Role of PKC and CaV1.2 in Detrusor Overactivity in a Model of Obesity Associated with Insulin Resistance in Mice
Autor(a) principal: | |
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Data de Publicação: | 2012 |
Outros Autores: | , , , , , , , , |
Tipo de documento: | Artigo |
Idioma: | eng |
Título da fonte: | Repositório Institucional da UNESP |
Texto Completo: | http://dx.doi.org/10.1371/journal.pone.0048507 http://hdl.handle.net/11449/20922 |
Resumo: | Obesity/metabolic syndrome are common risk factors for overactive bladder. This study aimed to investigate the functional and molecular changes of detrusor smooth muscle (DSM) in high-fat insulin resistant obese mice, focusing on the role of protein kinase C (PKC) and Ca(v)1.2 in causing bladder dysfunction. Male C57BL/6 mice were fed with high-fat diet for 10 weeks. In vitro functional responses and cystometry, as well as PKC and Ca(v)1.2 expression in bladder were evaluated. Obese mice exhibited higher body weight, epididymal fat mass, fasting glucose and insulin resistance. Carbachol (0.001-100 mu M), alpha,beta-methylene ATP (1-10 mu M), KCl (1-300 mM), extracellular Ca2+ (0.01-100 mM) and phorbol-12,13-dibutyrate (PDBu; 0.001-3 mu M) all produced greater DSM contractions in obese mice, which were fully reversed by the Ca(v)1.2 blocker amlodipine. Cystometry evidenced augmented frequency, non-void contractions and post-void pressure in obese mice that were also prevented by amlodipine. Metformin treatment improved the insulin sensitivity, and normalized the in vitro bladder hypercontractility and cystometric dysfunction in obese mice. The PKC inhibitor GF109203X (1 mu M) also reduced the carbachol induced contractions. PKC protein expression was markedly higher in bladder tissues from obese mice, which was normalized by metformin treatment. The Ca(v)1.2 channel protein expression was not modified in any experimental group. Our findings show that Ca(v)1.2 blockade and improvement of insulin sensitization restores the enhanced PKC protein expression in bladder tissues and normalizes the overactive detrusor. It is likely that insulin resistance importantly contributes for the pathophysiology of this urological disorder in obese mice. |
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Role of PKC and CaV1.2 in Detrusor Overactivity in a Model of Obesity Associated with Insulin Resistance in MiceObesity/metabolic syndrome are common risk factors for overactive bladder. This study aimed to investigate the functional and molecular changes of detrusor smooth muscle (DSM) in high-fat insulin resistant obese mice, focusing on the role of protein kinase C (PKC) and Ca(v)1.2 in causing bladder dysfunction. Male C57BL/6 mice were fed with high-fat diet for 10 weeks. In vitro functional responses and cystometry, as well as PKC and Ca(v)1.2 expression in bladder were evaluated. Obese mice exhibited higher body weight, epididymal fat mass, fasting glucose and insulin resistance. Carbachol (0.001-100 mu M), alpha,beta-methylene ATP (1-10 mu M), KCl (1-300 mM), extracellular Ca2+ (0.01-100 mM) and phorbol-12,13-dibutyrate (PDBu; 0.001-3 mu M) all produced greater DSM contractions in obese mice, which were fully reversed by the Ca(v)1.2 blocker amlodipine. Cystometry evidenced augmented frequency, non-void contractions and post-void pressure in obese mice that were also prevented by amlodipine. Metformin treatment improved the insulin sensitivity, and normalized the in vitro bladder hypercontractility and cystometric dysfunction in obese mice. The PKC inhibitor GF109203X (1 mu M) also reduced the carbachol induced contractions. PKC protein expression was markedly higher in bladder tissues from obese mice, which was normalized by metformin treatment. The Ca(v)1.2 channel protein expression was not modified in any experimental group. Our findings show that Ca(v)1.2 blockade and improvement of insulin sensitization restores the enhanced PKC protein expression in bladder tissues and normalizes the overactive detrusor. It is likely that insulin resistance importantly contributes for the pathophysiology of this urological disorder in obese mice.Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Univ Campinas UNICAMP, Fac Med Sci, Dept Pharmacol, São Paulo, BrazilUniv São Paulo State UNESP, Dept Phys Educ, Inst Biosci, São Paulo, BrazilKings Coll London, Wolfson Ctr Age Related Dis, London WC2R 2LS, EnglandUniv São Paulo State UNESP, Dept Phys Educ, Inst Biosci, São Paulo, BrazilFAPESP: 10/01452-4Public Library ScienceUniversidade Estadual de Campinas (UNICAMP)Universidade Estadual Paulista (Unesp)Kings Coll LondonLeiria, Luiz O.Sollon, CarolinaCalixto, Marina C.Lintomen, LeticiaMonica, Fabiola Z.Anhe, Gabriel F.De Nucci, GilbertoZanesco, Angelina [UNESP]Grant, Andrew D.Antunes, Edson2013-09-30T18:49:33Z2014-05-20T13:58:56Z2013-09-30T18:49:33Z2014-05-20T13:58:56Z2012-11-07info:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/article12application/pdfhttp://dx.doi.org/10.1371/journal.pone.0048507Plos One. San Francisco: Public Library Science, v. 7, n. 11, p. 12, 2012.1932-6203http://hdl.handle.net/11449/2092210.1371/journal.pone.0048507WOS:000311935800071WOS000311935800071.pdf4472007237545596Web of Sciencereponame:Repositório Institucional da UNESPinstname:Universidade Estadual Paulista (UNESP)instacron:UNESPengPLOS ONE2.7661,164info:eu-repo/semantics/openAccess2023-12-25T06:17:20Zoai:repositorio.unesp.br:11449/20922Repositório InstitucionalPUBhttp://repositorio.unesp.br/oai/requestopendoar:29462023-12-25T06:17:20Repositório Institucional da UNESP - Universidade Estadual Paulista (UNESP)false |
dc.title.none.fl_str_mv |
Role of PKC and CaV1.2 in Detrusor Overactivity in a Model of Obesity Associated with Insulin Resistance in Mice |
title |
Role of PKC and CaV1.2 in Detrusor Overactivity in a Model of Obesity Associated with Insulin Resistance in Mice |
spellingShingle |
Role of PKC and CaV1.2 in Detrusor Overactivity in a Model of Obesity Associated with Insulin Resistance in Mice Leiria, Luiz O. |
title_short |
Role of PKC and CaV1.2 in Detrusor Overactivity in a Model of Obesity Associated with Insulin Resistance in Mice |
title_full |
Role of PKC and CaV1.2 in Detrusor Overactivity in a Model of Obesity Associated with Insulin Resistance in Mice |
title_fullStr |
Role of PKC and CaV1.2 in Detrusor Overactivity in a Model of Obesity Associated with Insulin Resistance in Mice |
title_full_unstemmed |
Role of PKC and CaV1.2 in Detrusor Overactivity in a Model of Obesity Associated with Insulin Resistance in Mice |
title_sort |
Role of PKC and CaV1.2 in Detrusor Overactivity in a Model of Obesity Associated with Insulin Resistance in Mice |
author |
Leiria, Luiz O. |
author_facet |
Leiria, Luiz O. Sollon, Carolina Calixto, Marina C. Lintomen, Leticia Monica, Fabiola Z. Anhe, Gabriel F. De Nucci, Gilberto Zanesco, Angelina [UNESP] Grant, Andrew D. Antunes, Edson |
author_role |
author |
author2 |
Sollon, Carolina Calixto, Marina C. Lintomen, Leticia Monica, Fabiola Z. Anhe, Gabriel F. De Nucci, Gilberto Zanesco, Angelina [UNESP] Grant, Andrew D. Antunes, Edson |
author2_role |
author author author author author author author author author |
dc.contributor.none.fl_str_mv |
Universidade Estadual de Campinas (UNICAMP) Universidade Estadual Paulista (Unesp) Kings Coll London |
dc.contributor.author.fl_str_mv |
Leiria, Luiz O. Sollon, Carolina Calixto, Marina C. Lintomen, Leticia Monica, Fabiola Z. Anhe, Gabriel F. De Nucci, Gilberto Zanesco, Angelina [UNESP] Grant, Andrew D. Antunes, Edson |
description |
Obesity/metabolic syndrome are common risk factors for overactive bladder. This study aimed to investigate the functional and molecular changes of detrusor smooth muscle (DSM) in high-fat insulin resistant obese mice, focusing on the role of protein kinase C (PKC) and Ca(v)1.2 in causing bladder dysfunction. Male C57BL/6 mice were fed with high-fat diet for 10 weeks. In vitro functional responses and cystometry, as well as PKC and Ca(v)1.2 expression in bladder were evaluated. Obese mice exhibited higher body weight, epididymal fat mass, fasting glucose and insulin resistance. Carbachol (0.001-100 mu M), alpha,beta-methylene ATP (1-10 mu M), KCl (1-300 mM), extracellular Ca2+ (0.01-100 mM) and phorbol-12,13-dibutyrate (PDBu; 0.001-3 mu M) all produced greater DSM contractions in obese mice, which were fully reversed by the Ca(v)1.2 blocker amlodipine. Cystometry evidenced augmented frequency, non-void contractions and post-void pressure in obese mice that were also prevented by amlodipine. Metformin treatment improved the insulin sensitivity, and normalized the in vitro bladder hypercontractility and cystometric dysfunction in obese mice. The PKC inhibitor GF109203X (1 mu M) also reduced the carbachol induced contractions. PKC protein expression was markedly higher in bladder tissues from obese mice, which was normalized by metformin treatment. The Ca(v)1.2 channel protein expression was not modified in any experimental group. Our findings show that Ca(v)1.2 blockade and improvement of insulin sensitization restores the enhanced PKC protein expression in bladder tissues and normalizes the overactive detrusor. It is likely that insulin resistance importantly contributes for the pathophysiology of this urological disorder in obese mice. |
publishDate |
2012 |
dc.date.none.fl_str_mv |
2012-11-07 2013-09-30T18:49:33Z 2013-09-30T18:49:33Z 2014-05-20T13:58:56Z 2014-05-20T13:58:56Z |
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://dx.doi.org/10.1371/journal.pone.0048507 Plos One. San Francisco: Public Library Science, v. 7, n. 11, p. 12, 2012. 1932-6203 http://hdl.handle.net/11449/20922 10.1371/journal.pone.0048507 WOS:000311935800071 WOS000311935800071.pdf 4472007237545596 |
url |
http://dx.doi.org/10.1371/journal.pone.0048507 http://hdl.handle.net/11449/20922 |
identifier_str_mv |
Plos One. San Francisco: Public Library Science, v. 7, n. 11, p. 12, 2012. 1932-6203 10.1371/journal.pone.0048507 WOS:000311935800071 WOS000311935800071.pdf 4472007237545596 |
dc.language.iso.fl_str_mv |
eng |
language |
eng |
dc.relation.none.fl_str_mv |
PLOS ONE 2.766 1,164 |
dc.rights.driver.fl_str_mv |
info:eu-repo/semantics/openAccess |
eu_rights_str_mv |
openAccess |
dc.format.none.fl_str_mv |
12 application/pdf |
dc.publisher.none.fl_str_mv |
Public Library Science |
publisher.none.fl_str_mv |
Public Library Science |
dc.source.none.fl_str_mv |
Web of Science reponame:Repositório Institucional da UNESP instname:Universidade Estadual Paulista (UNESP) instacron:UNESP |
instname_str |
Universidade Estadual Paulista (UNESP) |
instacron_str |
UNESP |
institution |
UNESP |
reponame_str |
Repositório Institucional da UNESP |
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Repositório Institucional da UNESP |
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Repositório Institucional da UNESP - Universidade Estadual Paulista (UNESP) |
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