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Transition from Cyclosporine-Induced Renal Dysfunction to Nephrotoxicity in an in Vivo Rat Model

2014Journal article Open access
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dc.contributor.authorSereno, José
dc.contributor.authorRodrigues-Santos, Paulo
dc.contributor.authorVala, Helena
dc.contributor.authorRocha-Pereira, Petronila
dc.contributor.authorAlves, Rui
dc.contributor.authorFernandes, João
dc.contributor.authorSantos-Silva, Alice
dc.contributor.authorCarvalho, Eugénia
dc.contributor.authorTeixeira, Frederico
dc.contributor.authorReis, Flávio
dc.date.accessioned2014-06-02T09:10:54Z
dc.date.available2014-06-02T09:10:54Z
dc.date.issued2014
dc.description.abstractCyclosporin A (CsA), a calcineurin inhibitor, remain the cornerstone of immunosuppressive regimens, regardless of nephrotoxicity, which depends on the duration of drug exposure. The mechanisms and biomarkers underlying the transition from CsA-induced renal dysfunction to nephrotoxicity deserve better elucidation, and would help clinical decisions. This study aimed to clarify these issues, using a rat model of short- and long-term CsA (5 mg/kg bw/day) treatments (3 and 9 weeks, respectively). Renal function was assessed on serum and urine; kidney tissue was used for histopathological characterization and gene and/or protein expression of markers of proliferation, fibrosis and inflammation. In the short-term, creatinine and blood urea nitrogen (BUN) levels increased and clearances decreased, accompanied by glomerular filtration rate (GFR) reduction, but without kidney lesions; at that stage, CsA exposure induced proliferating cell nuclear antigen (PCNA), transforming growth factor beta 1 (TGF-β1), factor nuclear kappa B (NF-κβ) and Tumor Protein P53 (TP53) kidney mRNA up-regulation. In the long-term treatment, renal dysfunction data was accompanied by glomerular and tubulointerstitial lesions, with remarkable kidney mRNA up-regulation of the mammalian target of rapamycin (mTOR) and the antigen identified by monoclonal antibody Ki-67 (Mki67), accompanied by mTOR protein overexpression. Transition from CsA-induced renal dysfunction to nephrotoxicity is accompanied by modification of molecular mechanisms and biomarkers, being mTOR one of the key players for kidney lesion evolution, thus suggesting, by mean of molecular evidences, that early CsA replacement by mTOR inhibitors is indeed the better therapeutic choice to prevent chronic allograft nephropathy.por
dc.description.sponsorshipThis work was supported by the Portuguese Foundation for Science and Technology (SFRH/BD/63962/2009, PTDC/SAU-OSM/104124/2008 and PEST-C/SAU/UI3282/2011) and COMPETE. The study also received a Grant from Sociedade Portuguesa de Diabetologia.por
dc.identifier.citationJosé Sereno, Paulo Rodrigues-Santos, Helena Vala, Petronila Rocha-Pereira, Rui Alves, João Fernandes, Alice Santos-Silva, Eugénia Carvalho, Frederico Teixeira, Flávio Reis (2014). Transition from cyclosporine-induced renal dysfunction to nephrotoxicity in an in vivo rat model. Int. J. Mol. Sci (ISSN 1422-0067). 15: 8979-8997; doi:10.3390/ijms15058979por
dc.identifier.doi10.3390/ijms15058979
dc.identifier.urihttp://hdl.handle.net/10400.19/2181
dc.language.isoengpor
dc.peerreviewedyespor
dc.subjectCyclosporin Apor
dc.subjecttransition from dysfunction to nephrotoxicitypor
dc.subjectbiomarkerspor
dc.subjectfibrosispor
dc.subjectproliferationpor
dc.subjectanimal modelpor
dc.titleTransition from Cyclosporine-Induced Renal Dysfunction to Nephrotoxicity in an in Vivo Rat Modelpor
dc.typejournal article
dspace.entity.typePublication
person.familyNameVala Correia
person.givenNameHelena Maria
person.identifier.ciencia-id7A1E-E85E-FFA4
person.identifier.orcid0000-0001-6829-4867
rcaap.rightsopenAccesspor
rcaap.typearticlepor
relation.isAuthorOfPublicationcdc3d2e2-df06-40ed-8900-1ecbc8a06c8a
relation.isAuthorOfPublication.latestForDiscoverycdc3d2e2-df06-40ed-8900-1ecbc8a06c8a

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