title: CD154-CD40 T-cell co-stimulation pathway is a key mechanism in kidney ischemia-reperfusion injury.
abstract: Ischemia-reperfusion occurs in a great many clinical settings and contributes to organ failure or dysfunction. CD154-CD40 signaling in leukocyte-endothelial cell interactions or T-cell activation facilitates tissue inflammation and injury. Here we tested a siRNA anti-CD40 in rodent warm and cold ischemia models to check the therapeutic efficacy and anti-inflammatory outcome of in vivo gene silencing. In the warm ischemia model different doses were used, resulting in clear renal function improvement and a structural renoprotective effect. Renal ischemia activated the CD40 gene and protein expression, which was inhibited by intravenous siRNA administration. CD40 gene silencing improved renal inflammatory status, as seen by the reduction of CD68 and CD3 T-cell infiltrates, attenuated pro-inflammatory, and enhanced anti-inflammatory mediators. Furthermore, siRNA administration decreased a spleen pro-inflammatory monocyte subset and reduced TNFα secretion by splenic T cells. In the cold ischemia model with syngeneic and allogeneic renal transplantation, the most effective dose induced similar functional and structural renoprotective effects. Our data show the efficacy of our siRNA in modulating both the local and the systemic inflammatory milieu after an ischemic insult. Thus, CD40 silencing could emerge as a novel therapeutic strategy in solid organ transplantation.
authors.affiliation: Experimental Nephrology, Departament de Ciències Clíniques, Universitat de Barcelona, Institut d'investigació biomedica de Bellvitge (IDIBELL), Hospitalet Llobregat, Barcelona, Spain.
authors.forename: Laura
authors.initials: L
authors.lastname: de Ramon
authors.affiliation: Experimental Nephrology, Departament de Ciències Clíniques, Universitat de Barcelona, Institut d'investigació biomedica de Bellvitge (IDIBELL), Hospitalet Llobregat, Barcelona, Spain.
authors.forename: Elia
authors.initials: E
authors.lastname: Ripoll
authors.affiliation: Experimental Nephrology, Departament de Ciències Clíniques, Universitat de Barcelona, Institut d'investigació biomedica de Bellvitge (IDIBELL), Hospitalet Llobregat, Barcelona, Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: Merino
authors.affiliation: Experimental Nephrology, Departament de Ciències Clíniques, Universitat de Barcelona, Institut d'investigació biomedica de Bellvitge (IDIBELL), Hospitalet Llobregat, Barcelona, Spain.
authors.forename: Marc
authors.initials: M
authors.lastname: Lúcia
authors.affiliation: Medical and Molecular Genetics Center, Institut d'investigació biomedica de Bellvitge (IDIBELL), Hospital Duran i Reynals. Hospitalet Llobregat, Barcelona, Spain.
authors.forename: Josep M
authors.initials: JM
authors.lastname: Aran
authors.affiliation: Institute for Advanced Chemistry of Catalonia (IQAC), Consejo Superior de Investigaciones Científicas (CSIC), Barcelona, Spain.
authors.forename: S
authors.initials: S
authors.lastname: Pérez-Rentero
authors.affiliation: Experimental Nephrology, Departament de Ciències Clíniques, Universitat de Barcelona, Institut d'investigació biomedica de Bellvitge (IDIBELL), Hospitalet Llobregat, Barcelona, Spain.
authors.forename: Nuria
authors.initials: N
authors.lastname: Lloberas
authors.affiliation: Experimental Nephrology, Departament de Ciències Clíniques, Universitat de Barcelona, Institut d'investigació biomedica de Bellvitge (IDIBELL), Hospitalet Llobregat, Barcelona, Spain.|Hospital Universitari de Bellvitge, Hospitalet Llobregat, Barcelona, Spain.
authors.forename: Josep M
authors.initials: JM
authors.lastname: Cruzado
authors.affiliation: Experimental Nephrology, Departament de Ciències Clíniques, Universitat de Barcelona, Institut d'investigació biomedica de Bellvitge (IDIBELL), Hospitalet Llobregat, Barcelona, Spain.|Hospital Universitari de Bellvitge, Hospitalet Llobregat, Barcelona, Spain.
authors.forename: Josep M
authors.initials: JM
authors.lastname: Grinyó
authors.affiliation: Experimental Nephrology, Departament de Ciències Clíniques, Universitat de Barcelona, Institut d'investigació biomedica de Bellvitge (IDIBELL), Hospitalet Llobregat, Barcelona, Spain.|Hospital Universitari de Bellvitge, Hospitalet Llobregat, Barcelona, Spain.
authors.forename: Juan
authors.initials: J
authors.lastname: Torras
mesh_terms: D000818:Animals; D019013:CD40 Antigens / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D023201:CD40 Ligand / Q000276:immunology / Q000378:metabolism*; D050377:Cold Ischemia; D004195:Disease Models, Animal; D018836:Inflammation Mediators / Q000378:metabolism; D007668:Kidney / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D016030:Kidney Transplantation; D008213:Lymphocyte Activation; D008297:Male; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D000067492:RNAi Therapeutics; D011917:Rats, Inbred Lew; D017208:Rats, Wistar; D015427:Reperfusion Injury / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D015398:Signal Transduction; D013154:Spleen / Q000276:immunology / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism*; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D052096:Warm Ischemia
chemical_list: D019013:CD40 Antigens; D018836:Inflammation Mediators; D034741:RNA, Small Interfering; D014409:Tumor Necrosis Factor-alpha; D023201:CD40 Ligand