Role of PKC and CaV1.2 in detrusor overactivity in a model of obesity associated with insulin resistance in mice.

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 dys...

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Autores principales:	Luiz O Leiria, Carolina Sollon, Marina C Calixto, Letícia Lintomen, Fabíola Z Mónica, Gabriel F Anhê, Gilberto De Nucci, Angelina Zanesco, Andrew D Grant, Edson Antunes
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2012
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/3fd31b1e20ca40359c22230386b9b370
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spelling	oai:doaj.org-article:3fd31b1e20ca40359c22230386b9b3702021-11-18T08:09:45ZRole of PKC and CaV1.2 in detrusor overactivity in a model of obesity associated with insulin resistance in mice.1932-620310.1371/journal.pone.0048507https://doaj.org/article/3fd31b1e20ca40359c22230386b9b3702012-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/23144896/?tool=EBIhttps://doaj.org/toc/1932-6203Obesity/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 µM), α,β-methylene ATP (1-10 µM), KCl (1-300 mM), extracellular Ca(2+) (0.01-100 mM) and phorbol-12,13-dibutyrate (PDBu; 0.001-3 µM) 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 µM) 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.Luiz O LeiriaCarolina SollonMarina C CalixtoLetícia LintomenFabíola Z MónicaGabriel F AnhêGilberto De NucciAngelina ZanescoAndrew D GrantEdson AntunesPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 7, Iss 11, p e48507 (2012)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Luiz O Leiria Carolina Sollon Marina C Calixto Letícia Lintomen Fabíola Z Mónica Gabriel F Anhê Gilberto De Nucci Angelina Zanesco Andrew D Grant Edson Antunes Role of PKC and CaV1.2 in detrusor overactivity in a model of obesity associated with insulin resistance in mice.
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 µM), α,β-methylene ATP (1-10 µM), KCl (1-300 mM), extracellular Ca(2+) (0.01-100 mM) and phorbol-12,13-dibutyrate (PDBu; 0.001-3 µM) 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 µM) 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.
format	article
author	Luiz O Leiria Carolina Sollon Marina C Calixto Letícia Lintomen Fabíola Z Mónica Gabriel F Anhê Gilberto De Nucci Angelina Zanesco Andrew D Grant Edson Antunes
author_facet	Luiz O Leiria Carolina Sollon Marina C Calixto Letícia Lintomen Fabíola Z Mónica Gabriel F Anhê Gilberto De Nucci Angelina Zanesco Andrew D Grant Edson Antunes
author_sort	Luiz O Leiria
title	Role of PKC and CaV1.2 in detrusor overactivity in a model of obesity associated with insulin resistance in mice.
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.
publisher	Public Library of Science (PLoS)
publishDate	2012
url	https://doaj.org/article/3fd31b1e20ca40359c22230386b9b370
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Role of PKC and CaV1.2 in detrusor overactivity in a model of obesity associated with insulin resistance in mice.

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