mTOR inhibition, AKT proteins and chronic kidney disease
Inhibición de mTOR, proteínas AKT y enfermedad renal crónica
Read
17390
Timeswas read the article
4932
Total PDF
12458
Total HTML
Share statistics
array:20 [ "pii" => "X2013251414054405" "issn" => "20132514" "doi" => "10.3265/Nefrologia.pre2014.Apr.12381" "estado" => "S300" "fechaPublicacion" => "2014-07-01" "documento" => "article" "licencia" => "http://www.elsevier.com/open-access/userlicense/1.0/" "subdocumento" => "fla" "cita" => "Nefrologia (English Version). 2014;34:425-7" "abierto" => array:3 [ "ES" => true "ES2" => true "LATM" => true ] "gratuito" => true "lecturas" => array:2 [ "total" => 8862 "formatos" => array:3 [ "EPUB" => 346 "HTML" => 7728 "PDF" => 788 ] ] "Traduccion" => array:1 [ "es" => array:17 [ "pii" => "X0211699514054408" "issn" => "02116995" "doi" => "10.3265/Nefrologia.pre2014.Apr.12381" "estado" => "S300" "fechaPublicacion" => "2014-07-01" "documento" => "article" "licencia" => "http://www.elsevier.com/open-access/userlicense/1.0/" "subdocumento" => "fla" "cita" => "Nefrologia. 2014;34:425-7" "abierto" => array:3 [ "ES" => true "ES2" => true "LATM" => true ] "gratuito" => true "lecturas" => array:2 [ "total" => 9281 "formatos" => array:3 [ "EPUB" => 318 "HTML" => 8175 "PDF" => 788 ] ] "es" => array:10 [ "idiomaDefecto" => true "titulo" => "Inhibición de mTOR, proteínas AKT y enfermedad renal crónica" "tienePdf" => "es" "tieneTextoCompleto" => "es" "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "425" "paginaFinal" => "427" ] ] "titulosAlternativos" => array:1 [ "en" => array:1 [ "titulo" => "mTOR inhibition, AKT proteins and chronic kidney disease" ] ] "contieneTextoCompleto" => array:1 [ "es" => true ] "contienePdf" => array:1 [ "es" => true ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:8 [ "identificador" => "fig1" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "copyright" => "Elsevier España" "figura" => array:1 [ 0 => array:4 [ "imagen" => "12381_19904_53630_es_12381_f1_copy1.jpg" "Alto" => 554 "Ancho" => 700 "Tamanyo" => 261034 ] ] "descripcion" => array:1 [ "es" => "Visión esquemática y simplificada de las vías de acción de Akt" ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "Eva Márquez, Julio Pascual" "autores" => array:2 [ 0 => array:2 [ "nombre" => "Eva" "apellidos" => "Márquez" ] 1 => array:2 [ "nombre" => "Julio" "apellidos" => "Pascual" ] ] ] ] ] "idiomaDefecto" => "es" "Traduccion" => array:1 [ "en" => array:9 [ "pii" => "X2013251414054405" "doi" => "10.3265/Nefrologia.pre2014.Apr.12381" "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/X2013251414054405?idApp=UINPBA000064" ] ] "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/X0211699514054408?idApp=UINPBA000064" "url" => "/02116995/0000003400000004/v0_201502091342/X0211699514054408/v0_201502091342/es/main.assets" ] ] "itemSiguiente" => array:17 [ "pii" => "X2013251414054390" "issn" => "20132514" "doi" => "10.3265/Nefrologia.pre2014.Apr.12375" "estado" => "S300" "fechaPublicacion" => "2014-07-01" "documento" => "article" "licencia" => "http://www.elsevier.com/open-access/userlicense/1.0/" "subdocumento" => "fla" "cita" => "Nefrologia (English Version). 2014;34:428-38" "abierto" => array:3 [ "ES" => true "ES2" => true "LATM" => true ] "gratuito" => true "lecturas" => array:2 [ "total" => 15106 "formatos" => array:3 [ "EPUB" => 349 "HTML" => 13602 "PDF" => 1155 ] ] "en" => array:12 [ "idiomaDefecto" => true "titulo" => "Renal function, nephrogenic systemic fibrosis and other adverse reactions associated with gadolinium-based contrast media" "tienePdf" => "en" "tieneTextoCompleto" => "en" "tieneResumen" => array:2 [ 0 => "es" 1 => "en" ] "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "428" "paginaFinal" => "438" ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Función renal, fibrosis sistémica nefrogénica y otras reacciones adversas asociadas a los medios de contraste basados en el gadolinio" ] ] "contieneResumen" => array:2 [ "es" => true "en" => true ] "contieneTextoCompleto" => array:1 [ "en" => true ] "contienePdf" => array:1 [ "en" => true ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:8 [ "identificador" => "fig1" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "copyright" => "Elsevier España" "figura" => array:1 [ 0 => array:4 [ "imagen" => "12375_19904_59997_en_12375_f1.jpg" "Alto" => 671 "Ancho" => 874 "Tamanyo" => 396611 ] ] "descripcion" => array:1 [ "en" => "Classification of the different gadolinium-based contrasts according to their distribution" ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "Ana Canga, Maria Kislikova, María Martínez-Gálvez, Mercedes Arias, Patricia Fraga-Rivas, Cecilio Poyatos, Ángel L.M. de Francisco" "autores" => array:8 [ 0 => array:2 [ "nombre" => "Ana" "apellidos" => "Canga" ] 1 => array:2 [ "nombre" => "Maria" "apellidos" => "Kislikova" ] 2 => array:2 [ "nombre" => "María" "apellidos" => "Martínez-Gálvez" ] 3 => array:2 [ "nombre" => "Mercedes" "apellidos" => "Arias" ] 4 => array:2 [ "nombre" => "Patricia" "apellidos" => "Fraga-Rivas" ] 5 => array:2 [ "nombre" => "Cecilio" "apellidos" => "Poyatos" ] 6 => array:2 [ "nombre" => "Ángel L.M." "apellidos" => "de Francisco" ] 7 => array:2 [ "nombre" => "Ángel L.M." "apellidos" => "de Francisco" ] ] ] ] ] "idiomaDefecto" => "en" "Traduccion" => array:1 [ "es" => array:9 [ "pii" => "X0211699514054393" "doi" => "10.3265/Nefrologia.pre2014.Apr.12375" "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/X0211699514054393?idApp=UINPBA000064" ] ] "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/X2013251414054390?idApp=UINPBA000064" "url" => "/20132514/0000003400000004/v0_201502091609/X2013251414054390/v0_201502091609/en/main.assets" ] "en" => array:12 [ "idiomaDefecto" => true "titulo" => "mTOR inhibition, AKT proteins and chronic kidney disease" "tieneTextoCompleto" => true "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "425" "paginaFinal" => "427" ] ] "autores" => array:1 [ 0 => array:3 [ "autoresLista" => "Eva Márquez, Julio Pascual" "autores" => array:2 [ 0 => array:3 [ "nombre" => "Eva" "apellidos" => "Márquez" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "affa" ] ] ] 1 => array:4 [ "nombre" => "Julio" "apellidos" => "Pascual" "email" => array:1 [ 0 => "julpascual@gmail.com" ] "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "affa" ] ] ] ] "afiliaciones" => array:1 [ 0 => array:3 [ "entidad" => "Servicio de Nefrología, Hospital del Mar. Institut Mar d¿Investigacions Mediques. Red Temática de Investigación Renal (RedinRen), Barcelona, " "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "affa" ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Inhibición de mTOR, proteínas AKT y enfermedad renal crónica" ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:8 [ "identificador" => "fig1" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "copyright" => "Elsevier España" "figura" => array:1 [ 0 => array:4 [ "imagen" => "12381_16025_59940_en_f1.12381_hoy_copy1.jpg" "Alto" => 1631 "Ancho" => 2106 "Tamanyo" => 411607 ] ] "descripcion" => array:1 [ "en" => "Schematic and simplified view of Akt action pathways" ] ] ] "textoCompleto" => "<p class="elsevierStylePara">Despite up to 9 % of the population suffering from some degree of chronic kidney disease (CKD), the physiopathological pathways that participate in the disease’s progression are still unknown in detail<span class="elsevierStyleSup">1</span>. Podocytes, highly specialised glomerular epithelial cells, play an essential role in maintaining the glomerular filtration barrier. Precise regulation of actin cytoskeleton is necessary for this maintenance; its reorganisation produces functional and morphological alterations that cause proteinuria. The Akt protein family are serine/threonine kinases that regulate metabolic, growth and cell survival factors (Figure 1)<span class="elsevierStyleSup">2</span>. Podocytes have a protective role against apoptosis<span class="elsevierStyleSup">3-6</span>. Nephrin and CD2AP, essential for maintaining cell structure and function, play a role in the regulation of cell apoptosis<span class="elsevierStyleSup">7</span> and a possible function in the regulation of cytoskeleton<span class="elsevierStyleSup">8</span>, both Akt effects.</p><p class="elsevierStylePara">Canaud et al. have recently published the results of a study in which they demonstrate, using experimental <span class="elsevierStyleItalic">in vivo</span>, <span class="elsevierStyleItalic">in vitro</span> models and human biopsies, Akt2 activation as a protective mechanism in the podocyte against a reduction of kidney mass<span class="elsevierStyleSup">9</span>. The loss of Akt2 or the decrease in one of the phosphorylations required for its activity [pAkt (Ser473)] worsens podocyte injury, causing proteinuria. A failure in its phosphorylation, blocking the mTOR2 complex by sirolimus, could explain, at least in part, the undesirable effects of this drug group observed in some transplant patients.</p><p class="elsevierStylePara">This study stands out methodologically for the use of genetically engineered animals. Its authors created knockout (KO) animals for Akt2 and podocyte-specific KO, enabling the evaluation of these cells’ significance in the evolution of renal lesions. These animals, together with their respective and suitable controls, are subjected to a reduction of kidney mass through subtotal nephrectomy or assessed at 13 months old as an ageing model. Similarly, they develop a KO-specific mouse for Rictor, an essential component of the mTOR2 complex.</p><p class="elsevierStylePara">An increase in Akt2 protein level, primarily present at a podocyte level, is observed in the reduction of kidney mass. Its increase seems to be a protective mechanism against damage, since, in relation to their respective controls, the KO animals for Akt2 show podocyte injury with pedicel effacement associated with an increase in Rac1, increase in apoptosis at a glomerular level, higher degree of glomerular lesion and as a result, higher albumin level. Similar alterations are found in KO mice for Akt 2 specifically in the podocytes, which confirms the significance of podocyte Akt2 in renal function maintenance. However, not only the absence of Akt2 causes renal alterations: phosphorylation deficiency, as that observed in KO mice for Rictor, causes equivalent alterations. <span class="elsevierStyleItalic">The</span><span class="elsevierStyleItalic"> in vitro</span> results reinforce the <span class="elsevierStyleItalic">in vivo </span>findings. KO podocytes for Akt2 or treated with sirolimus show alteration of its cytoskeleton with redistribution of actin fibres and appearance of adhesion foci.</p><p class="elsevierStylePara">The studies carried out on human biopsies show, in the same way as in the animal model, that Akt2 is mainly expressed in podocytes. An increase of pAkt (Ser473) is also observed at a glomerular level in patients with various pathologies, mainly of vascular origin.</p><p class="elsevierStylePara">The study of transplant patients with different degrees of renal dysfunction shows that only patients with <span class="elsevierStyleItalic">severe nephron reduction</span> present proteinuria when undergoing treatment with sirolimus. Patients with worse renal function show intense stains for pAkt (Ser473) and Rictor; this is not the case for patients with worse renal function being treated with sirolimus. This group shows greater cell apoptosis at a glomerular level and, clinically, the presence of proteinuria. One of the most noteworthy findings is the correlation in time between sirolimus withdrawal, increase of pAkt (Ser473) in renal biopsy and reduction of proteinuria.</p><p class="elsevierStylePara">With an excellent design in the <span class="elsevierStyleItalic">in vivo</span> and <span class="elsevierStyleItalic">in vitro</span> studies, this study identifies Akt2 as the central element in the pathophysiology of podocyte injury in CKD. <span class="elsevierStyleItalic">Severe nephron reduction</span> models were used, making the findings potentially applicable to CKD of any aetiology. It was recently demonstrated that the activation of Rac1 causes alterations of podocyte cytoskeleton, leading to pedicel effacement<span class="elsevierStyleSup">10</span>. Canaud et al. showed that Akt2 reduction activates Rac1 causing cytoskeletal alterations.</p><p class="elsevierStylePara">In this way, previous studies on podocytes and on other experimental models which show that mTOR inhibitors do not only block mTOR1, but also mTOR2, are reaffirmed<span class="elsevierStyleSup">11,12</span>. In addition, from the study by Canaud et al., it can be concluded that there is another kinase, aside from mTOR2, that phosphorylates Akt, since pAkt (Ser473) is not totally absent in the KO model for Rictor. Akt analysis is carried out through studies of total Akt, its isoforms and pAkt (Ser473); however no study was undertaken on the status of specifically Akt2 nor pAkt (Thr308) phosphorylation, which, although not dependent on the mTOR2 complex, would supply relevant information for the complete evaluation of the functional status of Akt<span class="elsevierStyleSup">13</span>. In addition, the valuation of Rictor-mTOR2 in the various animal models could contribute to clarifying its role and regulation. Surprisingly, in presence of sirolimus, modifications in molecules phosphorylated by the mTOR1 complex, not specifically studied, were not detected.</p><p class="elsevierStylePara">One of the most remarkable findings is that the defect in Akt phosphorylation seems to explain, at least in part, the development of proteinuria observed in transplant patients with poor renal function when an mTOR inhibitor is introduced<span class="elsevierStyleSup">14</span>. The patients were grouped into high and low estimated glomerular filtration rate; renal function and proteinuria prior to sirolimus introduction or duration of treatment with sirolimus, data which would help to establish the possible predictive role of Akt on renal function following the onset of treatment, were not explained. Studies on human renal biopsies show an increase in glomerular pAkt (Ser473) in various pathologies, but the Akt2 isoform was not specifically studied in any of the groups, which would obviously be of interest in the context of the present study.</p><p class="elsevierStylePara">Future research, in both animal and cell models, should be directed at determining which are the stimuli causing the elevation of Akt2, which could be specific to different pathologies. This aforementioned study focused on established renal damage models, but the study of this pathway in models with early damage would be significant. The prevalence of diabetic nephropathy and the role of the PI3K/Akt pathway in its pathophysiology, including podocyte injury<span class="elsevierStyleSup">3-6</span>, make it a clear objective for furthering analysis of the role of Akt2. In addition, in-depth research on apoptosis mechanisms, regulation of the cell cycle (especially in the podocyte, terminally differentiated cell) and modifications of cytoskeleton, all regulated by Akt, is necessary to understand the pathophysiological consequences of the changes in this molecule.</p><p class="elsevierStylePara">In-depth research in these different fields would facilitate the ability to define possible therapeutic targets which would lead to the design of new drugs or the use of current drugs to stop, or even prevent, the development of established renal damage.</p><p class="elsevierStylePara">Finally, findings in human biopsies open the door to new clinical decision-making tools in the management of immunosuppression. With specifically designed studies, it would be possible to confirm the probable prognostic value of total Akt, its phosphorylations and its isoforms when assessing post-transplant biopsies as a step prior to converting to mTOR inhibitors. The study of possible non-invasive markers associated with the results of this study would result in an improvement in routine clinical practice.</p><p class="elsevierStylePara"><a href="grande/12381_16025_59940_en_f1.12381_hoy_copy1.jpg" class="elsevierStyleCrossRefs"><img src="12381_16025_59940_en_f1.12381_hoy_copy1.jpg" alt="Schematic and simplified view of Akt action pathways"></img></a></p><p class="elsevierStylePara">Figure 1. Schematic and simplified view of Akt action pathways</p>" "pdfFichero" => "P1-E572-S4643-A12381-EN.pdf" "tienePdf" => true "multimedia" => array:1 [ 0 => array:8 [ "identificador" => "fig1" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "copyright" => "Elsevier España" "figura" => array:1 [ 0 => array:4 [ "imagen" => "12381_16025_59940_en_f1.12381_hoy_copy1.jpg" "Alto" => 1631 "Ancho" => 2106 "Tamanyo" => 411607 ] ] "descripcion" => array:1 [ "en" => "Schematic and simplified view of Akt action pathways" ] ] ] "bibliografia" => array:2 [ "titulo" => "Bibliography" "seccion" => array:1 [ 0 => array:1 [ "bibliografiaReferencia" => array:14 [ 0 => array:3 [ "identificador" => "bib1" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Otero A, de Francisco A, Gayoso P, Garcia F, Group ES. Prevalence of chronic renal disease in Spain: results of the EPIRCE study. Nefrologia 2010;30(1):78-86. <a href="http://www.ncbi.nlm.nih.gov/pubmed/20038967" 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" => "Manning BD, Cantley LC. AKT/PKB signaling: navigating downstream. Cell 2007;129(7):1261-74. <a href="http://www.ncbi.nlm.nih.gov/pubmed/17604717" 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" => "Wang XM, Yao M, Liu SX, Hao J, Liu QJ, Gao F. Interplay between the Notch and PI3K/Akt pathways in high glucose-induced podocyte apoptosis. Am J Physiol Renal Physiol 2014;306:F205-13. <a href="http://www.ncbi.nlm.nih.gov/pubmed/24226527" 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" => "Tejada T, Catanuto P, Ijaz A, Santos JV, Xia X, Sanchez P, et al. Failure to phosphorylate AKT in podocytes from mice with early diabetic nephropathy promotes cell death. Kidney Int 2008;73(12):1385-93. <a href="http://www.ncbi.nlm.nih.gov/pubmed/18385666" 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" => "Bussolati B, Deregibus MC, Fonsato V, Doublier S, Spatola T, Procida S, et al. Statins prevent oxidized LDL-induced injury of glomerular podocytes by activating the phosphatidylinositol 3-kinase/AKT-signaling pathway. J Am Soc Nephrol 2005;16(7):1936-47. <a href="http://www.ncbi.nlm.nih.gov/pubmed/15843472" 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" => "Logar CM, Brinkkoetter PT, Krofft RD, Pippin JW, Shankland SJ. Darbepoetin alfa protects podocytes from apoptosis in vitro and in vivo. Kidney Int 2007;72(4):489-98. <a href="http://www.ncbi.nlm.nih.gov/pubmed/17554257" 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" => "Huber TB, Hartleben B, Kim J, Schmidts M, Schermer B, Keil A, et al. Nephrin and CD2AP associate with phosphoinositide 3-OH kinase and stimulate AKT-dependent signaling. Mol Cell Biol 2003;23(14):4917-28. <a href="http://www.ncbi.nlm.nih.gov/pubmed/12832477" target="_blank">[Pubmed]</a>" "contribucion" => array:1 [ 0 => null ] "host" => array:1 [ 0 => null ] ] ] ] 7 => array:3 [ "identificador" => "bib8" "etiqueta" => "8" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Zhu J, Sun N, Aoudjit L, Li H, Kawachi H, Lemay S, et al. Nephrin mediates actin reorganization via phosphoinositide 3-kinase in podocytes. Kidney Int 2008;73(5):556-66. <a href="http://www.ncbi.nlm.nih.gov/pubmed/18033240" target="_blank">[Pubmed]</a>" "contribucion" => array:1 [ 0 => null ] "host" => array:1 [ 0 => null ] ] ] ] 8 => array:3 [ "identificador" => "bib9" "etiqueta" => "9" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Canaud G, Bienaime F, Viau A, Treins C, Baron W, Nguyen C, et al. AKT2 is essential to maintain podocyte viability and function during chronic kidney disease. Nat Med 2013;19(10):1288-96. <a href="http://www.ncbi.nlm.nih.gov/pubmed/24056770" target="_blank">[Pubmed]</a>" "contribucion" => array:1 [ 0 => null ] "host" => array:1 [ 0 => null ] ] ] ] 9 => array:3 [ "identificador" => "bib10" "etiqueta" => "10" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Yu H, Suleiman H, Kim AH, Miner JH, Dani A, Shaw AS, et al. Rac1 activation in podocytes induces rapid foot process effacement and proteinuria. Mol Cell Biol 2013;33(23):4755-64. <a href="http://www.ncbi.nlm.nih.gov/pubmed/24061480" target="_blank">[Pubmed]</a>" "contribucion" => array:1 [ 0 => null ] "host" => array:1 [ 0 => null ] ] ] ] 10 => array:3 [ "identificador" => "bib11" "etiqueta" => "11" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Vollenbroker B, George B, Wolfgart M, Saleem MA, Pavenstadt H, Weide T. mTOR regulates expression of slit diaphragm proteins and cytoskeleton structure in podocytes. Am J Physiol Renal Physiol 2009;296(2):F418-26. <a href="http://www.ncbi.nlm.nih.gov/pubmed/19019920" target="_blank">[Pubmed]</a>" "contribucion" => array:1 [ 0 => null ] "host" => array:1 [ 0 => null ] ] ] ] 11 => array:3 [ "identificador" => "bib12" "etiqueta" => "12" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Lamming DW, Ye L, Katajisto P, Goncalves MD, Saitoh M, Stevens DM, et al. Rapamycin-induced insulin resistance is mediated by mTORC2 loss and uncoupled from longevity. Science 2012;335(6076):1638-43. <a href="http://www.ncbi.nlm.nih.gov/pubmed/22461615" target="_blank">[Pubmed]</a>" "contribucion" => array:1 [ 0 => null ] "host" => array:1 [ 0 => null ] ] ] ] 12 => array:3 [ "identificador" => "bib13" "etiqueta" => "13" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Song G, Ouyang G, Bao S. The activation of Akt/PKB signaling pathway and cell survival. J Cell Mol Med 2005;9(1):59-71. <a href="http://www.ncbi.nlm.nih.gov/pubmed/15784165" target="_blank">[Pubmed]</a>" "contribucion" => array:1 [ 0 => null ] "host" => array:1 [ 0 => null ] ] ] ] 13 => array:3 [ "identificador" => "bib14" "etiqueta" => "14" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Diekmann F, Budde K, Oppenheimer F, Fritsche L, Neumayer HH, Campistol JM. Predictors of success in conversion from calcineurin inhibitor to sirolimus in chronic allograft dysfunction. Am J Transplant 2004;4(11):1869-75. <a href="http://www.ncbi.nlm.nih.gov/pubmed/15476488" target="_blank">[Pubmed]</a>" "contribucion" => array:1 [ 0 => null ] "host" => array:1 [ 0 => null ] ] ] ] ] ] ] ] ] "idiomaDefecto" => "en" "url" => "/20132514/0000003400000004/v0_201502091609/X2013251414054405/v0_201502091609/en/main.assets" "Apartado" => array:4 [ "identificador" => "35428" "tipo" => "SECCION" "en" => array:2 [ "titulo" => "Editorial Comments" "idiomaDefecto" => true ] "idiomaDefecto" => "en" ] "PDF" => "https://static.elsevier.es/multimedia/20132514/0000003400000004/v0_201502091609/X2013251414054405/v0_201502091609/en/P1-E572-S4643-A12381-EN.pdf?idApp=UINPBA000064&text.app=https://revistanefrologia.com/" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/X2013251414054405?idApp=UINPBA000064" ]
| Year/Month | Html | Total | |
|---|---|---|---|
| 2024 November | 1 | 4 | 5 |
| 2024 October | 70 | 31 | 101 |
| 2024 September | 57 | 30 | 87 |
| 2024 August | 66 | 56 | 122 |
| 2024 July | 55 | 28 | 83 |
| 2024 June | 77 | 42 | 119 |
| 2024 May | 90 | 44 | 134 |
| 2024 April | 74 | 36 | 110 |
| 2024 March | 62 | 2254 | 2316 |
| 2024 February | 59 | 41 | 100 |
| 2024 January | 54 | 24 | 78 |
| 2023 December | 72 | 29 | 101 |
| 2023 November | 78 | 45 | 123 |
| 2023 October | 164 | 46 | 210 |
| 2023 September | 328 | 26 | 354 |
| 2023 August | 244 | 27 | 271 |
| 2023 July | 85 | 29 | 114 |
| 2023 June | 143 | 23 | 166 |
| 2023 May | 98 | 35 | 133 |
| 2023 April | 51 | 18 | 69 |
| 2023 March | 55 | 22 | 77 |
| 2023 February | 57 | 20 | 77 |
| 2023 January | 38 | 31 | 69 |
| 2022 December | 66 | 28 | 94 |
| 2022 November | 66 | 31 | 97 |
| 2022 October | 61 | 51 | 112 |
| 2022 September | 52 | 33 | 85 |
| 2022 August | 70 | 48 | 118 |
| 2022 July | 48 | 49 | 97 |
| 2022 June | 62 | 44 | 106 |
| 2022 May | 88 | 29 | 117 |
| 2022 April | 70 | 53 | 123 |
| 2022 March | 70 | 48 | 118 |
| 2022 February | 87 | 53 | 140 |
| 2022 January | 86 | 33 | 119 |
| 2021 December | 75 | 40 | 115 |
| 2021 November | 81 | 31 | 112 |
| 2021 October | 108 | 49 | 157 |
| 2021 September | 66 | 43 | 109 |
| 2021 August | 92 | 37 | 129 |
| 2021 July | 69 | 37 | 106 |
| 2021 June | 66 | 30 | 96 |
| 2021 May | 76 | 48 | 124 |
| 2021 April | 149 | 85 | 234 |
| 2021 March | 126 | 47 | 173 |
| 2021 February | 110 | 31 | 141 |
| 2021 January | 71 | 15 | 86 |
| 2020 December | 79 | 22 | 101 |
| 2020 November | 78 | 18 | 96 |
| 2020 October | 45 | 21 | 66 |
| 2020 September | 64 | 15 | 79 |
| 2020 August | 66 | 14 | 80 |
| 2020 July | 76 | 22 | 98 |
| 2020 June | 66 | 28 | 94 |
| 2020 May | 86 | 17 | 103 |
| 2020 April | 73 | 29 | 102 |
| 2020 March | 74 | 16 | 90 |
| 2020 February | 67 | 20 | 87 |
| 2020 January | 70 | 19 | 89 |
| 2019 December | 92 | 22 | 114 |
| 2019 November | 59 | 19 | 78 |
| 2019 October | 58 | 18 | 76 |
| 2019 September | 56 | 15 | 71 |
| 2019 August | 54 | 27 | 81 |
| 2019 July | 74 | 12 | 86 |
| 2019 June | 85 | 25 | 110 |
| 2019 May | 64 | 19 | 83 |
| 2019 April | 121 | 34 | 155 |
| 2019 March | 82 | 35 | 117 |
| 2019 February | 43 | 25 | 68 |
| 2019 January | 59 | 28 | 87 |
| 2018 December | 155 | 61 | 216 |
| 2018 November | 146 | 21 | 167 |
| 2018 October | 122 | 20 | 142 |
| 2018 September | 176 | 21 | 197 |
| 2018 August | 99 | 15 | 114 |
| 2018 July | 79 | 20 | 99 |
| 2018 June | 95 | 21 | 116 |
| 2018 May | 91 | 15 | 106 |
| 2018 April | 108 | 16 | 124 |
| 2018 March | 78 | 9 | 87 |
| 2018 February | 64 | 13 | 77 |
| 2018 January | 94 | 10 | 104 |
| 2017 December | 87 | 10 | 97 |
| 2017 November | 85 | 19 | 104 |
| 2017 October | 94 | 12 | 106 |
| 2017 September | 61 | 15 | 76 |
| 2017 August | 73 | 13 | 86 |
| 2017 July | 79 | 12 | 91 |
| 2017 June | 75 | 13 | 88 |
| 2017 May | 110 | 19 | 129 |
| 2017 April | 100 | 20 | 120 |
| 2017 March | 78 | 15 | 93 |
| 2017 February | 198 | 11 | 209 |
| 2017 January | 58 | 10 | 68 |
| 2016 December | 111 | 10 | 121 |
| 2016 November | 130 | 15 | 145 |
| 2016 October | 211 | 20 | 231 |
| 2016 September | 335 | 9 | 344 |
| 2016 August | 382 | 4 | 386 |
| 2016 July | 318 | 9 | 327 |
| 2016 June | 253 | 0 | 253 |
| 2016 May | 228 | 0 | 228 |
| 2016 April | 261 | 0 | 261 |
| 2016 March | 210 | 0 | 210 |
| 2016 February | 290 | 0 | 290 |
| 2016 January | 201 | 0 | 201 |
| 2015 December | 184 | 0 | 184 |
| 2015 November | 202 | 0 | 202 |
| 2015 October | 210 | 0 | 210 |
| 2015 September | 165 | 0 | 165 |
| 2015 August | 161 | 0 | 161 |
| 2015 July | 178 | 0 | 178 |
| 2015 June | 119 | 0 | 119 |
| 2015 May | 175 | 0 | 175 |
| 2015 April | 45 | 0 | 45 |
Show all
