Aspectos moleculares envolvidos na nefrotoxicidade induzida pela cisplatina

Detalhes bibliográficos
Autor(a) principal: Estrela, Gabriel Rufino [UNIFESP]
Data de Publicação: 2017
Tipo de documento: Tese
Idioma: por
Título da fonte: Repositório Institucional da UNIFESP
Texto Completo: https://sucupira.capes.gov.br/sucupira/public/consultas/coleta/trabalhoConclusao/viewTrabalhoConclusao.jsf?popup=true&id_trabalho=5263196
http://repositorio.unifesp.br/handle/11600/50637
Resumo: Cisplatin is one of the antitumor agents most commonly used in chemotherapy, but nephrotoxicity is frequent and one of the limitations of its use. There are several mechanisms that contribute to renal dysfunction following exposure to cisplatin: direct tubular toxicity inducing apoptosis, necrosis and inflammation. Kinin B1 receptor is a receptor induced in inflammatory states, it is known that the increase of TNF-α and IL-1β, as well as the activation of NF-κB are able to regulate the expression of this receptor. Recently our group has shown that deletion and blockage of kinin B1 receptor is able to attenuate cisplatin-induced nephrotoxicity. It is known that clearance of cisplatin is primarily dependent on organic transporters, OCT-2 responsible for the transport of cisplatin into the renal epithelial cell and MATE-1, which is responsible for the extrusion of drug in renal cells. Several studies show that both physical exercise and caloric restriction are excellent tools to attenuate the inflammatory response, reducing apoptosis, cytokine expression, production of reactive oxygen species, increase of antioxidants and anti-inflammatory and anti-apoptotic mediators. Because both B1 receptor deletion and antagonism attenuates cisplatin-induced nephrotoxicity, we have examined whether this protection is due to modulation of influx and efflux of cisplatin into the renal cell. In addition, we used physical exercise and caloric restriction against cisplatin-induced nephrotoxicity to see if both tools are able to attenuate renal toxicity. Cisplatin decreases the expression of OCT-2 and MATE-1 in the kidneys, animals knockouts for the B1 receptor are able to preserve the expression of these transporters and present lower concentration of platinum in renal tissue. Moreover, we observed that both physical exercise and caloric restriction are able to attenuate cisplatin-induced nephrotoxicity, decreasing the expression of pro-inflammatory cytokines and apoptosis. Caloric restriction together with physical exercise increases the expression of PPAR-α, but only the restriction increases the expression of PPAR target genes. The combined treatment of caloric restriction with PPAR-α antagonism does not attenuate acute tubular necrosis, shows no decrease in TNF-α expression, and does not demonstrate a decrease in expression in genes related to intrinsic apoptosis. By this we showed that kinin B1 receptor has a role in nephrotoxicity induced by cisplatin and it is by part due to modulation of organic transporters and that some of benefical effects of caloric restriction is mediated by PPAR- α.
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spelling Aspectos moleculares envolvidos na nefrotoxicidade induzida pela cisplatinaMolecular aspects envolved in cisplatin nephrotoxicityMolecular aspectsCisplatinNephrotoxicityCaloric restrictionReceptor, bradykinin B1ExerciseNefrotoxicidadeCisplatinaExercício físicoRestrição calóricaReceptor B1 de cininasTransportadores orgânicosCisplatin is one of the antitumor agents most commonly used in chemotherapy, but nephrotoxicity is frequent and one of the limitations of its use. There are several mechanisms that contribute to renal dysfunction following exposure to cisplatin: direct tubular toxicity inducing apoptosis, necrosis and inflammation. Kinin B1 receptor is a receptor induced in inflammatory states, it is known that the increase of TNF-α and IL-1β, as well as the activation of NF-κB are able to regulate the expression of this receptor. Recently our group has shown that deletion and blockage of kinin B1 receptor is able to attenuate cisplatin-induced nephrotoxicity. It is known that clearance of cisplatin is primarily dependent on organic transporters, OCT-2 responsible for the transport of cisplatin into the renal epithelial cell and MATE-1, which is responsible for the extrusion of drug in renal cells. Several studies show that both physical exercise and caloric restriction are excellent tools to attenuate the inflammatory response, reducing apoptosis, cytokine expression, production of reactive oxygen species, increase of antioxidants and anti-inflammatory and anti-apoptotic mediators. Because both B1 receptor deletion and antagonism attenuates cisplatin-induced nephrotoxicity, we have examined whether this protection is due to modulation of influx and efflux of cisplatin into the renal cell. In addition, we used physical exercise and caloric restriction against cisplatin-induced nephrotoxicity to see if both tools are able to attenuate renal toxicity. Cisplatin decreases the expression of OCT-2 and MATE-1 in the kidneys, animals knockouts for the B1 receptor are able to preserve the expression of these transporters and present lower concentration of platinum in renal tissue. Moreover, we observed that both physical exercise and caloric restriction are able to attenuate cisplatin-induced nephrotoxicity, decreasing the expression of pro-inflammatory cytokines and apoptosis. Caloric restriction together with physical exercise increases the expression of PPAR-α, but only the restriction increases the expression of PPAR target genes. The combined treatment of caloric restriction with PPAR-α antagonism does not attenuate acute tubular necrosis, shows no decrease in TNF-α expression, and does not demonstrate a decrease in expression in genes related to intrinsic apoptosis. By this we showed that kinin B1 receptor has a role in nephrotoxicity induced by cisplatin and it is by part due to modulation of organic transporters and that some of benefical effects of caloric restriction is mediated by PPAR- α.A cisplatina é um dos agentes antitumorais mais usados em quimioterapia, entretanto a nefrotoxicidade é freqüente e é uma das limitações para o seu uso. Há vários mecanismos que contribuem para a disfunção renal após a exposição à cisplatina: toxicidade tubular direta induzindo apoptose, necrose e inflamação. O receptor B1 de cininas é um receptor induzido em estados inflamatórios, sabe-se que o aumento de TNF-α e IL-1b, assim como a ativação de NF-kB são capazes de regular a expressão desse receptor. Recentemente nosso grupo mostrou que a deleção e o bloqueio do receptor B1 de cininas é capaz de atenuar a nefrotoxicidade induzida pela cisplatina. Sabe-se que o clearance da cisplatina é dependente principalmente dos transportadores orgânicos, o OCT-2 responsável pelo transporte de cisplatina para dentro da célula epitelial renal e o MATE-1 que é responsável pela extrusão da droga da célula renal. Vários trabalhos mostram que tanto o exercício físico como a restrição calórica são ótimas ferramentas para atenuar a resposta inflamatória, diminuindo apoptose, expressão de citocinas, produção de espécies reativas de oxigênio, aumento de antioxidantes e mediadores anti-inflamatórios e anti-apoptóticos. Tendo em vista que tanto a deleção quanto o antagonismo do receptor B1 atenua a nefrotoxicidade induzida pela cisplatina, analisamos se essa proteção é devido a modulação do influxo e efluxo de cisplatina para a célula renal. No mais, utilizamos o exercício físico e a restrição calórica frente a nefrotoxicidade induzida pela cisplatina para ver se ambas as ferramentas são capazes de atenuar a toxicidade renal. A cisplatina diminui a expressão de OCT-2 e MATE-1 nos rins, os animais nocautes para o receptor B1 conseguem preservar a expressão desses transportadores e apresentam menor concentração de platina no tecido renal. No mais, observamos que tanto o exercício físico quanto a restrição calórica, são capazes de atenuar a nefrotoxicidade induzida pela cisplatina, diminuindo a expressão de citocinas pró-inflamatórias e apoptose. A restrição calórica juntamente ao exercício físico aumenta a expressão de PPAR-α, porém apenas a restrição aumenta a expressão dos genes alvos do PPAR. O tratamento combinado de restrição calórica com o antagonismo do PPAR-α não atenua a necrose tubular aguda, não apresenta diminuição na expressão de TNF-α e não demonstra diminuição da expressão nos genes relacionados a apoptose de via intrínseca. Assim mostramos que o papel do receptor B1 frente a nefrotoxicidade causada pela cisplatina é em parte devido a modulação dos transportadores organicos e que a parte dos efeitos benéficos da restrição calórica é mediado pelo PPAR-α.Dados abertos - Sucupira - Teses e dissertações (2017)Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)FAPESP: 2013/062076CAPES: 7191/154Universidade Federal de São Paulo (UNIFESP)Araujo, Ronaldo de Carvalho [UNIFESP]Câmara, Niels Olsen Saraiva [UNIFESP]Barros, Carlos Castilho de [UNIFESP]http://lattes.cnpq.br/8098379714093877http://lattes.cnpq.br/7429609548804288http://lattes.cnpq.br/8650749833791970http://lattes.cnpq.br/2039649004832444Universidade Federal de São Paulo (UNIFESP)Estrela, Gabriel Rufino [UNIFESP]2019-06-19T14:58:12Z2019-06-19T14:58:12Z2017-05-31info:eu-repo/semantics/doctoralThesisinfo:eu-repo/semantics/publishedVersion81 f.application/pdfhttps://sucupira.capes.gov.br/sucupira/public/consultas/coleta/trabalhoConclusao/viewTrabalhoConclusao.jsf?popup=true&id_trabalho=5263196http://repositorio.unifesp.br/handle/11600/50637porSão Pauloinfo:eu-repo/semantics/openAccessreponame:Repositório Institucional da UNIFESPinstname:Universidade Federal de São Paulo (UNIFESP)instacron:UNIFESP2024-08-10T15:26:05Zoai:repositorio.unifesp.br/:11600/50637Repositório InstitucionalPUBhttp://www.repositorio.unifesp.br/oai/requestbiblioteca.csp@unifesp.bropendoar:34652024-08-10T15:26:05Repositório Institucional da UNIFESP - Universidade Federal de São Paulo (UNIFESP)false
dc.title.none.fl_str_mv Aspectos moleculares envolvidos na nefrotoxicidade induzida pela cisplatina
Molecular aspects envolved in cisplatin nephrotoxicity
title Aspectos moleculares envolvidos na nefrotoxicidade induzida pela cisplatina
spellingShingle Aspectos moleculares envolvidos na nefrotoxicidade induzida pela cisplatina
Estrela, Gabriel Rufino [UNIFESP]
Molecular aspects
Cisplatin
Nephrotoxicity
Caloric restriction
Receptor, bradykinin B1
Exercise
Nefrotoxicidade
Cisplatina
Exercício físico
Restrição calórica
Receptor B1 de cininas
Transportadores orgânicos
title_short Aspectos moleculares envolvidos na nefrotoxicidade induzida pela cisplatina
title_full Aspectos moleculares envolvidos na nefrotoxicidade induzida pela cisplatina
title_fullStr Aspectos moleculares envolvidos na nefrotoxicidade induzida pela cisplatina
title_full_unstemmed Aspectos moleculares envolvidos na nefrotoxicidade induzida pela cisplatina
title_sort Aspectos moleculares envolvidos na nefrotoxicidade induzida pela cisplatina
author Estrela, Gabriel Rufino [UNIFESP]
author_facet Estrela, Gabriel Rufino [UNIFESP]
author_role author
dc.contributor.none.fl_str_mv Araujo, Ronaldo de Carvalho [UNIFESP]
Câmara, Niels Olsen Saraiva [UNIFESP]
Barros, Carlos Castilho de [UNIFESP]
http://lattes.cnpq.br/8098379714093877
http://lattes.cnpq.br/7429609548804288
http://lattes.cnpq.br/8650749833791970
http://lattes.cnpq.br/2039649004832444
Universidade Federal de São Paulo (UNIFESP)
dc.contributor.author.fl_str_mv Estrela, Gabriel Rufino [UNIFESP]
dc.subject.por.fl_str_mv Molecular aspects
Cisplatin
Nephrotoxicity
Caloric restriction
Receptor, bradykinin B1
Exercise
Nefrotoxicidade
Cisplatina
Exercício físico
Restrição calórica
Receptor B1 de cininas
Transportadores orgânicos
topic Molecular aspects
Cisplatin
Nephrotoxicity
Caloric restriction
Receptor, bradykinin B1
Exercise
Nefrotoxicidade
Cisplatina
Exercício físico
Restrição calórica
Receptor B1 de cininas
Transportadores orgânicos
description Cisplatin is one of the antitumor agents most commonly used in chemotherapy, but nephrotoxicity is frequent and one of the limitations of its use. There are several mechanisms that contribute to renal dysfunction following exposure to cisplatin: direct tubular toxicity inducing apoptosis, necrosis and inflammation. Kinin B1 receptor is a receptor induced in inflammatory states, it is known that the increase of TNF-α and IL-1β, as well as the activation of NF-κB are able to regulate the expression of this receptor. Recently our group has shown that deletion and blockage of kinin B1 receptor is able to attenuate cisplatin-induced nephrotoxicity. It is known that clearance of cisplatin is primarily dependent on organic transporters, OCT-2 responsible for the transport of cisplatin into the renal epithelial cell and MATE-1, which is responsible for the extrusion of drug in renal cells. Several studies show that both physical exercise and caloric restriction are excellent tools to attenuate the inflammatory response, reducing apoptosis, cytokine expression, production of reactive oxygen species, increase of antioxidants and anti-inflammatory and anti-apoptotic mediators. Because both B1 receptor deletion and antagonism attenuates cisplatin-induced nephrotoxicity, we have examined whether this protection is due to modulation of influx and efflux of cisplatin into the renal cell. In addition, we used physical exercise and caloric restriction against cisplatin-induced nephrotoxicity to see if both tools are able to attenuate renal toxicity. Cisplatin decreases the expression of OCT-2 and MATE-1 in the kidneys, animals knockouts for the B1 receptor are able to preserve the expression of these transporters and present lower concentration of platinum in renal tissue. Moreover, we observed that both physical exercise and caloric restriction are able to attenuate cisplatin-induced nephrotoxicity, decreasing the expression of pro-inflammatory cytokines and apoptosis. Caloric restriction together with physical exercise increases the expression of PPAR-α, but only the restriction increases the expression of PPAR target genes. The combined treatment of caloric restriction with PPAR-α antagonism does not attenuate acute tubular necrosis, shows no decrease in TNF-α expression, and does not demonstrate a decrease in expression in genes related to intrinsic apoptosis. By this we showed that kinin B1 receptor has a role in nephrotoxicity induced by cisplatin and it is by part due to modulation of organic transporters and that some of benefical effects of caloric restriction is mediated by PPAR- α.
publishDate 2017
dc.date.none.fl_str_mv 2017-05-31
2019-06-19T14:58:12Z
2019-06-19T14:58:12Z
dc.type.driver.fl_str_mv info:eu-repo/semantics/doctoralThesis
dc.type.status.fl_str_mv info:eu-repo/semantics/publishedVersion
format doctoralThesis
status_str publishedVersion
dc.identifier.uri.fl_str_mv https://sucupira.capes.gov.br/sucupira/public/consultas/coleta/trabalhoConclusao/viewTrabalhoConclusao.jsf?popup=true&id_trabalho=5263196
http://repositorio.unifesp.br/handle/11600/50637
url https://sucupira.capes.gov.br/sucupira/public/consultas/coleta/trabalhoConclusao/viewTrabalhoConclusao.jsf?popup=true&id_trabalho=5263196
http://repositorio.unifesp.br/handle/11600/50637
dc.language.iso.fl_str_mv por
language por
dc.rights.driver.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv 81 f.
application/pdf
dc.coverage.none.fl_str_mv São Paulo
dc.publisher.none.fl_str_mv Universidade Federal de São Paulo (UNIFESP)
publisher.none.fl_str_mv Universidade Federal de São Paulo (UNIFESP)
dc.source.none.fl_str_mv reponame:Repositório Institucional da UNIFESP
instname:Universidade Federal de São Paulo (UNIFESP)
instacron:UNIFESP
instname_str Universidade Federal de São Paulo (UNIFESP)
instacron_str UNIFESP
institution UNIFESP
reponame_str Repositório Institucional da UNIFESP
collection Repositório Institucional da UNIFESP
repository.name.fl_str_mv Repositório Institucional da UNIFESP - Universidade Federal de São Paulo (UNIFESP)
repository.mail.fl_str_mv biblioteca.csp@unifesp.br
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