Transition from Cyclosporine-Induced Renal Dysfunction to Nephrotoxicity in an in Vivo Rat Model
Autor(a) principal: | |
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Data de Publicação: | 2014 |
Outros Autores: | , , , , , , , , |
Tipo de documento: | Artigo |
Idioma: | eng |
Título da fonte: | Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
Texto Completo: | http://hdl.handle.net/10400.19/2181 |
Resumo: | Cyclosporin 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. |
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Transition from Cyclosporine-Induced Renal Dysfunction to Nephrotoxicity in an in Vivo Rat ModelCyclosporin Atransition from dysfunction to nephrotoxicitybiomarkersfibrosisproliferationanimal modelCyclosporin 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.This 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.Repositório Científico do Instituto Politécnico de ViseuSereno, JoséRodrigues-Santos, PauloVala, HelenaRocha-Pereira, PetronilaAlves, RuiFernandes, JoãoSantos-Silva, AliceCarvalho, EugéniaTeixeira, FredericoReis, Flávio2014-06-02T09:10:54Z20142014-01-01T00:00:00Zinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleapplication/pdfhttp://hdl.handle.net/10400.19/2181engJosé 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/ijms1505897910.3390/ijms15058979info:eu-repo/semantics/openAccessreponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãoinstacron:RCAAP2023-01-16T15:25:28Zoai:repositorio.ipv.pt:10400.19/2181Portal AgregadorONGhttps://www.rcaap.pt/oai/openaireopendoar:71602024-03-19T16:41:25.600079Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãofalse |
dc.title.none.fl_str_mv |
Transition from Cyclosporine-Induced Renal Dysfunction to Nephrotoxicity in an in Vivo Rat Model |
title |
Transition from Cyclosporine-Induced Renal Dysfunction to Nephrotoxicity in an in Vivo Rat Model |
spellingShingle |
Transition from Cyclosporine-Induced Renal Dysfunction to Nephrotoxicity in an in Vivo Rat Model Sereno, José Cyclosporin A transition from dysfunction to nephrotoxicity biomarkers fibrosis proliferation animal model |
title_short |
Transition from Cyclosporine-Induced Renal Dysfunction to Nephrotoxicity in an in Vivo Rat Model |
title_full |
Transition from Cyclosporine-Induced Renal Dysfunction to Nephrotoxicity in an in Vivo Rat Model |
title_fullStr |
Transition from Cyclosporine-Induced Renal Dysfunction to Nephrotoxicity in an in Vivo Rat Model |
title_full_unstemmed |
Transition from Cyclosporine-Induced Renal Dysfunction to Nephrotoxicity in an in Vivo Rat Model |
title_sort |
Transition from Cyclosporine-Induced Renal Dysfunction to Nephrotoxicity in an in Vivo Rat Model |
author |
Sereno, José |
author_facet |
Sereno, José Rodrigues-Santos, Paulo Vala, Helena Rocha-Pereira, Petronila Alves, Rui Fernandes, João Santos-Silva, Alice Carvalho, Eugénia Teixeira, Frederico Reis, Flávio |
author_role |
author |
author2 |
Rodrigues-Santos, Paulo Vala, Helena Rocha-Pereira, Petronila Alves, Rui Fernandes, João Santos-Silva, Alice Carvalho, Eugénia Teixeira, Frederico Reis, Flávio |
author2_role |
author author author author author author author author author |
dc.contributor.none.fl_str_mv |
Repositório Científico do Instituto Politécnico de Viseu |
dc.contributor.author.fl_str_mv |
Sereno, José Rodrigues-Santos, Paulo Vala, Helena Rocha-Pereira, Petronila Alves, Rui Fernandes, João Santos-Silva, Alice Carvalho, Eugénia Teixeira, Frederico Reis, Flávio |
dc.subject.por.fl_str_mv |
Cyclosporin A transition from dysfunction to nephrotoxicity biomarkers fibrosis proliferation animal model |
topic |
Cyclosporin A transition from dysfunction to nephrotoxicity biomarkers fibrosis proliferation animal model |
description |
Cyclosporin 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. |
publishDate |
2014 |
dc.date.none.fl_str_mv |
2014-06-02T09:10:54Z 2014 2014-01-01T00:00:00Z |
dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
dc.type.driver.fl_str_mv |
info:eu-repo/semantics/article |
format |
article |
status_str |
publishedVersion |
dc.identifier.uri.fl_str_mv |
http://hdl.handle.net/10400.19/2181 |
url |
http://hdl.handle.net/10400.19/2181 |
dc.language.iso.fl_str_mv |
eng |
language |
eng |
dc.relation.none.fl_str_mv |
José 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/ijms15058979 10.3390/ijms15058979 |
dc.rights.driver.fl_str_mv |
info:eu-repo/semantics/openAccess |
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openAccess |
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