Insulin relaxes bladder via PI3K/AKT/eNOS pathway activation in mucosa: unfolded protein response-dependent insulin resistance as a cause of obesity-associated overactive bladder

dc.creatorLeiria, LO
dc.creatorSollon, C
dc.creatorBau, FR
dc.creatorMonica, FZ
dc.creatorD'Ancona, CL
dc.creatorDe Nucci, G
dc.creatorGrant, AD
dc.creatorAnhe, GF
dc.creatorAntunes, E
dc.date2013
dc.dateMAY
dc.date2014-07-30T14:33:45Z
dc.date2015-11-26T16:35:01Z
dc.date2014-07-30T14:33:45Z
dc.date2015-11-26T16:35:01Z
dc.date.accessioned2018-03-28T23:17:23Z
dc.date.available2018-03-28T23:17:23Z
dc.identifierJournal Of Physiology-london. Wiley-blackwell, v. 591, n. 9, n. 2259, n. 2273, 2013.
dc.identifier0022-3751
dc.identifierWOS:000318299200009
dc.identifier10.1113/jphysiol.2013.251843
dc.identifierhttp://www.repositorio.unicamp.br/jspui/handle/REPOSIP/60300
dc.identifierhttp://repositorio.unicamp.br/jspui/handle/REPOSIP/60300
dc.identifier.urihttp://repositorioslatinoamericanos.uchile.cl/handle/2250/1271381
dc.descriptionFundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)
dc.descriptionWe aimed to investigate the role of insulin in the bladder and its relevance for the development of overactive bladder (OAB) in insulin-resistant obese mice. Bladders from male individuals who were involved in multiple organ donations were used. C57BL6/J mice were fed with a high-fat diet for 10 weeks to induce insulin-resistant obesity. Concentrationresponse curves to insulin were performed in human and mouse isolated mucosa-intact and mucosa-denuded bladders. Cystometric study was performed in terminally anaesthetized mice. Western blot was performed in bladders to detect phosphorylated endothelial NO synthase (eNOS) (Ser1177) and the phosphorylated protein kinase AKT (Ser473), as well as the unfolded protein response (UPR) markers TRIB3, CHOP and ATF4. Insulin (1100 nm) produced concentration-dependent mouse and human bladder relaxations that were markedly reduced by mucosal removal or inhibition of the PI3K/AKT/eNOS pathway. In mouse bladders, insulin produced a 3.0-fold increase in cGMP levels (P < 0.05) that was prevented by PI3K/AKT/eNOS pathway inhibition. Phosphoinositide 3-kinase (PI3K) inhibition abolished insulin-induced phosphorylation of AKT and eNOS in bladder mucosa. Obese mice showed greater voiding frequency and non-voiding contractions, indicating overactive detrusor smooth muscle. Insulin failed to relax the bladder or to increase cGMP in the obese group. Insulin-stimulated AKT and eNOS phosphorylation in mucosa was also impaired in obese mice. The UPR markers TRIB3, CHOP and ATF4 were increased in the mucosa of obese mice. The UPR inhibitor 4-phenyl butyric acid normalized all the functional and molecular parameters in obese mice. Our data show that insulin relaxes human and mouse bladder via activation of the PI3K/AKT/eNOS pathway in the bladder mucosa. Endoplasmic reticulum stress-dependent insulin resistance in bladder contributes to OAB in obese mice.
dc.description591
dc.description9
dc.description2259
dc.description2273
dc.descriptionFundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)
dc.descriptionFundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)
dc.languageen
dc.publisherWiley-blackwell
dc.publisherHoboken
dc.publisherEUA
dc.relationJournal Of Physiology-london
dc.relationJ. Physiol.-London
dc.rightsfechado
dc.rightshttp://olabout.wiley.com/WileyCDA/Section/id-406071.html
dc.sourceWeb of Science
dc.subjectUrinary-tract Symptoms
dc.subjectNitric-oxide Synthase
dc.subjectEarly Lactating Rats
dc.subjectMetabolic Syndrome
dc.subjectEndothelial-cells
dc.subjectErectile Dysfunction
dc.subjectAkt Phosphorylation
dc.subjectSignaling Pathways
dc.subjectSmooth-muscle
dc.subjectRisk-factor
dc.titleInsulin relaxes bladder via PI3K/AKT/eNOS pathway activation in mucosa: unfolded protein response-dependent insulin resistance as a cause of obesity-associated overactive bladder
dc.typeArtículos de revistas


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