a process that is mediated by thrombospondin. <span class="elsevierStyleSup">72</span> Expression levels for TGF-β, but not thrombospondin-1, appear to be higher after three days of AngII infusion. <br></br>However, active TGF-β protein levels did not increase for two weeks. <span class="elsevierStyleSup">73</span> This suggests that CTGF is induced before <br></br>TGF-β and that it participates in the onset of fibrosis and remains high until advanced stages, which contributes to <br></br>perpetuating kidney damage (figure 3). <br></br><br></br>Much evidence suggests that tubular epithelial cells under pathological conditions may suffer epithelialmesenchymal <br></br>transition (EMT) and become fibroblasts that produce extracellular matrix and contribute to renal fibrosis and the progression of the disease. <span class="elsevierStyleSup">74</span> Different factors participate in this process, notably CTGF, TGF-β, fibroblast growth factor (FGF), IL-1, EGF, advanced glycosylation end products (AGEs) and AngII. <span class="elsevierStyleSup">39,73,75-78</span> CTGF promotes the human tubular epithelial cell transdifferentiation to myofibroblasts in vitro and blocking CTGF results in inhibition of <br></br>transdifferentiation caused by TGF-β, by advanced glycosylation end products and AngII. <span class="elsevierStyleSup">39</span> In the model of AngII-induced kidney damage, the increase in CTGF expression remains present after two weeks. This coincides with the onset of EMT, which is characterised by an increase in the mesenchy marker α-SMA expression and a decrease in epithelial marker E-cadherin <span class="elsevierStyleSup">73</span> (figure 3). Furthermore, the increase in CTGF expression in the diabetic kidney is placed over the tubular epithelium in EMT sites. <span class="elsevierStyleSup">75</span> These data have been confirmed in other experimental models such as 5/6 nephrectomy in rats, where increased CTGF was associated with overexpression of TGF-β and PDGF in <br></br>interstitial fibroblast, increased fibrosis and increased severity of kidney damage. <span class="elsevierStyleSup">80</span> By citing these data, we may conclude that CTGF is an inducer of fibrosis and EMT in vivo, and that it mediates the actions of profibrotic factors such as TGF-β and AngII. Furthermore, by interacting with TGF-β it contributes to the perpetuation of fibrosis. <br></br><br></br>CTGF PARTICIPATES IN THE RENAL INFLAMMATORY RESPONSE <br></br><br></br>By using the AngII infusion model, we observed that a clear inflammatory response occurs in the kidney after three days, <span class="elsevierStyleSup">81</span> that this response is characterised by the presence of infiltrating inflammatory cells (T cells, macrophages and granulocytes) in tubulo-interstitial and glomerular areas (figure 3). In this animal study, we also observed an increase in production of classic inflammatory mediators such as IL-6, TNF-β and MCP-1, and in CTGF production in mesangial, podocytes and tubuloepithelial cells, <span class="elsevierStyleSup">70</span> which suggests that CTGF could be implicated in inflammatory response regulation in kidney damage situations. Numerous in vitro studies in glomerular mesangial, tubular epithelial, pancreatic and hepatic cells have demonstrated that CTGF regulates inflammatory mediators. <span class="elsevierStyleSup">58,82,83</span><br></br><br></br>Our group recently showed that systemic CTGF administration in mice caused an inflammatory response after 24 hours, which was characterised by inflammatory cell recruitment (macrophages and T cells) in the interstitium, production of chemotactic factors (MCP-1 and RANTES), proinflammatory cytokines (INF-γ, IL-6 and IL-4), and activation of the NF-κB transcription factor. <span class="elsevierStyleSup">84</span> Treatment with parthenolide, an NF-κB inhibitor (24 hours before the CTGF injection) reduced the renal inflammatory response, which shows that this factor is crucial for CTGF actions in the kidney. <span class="elsevierStyleSup">84</span><br></br><br></br>THERAPEUTIC STRATEGIES AGAINST THE PROGRESSION OF KIDNEY DAMAGE <br></br><br></br>For patients with diabetic nephropathy, it has been shown that high CTGF plasma levels can be considered early markers of progressing renal dysfunction in the diabetic kidney <span class="elsevierStyleSup">85</span>, and they also predict the evolution of renal disease. <span class="elsevierStyleSup">86</span> Studies of patients with IgA nephropathy have observed that high urine levels of CTGF and TGF-β are <br></br>correlated with the degree of tubulo-interstitial damage. <span class="elsevierStyleSup">87</span> On the other hand, in patients with chronic cardiac damage, plasma CTGF levels provide information on the appearance of myocardial fibrosis, and can be considered a new marker for cardiac dysfunction. <span class="elsevierStyleSup">88</span> These data suggest that CTGF may be a marker for fibrosis and damage progression in different diseases. <br></br><br></br>Out of current clinical treatments for stopping kidney damage progression, blocking AngII is one of the most widespread pharmacological options, and has proven protective effects on organs. <span class="elsevierStyleSup">89</span> Treatment with AT <span class="elsevierStyleInf">1</span> receptor antagonists and angiotensin conversing enzyme inhibitors <span class="elsevierStyleSup">89,90</span> decreases renal CTGF expression and fibrosis in various experimental models for kidney damage. <span class="elsevierStyleSup">70</span> However, these drugs only slow the advance of the disease, and a new therapeutic option is necessary if we are to reverse renal fibrosis and halt the EMT process. <br></br><br></br>CTGF blockage is one of the most promising options amongst the new therapeutic approaches. At present, CTGF inhibition studies are directed toward the development of antisense oligonucleotides, interference RNA or neutralising antibodies that block endogenic CTGF. Experimental studies have shown that blocking CTGF with antisense oligonucleotides reduces the ccumulation of ECM in transgenic TGF-β 1 mice with a nephrectomy <span class="elsevierStyleSup">91</span> and in mice with diabetic nephropathy. <span class="elsevierStyleSup">92</span> In one hepatic fibrosis model, treatment with interference RNA for CTGF via the intraportal vein attenuated hepatic fibrosis. <span class="elsevierStyleSup">93</span> However, CTGF blocking effects in the renal inflammatory response have not been studied yet, and a more in-depth examination of this field is necessary. All of these data suggest that <br></br>blocking endogenous CTGF could be a good alternative when treating renal pathologies associated with inflammation and fibrosis. <br></br><br></br>FINAL CONCLUSION <br></br><br></br>This review reveals the immense complexity of the intracellular signalling pathways that regulate CTGF, which vary according to the cell type and the induction factor. It also refers to the presence of the activating and negative regulatory factors determining CTGF synthesis and the development of CTGF responses. With regard to renal pathology, CTGF is involved in all stages of kidney damage: it participates in the inflammatory response (by activating the NF-κB factor that regulates chemokines and cytokines) and promotes fibrosis and EMT, thus showing itself as a good therapeutic target for the treatment of renal diseases. <br></br><p class="elsevierStylePara"><a href="grande/40718078_f1_pag384.jpg" class="elsevierStyleCrossRefs"><img src="40718078_f1_pag384.jpg"></img></a></p><p class="elsevierStylePara">Figure 1. </p><p class="elsevierStylePara"><a href="grande/40718078_f3_pag386.jpg" class="elsevierStyleCrossRefs"><img src="40718078_f3_pag386.jpg"></img></a></p><p class="elsevierStylePara">Figure 3. </p><p class="elsevierStylePara"><a href="grande/40718078_f2_pag385.jpg" class="elsevierStyleCrossRefs"><img src="40718078_f2_pag385.jpg"></img></a></p><p class="elsevierStylePara">Figure 2. </p>" "pdfFichero" => "P-E-S-A407-EN.pdf" "tienePdf" => true "PalabrasClave" => array:2 [ "es" => array:4 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec439649" "palabras" => array:1 [ 0 => "nefropatía" ] ] 1 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec439651" "palabras" => array:1 [ 0 => "inflamación" ] ] 2 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec439653" "palabras" => array:1 [ 0 => "fibrosis" ] ] 3 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec439655" "palabras" => array:1 [ 0 => "CTGF" ] ] ] "en" => array:4 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec439650" "palabras" => array:1 [ 0 => "kidney disease" ] ] 1 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec439652" "palabras" => array:1 [ 0 => "inflammation" ] ] 2 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec439654" "palabras" => array:1 [ 0 => "fibrosis" ] ] 3 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec439656" "palabras" => array:1 [ 0 => "CTGF" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "es" => array:1 [ "resumen" => "<p class="elsevierStylePara">El factor de crecimiento de tejido conectivo (CTGF) aparece aumentado en diferentes patologías asociadas a fibrosis, incluidas múltiples enfermedades renales. CTGF participa en procesos biológicos, como la regulación del ciclo celular, migración, adhesión y angiogénesis. Su expresión está regulada por diversos factores implicados en el daño renal, entre los que destacan el factor la angiotensina II, el factor de crecimiento transformante-beta, altas concentraciones de glucosa y situaciones de estres celular. CTGF participa en el inicio y progresión del daño renal al ser capaz de inducir una respuesta inflamatoria y promover la fibrosis, señalándole como una posible diana terapéutica en el tratamiento de patologías renales. En este trabajo revisamos las principales acciones de CTGF en la patología renal, los mecanismos intracelulares de actuación y las estrategias terapéuticas para su bloqueo.</p>" ] "en" => array:1 [ "resumen" => "Connective tissue growth factor (CTGF) is increased in several pathologies associated with fibrosis, including multiple renal diseases. CTGF is involved in biological processes such as cell cycle regulation, migration, adhesion and angiogenesis. Its expression is regulated by various factors involved in renal damage, such as Angiotensin II, transforming growth factor-beta, high concentrations of glucose and cellular stress. CTGF is involved in the initiation and progression of renal damage to be able to induce an inflammatory response and promote fibrosis, identified as a potential therapeutic target in the treatment of kidney diseases. In this paper we review the main actions of CTGF in renal disease, the intracellular action mechanisms and therapeutic strategies for its blocking." ] ] "multimedia" => array:3 [ 0 => array:7 [ "identificador" => "fig1" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "copyright" => "Elsevier España" "figura" => array:1 [ 0 => array:4 [ "imagen" => "40718078_f1_pag384.jpg" "Alto" => 856 "Ancho" => 822 "Tamanyo" => 67327 ] ] ] 1 => array:7 [ "identificador" => "fig2" "etiqueta" => "Fig. 3" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "copyright" => "Elsevier España" "figura" => array:1 [ 0 => array:4 [ "imagen" => "40718078_f3_pag386.jpg" "Alto" => 352 "Ancho" => 823 "Tamanyo" => 38352 ] ] ] 2 => array:7 [ "identificador" => "fig3" "etiqueta" => "Fig. 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "copyright" => "Elsevier España" "figura" => array:1 [ 0 => array:4 [ "imagen" => "40718078_f2_pag385.jpg" "Alto" => 568 "Ancho" => 823 "Tamanyo" => 34385 ] ] ] ] "bibliografia" => array:2 [ "titulo" => "Bibliography" "seccion" => array:1 [ 0 => array:1 [ "bibliografiaReferencia" => array:7 [ 0 => array:3 [ "identificador" => "bib1" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Gupta S, Clarkson MR, Duggan J, Brady HR. Connective tissue growth factor: potential role in glomerulosclerosis and tubulointerstitial fibrosis. Kidney Int 2000;58(4):1389-99. <a href="http://www.ncbi.nlm.nih.gov/pubmed/11012874" target="_blank">[Pubmed]</a>" "contribucion" => array:1 [ 0 => null ] "host" => array:1 [ 0 => null ] ] ] ] 1 => array:3 [ "identificador" => "bib2" "etiqueta" => "2" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Lau LF, Lam SC. The CCN family of angiogenic regulators: the integrin connection. Exp Cell Res 1999;248(1):44-57. <a href="http://www.ncbi.nlm.nih.gov/pubmed/10094812" target="_blank">[Pubmed]</a>" "contribucion" => array:1 [ 0 => null ] "host" => array:1 [ 0 => null ] ] ] ] 2 => array:3 [ "identificador" => "bib3" "etiqueta" => "3" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Perbal B. CCN proteins: multifunctional signalling regulators. Lancet 2004;363:62-4. <a href="http://www.ncbi.nlm.nih.gov/pubmed/14723997" target="_blank">[Pubmed]</a>" "contribucion" => array:1 [ 0 => null ] "host" => array:1 [ 0 => null ] ] ] ] 3 => array:3 [ "identificador" => "bib4" "etiqueta" => "4" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Yokoi H, Mukoyama M, Sugawara A, Mori K, Nagae T, Makino H, et al. Role of connective tissue growth factor in fibronectin expression and tubulointerstitial\u{A0} fibrosis. Am J Physiol Renal Physiol 2002;282(5):F933-42. <a href="http://www.ncbi.nlm.nih.gov/pubmed/11934704" target="_blank">[Pubmed]</a>" "contribucion" => array:1 [ 0 => null ] "host" => array:1 [ 0 => null ] ] ] ] 4 => array:3 [ "identificador" => "bib5" "etiqueta" => "5" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Ito Y, Aten J, Bende RJ, Oemar BS, Rabelink TJ, Weening JJ, et al. Expression of connective tissue growth factor in human renal fibrosis. Kidney Int 1998;53:853-61. <a href="http://www.ncbi.nlm.nih.gov/pubmed/9551391" target="_blank">[Pubmed]</a>" "contribucion" => array:1 [ 0 => null ] "host" => array:1 [ 0 => null ] ] ] ] 5 => array:3 [ "identificador" => "bib6" "etiqueta" => "6" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Bradham DM, Igarashi A, Potter RL, Grotendorst GR. Connective tissue growth factor: a cysteine-rich mitogen secreted by human vascular endothelial cells is related to the SRC-induced immediate early gene product CEF-10. J Cell Biol 1991;114:1285-94. <a href="http://www.ncbi.nlm.nih.gov/pubmed/1654338" target="_blank">[Pubmed]</a>" "contribucion" => array:1 [ 0 => null ] "host" => array:1 [ 0 => null ] ] ] ] 6 => array:3 [ "identificador" => "bib7" "etiqueta" => "7" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Brigstock DR. The connective tissue growth factor/cysteine ¿rich 61/nephroblastoma overexpressed (CCN) family. Endocr Rev 1999;20:189-206. <a href="http://www.ncbi.nlm.nih.gov/pubmed/10204117" target="_blank">[Pubmed]</a>" "contribucion" => array:1 [ 0 => null ] "host" => array:1 [ 0 => null ] ] ] ] ] ] ] ] ] "idiomaDefecto" => "en" "url" => "/20132514/0000002900000005/v0_201502091625/X2013251409003613/v0_201502091625/en/main.assets" "Apartado" => array:4 [ "identificador" => "35445" "tipo" => "SECCION" "en" => array:2 [ "titulo" => "Short Reviews" "idiomaDefecto" => true ] "idiomaDefecto" => "en" ] "PDF" => "https://static.elsevier.es/multimedia/20132514/0000002900000005/v0_201502091625/X2013251409003613/v0_201502091625/en/P-E-S-A407-EN.pdf?idApp=UINPBA000064&text.app=https://revistanefrologia.com/" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/X2013251409003613?idApp=UINPBA000064" ]
| Year/Month | Html | Total | |
|---|---|---|---|
| 2024 November | 5 | 5 | 10 |
| 2024 October | 62 | 49 | 111 |
| 2024 September | 57 | 80 | 137 |
| 2024 August | 74 | 74 | 148 |
| 2024 July | 47 | 38 | 85 |
| 2024 June | 57 | 31 | 88 |
| 2024 May | 73 | 31 | 104 |
| 2024 April | 63 | 45 | 108 |
| 2024 March | 54 | 30 | 84 |
| 2024 February | 50 | 43 | 93 |
| 2024 January | 27 | 36 | 63 |
| 2023 December | 34 | 33 | 67 |
| 2023 November | 54 | 49 | 103 |
| 2023 October | 63 | 37 | 100 |
| 2023 September | 34 | 44 | 78 |
| 2023 August | 91 | 54 | 145 |
| 2023 July | 64 | 65 | 129 |
| 2023 June | 50 | 30 | 80 |
| 2023 May | 79 | 47 | 126 |
| 2023 April | 51 | 27 | 78 |
| 2023 March | 41 | 29 | 70 |
| 2023 February | 53 | 24 | 77 |
| 2023 January | 56 | 27 | 83 |
| 2022 December | 41 | 27 | 68 |
| 2022 November | 57 | 31 | 88 |
| 2022 October | 72 | 50 | 122 |
| 2022 September | 74 | 47 | 121 |
| 2022 August | 84 | 47 | 131 |
| 2022 July | 54 | 58 | 112 |
| 2022 June | 53 | 47 | 100 |
| 2022 May | 85 | 60 | 145 |
| 2022 April | 86 | 51 | 137 |
| 2022 March | 89 | 63 | 152 |
| 2022 February | 65 | 42 | 107 |
| 2022 January | 75 | 31 | 106 |
| 2021 December | 113 | 44 | 157 |
| 2021 November | 66 | 36 | 102 |
| 2021 October | 68 | 45 | 113 |
| 2021 September | 96 | 442 | 538 |
| 2021 August | 87 | 31 | 118 |
| 2021 July | 91 | 46 | 137 |
| 2021 June | 72 | 23 | 95 |
| 2021 May | 79 | 27 | 106 |
| 2021 April | 216 | 37 | 253 |
| 2021 March | 107 | 22 | 129 |
| 2021 February | 104 | 43 | 147 |
| 2021 January | 79 | 17 | 96 |
| 2020 December | 70 | 21 | 91 |
| 2020 November | 61 | 6 | 67 |
| 2020 October | 48 | 11 | 59 |
| 2020 September | 62 | 8 | 70 |
| 2020 August | 45 | 8 | 53 |
| 2020 July | 71 | 8 | 79 |
| 2020 June | 84 | 10 | 94 |
| 2020 May | 76 | 19 | 95 |
| 2020 April | 82 | 27 | 109 |
| 2020 March | 63 | 16 | 79 |
| 2020 February | 46 | 19 | 65 |
| 2020 January | 74 | 27 | 101 |
| 2019 December | 76 | 39 | 115 |
| 2019 November | 60 | 34 | 94 |
| 2019 October | 79 | 27 | 106 |
| 2019 September | 71 | 20 | 91 |
| 2019 August | 50 | 18 | 68 |
| 2019 July | 65 | 20 | 85 |
| 2019 June | 55 | 16 | 71 |
| 2019 May | 67 | 20 | 87 |
| 2019 April | 86 | 40 | 126 |
| 2019 March | 69 | 19 | 88 |
| 2019 February | 45 | 18 | 63 |
| 2019 January | 60 | 18 | 78 |
| 2018 December | 94 | 38 | 132 |
| 2018 November | 117 | 17 | 134 |
| 2018 October | 120 | 24 | 144 |
| 2018 September | 102 | 11 | 113 |
| 2018 August | 70 | 15 | 85 |
| 2018 July | 66 | 8 | 74 |
| 2018 June | 74 | 10 | 84 |
| 2018 May | 64 | 15 | 79 |
| 2018 April | 74 | 7 | 81 |
| 2018 March | 109 | 16 | 125 |
| 2018 February | 95 | 8 | 103 |
| 2018 January | 96 | 14 | 110 |
| 2017 December | 60 | 9 | 69 |
| 2017 November | 53 | 12 | 65 |
| 2017 October | 55 | 12 | 67 |
| 2017 September | 88 | 8 | 96 |
| 2017 August | 85 | 15 | 100 |
| 2017 July | 63 | 9 | 72 |
| 2017 June | 90 | 15 | 105 |
| 2017 May | 86 | 10 | 96 |
| 2017 April | 58 | 10 | 68 |
| 2017 March | 84 | 13 | 97 |
| 2017 February | 96 | 17 | 113 |
| 2017 January | 60 | 15 | 75 |
| 2016 December | 89 | 6 | 95 |
| 2016 November | 129 | 10 | 139 |
| 2016 October | 183 | 9 | 192 |
| 2016 September | 250 | 11 | 261 |
| 2016 August | 330 | 18 | 348 |
| 2016 July | 236 | 17 | 253 |
| 2016 June | 147 | 0 | 147 |
| 2016 May | 150 | 0 | 150 |
| 2016 April | 116 | 0 | 116 |
| 2016 March | 118 | 0 | 118 |
| 2016 February | 142 | 0 | 142 |
| 2016 January | 116 | 0 | 116 |
| 2015 December | 151 | 0 | 151 |
| 2015 November | 111 | 0 | 111 |
| 2015 October | 102 | 0 | 102 |
| 2015 September | 92 | 0 | 92 |
| 2015 August | 78 | 0 | 78 |
| 2015 July | 83 | 0 | 83 |
| 2015 June | 58 | 0 | 58 |
| 2015 May | 74 | 0 | 74 |
| 2015 April | 5 | 0 | 5 |
Show all
