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Role of oxidative stress and soluble guanylate cyclase degradation in micturition dysfunction of insulin resistant obese mice

Grant number: 14/02196-2
Support Opportunities:Scholarships in Brazil - Doctorate
Effective date (Start): August 01, 2014
Effective date (End): July 31, 2017
Field of knowledge:Biological Sciences - Pharmacology
Acordo de Cooperação: Coordination of Improvement of Higher Education Personnel (CAPES)
Principal Investigator:Edson Antunes
Grantee:Eduardo Costa Alexandre
Host Institution: Faculdade de Ciências Médicas (FCM). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil


Clinical studies have shown an association between metabolic syndrome / obesity and lower urinary tract symptoms (LUTS), name given to a group of symptoms affecting the bladder during urine storage and voiding. These symptoms affect thousands of people throughout the world and are related with frequency, urgency, nocturia and often associated with overactive bladder (OAB), which may result in urinary incontinence. Despite epidemiological studies suggest a positive correlation between metabolic syndrome / obesity and LUTS, its pathophysiological mechanisms are still poorly studied. It is a well-estabilished that the urethra smooth muscle plays a pivotal role in the micturition cycle, participating in both urine storage and voiding phases. However, urethra is a neglected structure in the context of overactive bladder. Our group showed recently an impaired urethral smooth muscle (USM) relaxation in obese mice (Alexandre et al., 2014). Briefly, USM relaxations in response to NO and NO donors (S-nitrosoglutathione and glyceryltrinitrate) were markedly reduced in obese mice, which were associated with reduced protein expression of ²1 subunit of soluble guanylate cyclase (sGC) and lower cGMP production, as well as with higher generation of reactive-oxygen species (ROS) in the urethral tissues. Studies report that obese animals express TNF-± in adipose tissue, a proinflammatory cytokine capable of promoting insulin resistence and activation of NADPH oxidase complex. In the present study we hypothesized that OAB in obese animal is due, at least in part, to impairment of urethral relaxations via NO-sGC-cGMP signaling during the voiding phase. Therefore, it is possible that ROS overproduction accounts for sGC degradation. It seems relevant therefore to find the source of the oxidative stress in urethral tissue because it may play an important role in OAB in obese-insulin resistant mice. We propose to study the role of oxidative stress and sGC degradation on the micturition dysfunction of obese insulin resistant mice, with emphasis in urethra. Our specific aims are (1) to investigate the effects of cronic therapy with the antioxidants resveratrol and apocynin in urethral relaxations, ROS production, superoxide anion levels and protein expression of a1 and ²1 subunits of sGC; (2) to evaluate the importance of TNF-a for the micturition dysfunction in obese mice by quantifying this cytokine in urethral tissue and periurethral/perivesical fat and by studying the effects of TNF-a in the uretral smooth muscle reactivity, as well as testing the ability of anti-TNF-a to normalize the urethral dysfunction and molecular changes in the urethral tissues of obese mice; (3) to examine the NADPH oxidase and SOD 1 expression in urethra and periurethral/perivesical fat; (4) to study the expression and activation of key proteins involved in insulin signaling pathway and the effects of metformin (anti-hyperglicemiant agent) on urethral dysfunction and molecular-biochemical alterations. This study is an opportunity to elucidate how obesity and oxidative stress interfere with urethral and bladder functions. Studies aiming to understand the physiopathology of obesity-associated urogenital disorders are also useful to improve therapeutic treatment and prevention of this disorder. (AU)

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Scientific publications (4)
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
ALEXANDRE, EDUARDO C.; CALMASINI, FABIANO B.; DE OLIVEIRA, MARIANA G.; SILVA, FABIO H.; DA SILVA, CARMEM P. V.; ANDRE, DIANA M.; LEONARDO, FLAVIA C.; DELBIN, MARIA A.; ANTUNES, EDSON. Chronic treatment with resveratrol improves overactive bladder in obese mice via antioxidant activity. European Journal of Pharmacology, v. 788, p. 29-36, . (14/02196-2)
ALEXANDRE, EDUARDO C.; DE OLIVEIRA, MARIANA G.; CAMPOS, RAFAEL; KIGUTI, LUIZ R.; CALMASINI, FABIANO B.; SILVA, FABIO H.; GRANT, ANDREW D.; YOSHIMURA, NAOKI; ANTUNES, EDSON. How important is the alpha(1)-adrenoceptor in primate and rodent proximal urethra? Sex differences in the contribution of alpha(1)-adrenoceptor to urethral contractility. AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY, v. 312, n. 6, p. F1026-F1034, . (14/02196-2)
ALEXANDRE, EDUARDO C.; CALMASINI, FABIANO B.; SPONTON, AMANDA C. DA S.; DE OLIVEIRA, MARIANA G.; ANDRE, DIANA M.; SILVA, FABIO H.; DEBIN, MARIA ANDREIA; MONICA, FABIOLA Z.; ANTUNES, EDSON. Influence of the periprostatic adipose tissue in obesity-associated mouse urethral dysfunction and oxidative stress: Effect of resveratrol treatment. European Journal of Pharmacology, v. 836, p. 25-33, . (17/15175-1, 17/04556-4, 14/02196-2)
ALEXANDRE, E. C.; KIGUTI, L. R.; CALMASINI, F. B.; SILVA, F. H.; DA SILVA, K. P.; FERREIRA, R.; RIBEIRO, C. A.; MONICA, F. Z.; PUPO, A. S.; ANTUNES, E.. Mirabegron relaxes urethral smooth muscle by a dual mechanism involving (3)-adrenoceptor activation and (1)-adrenoceptor blockade. British Journal of Pharmacology, v. 173, n. 3, p. 415-428, . (14/02196-2)
Academic Publications
(References retrieved automatically from State of São Paulo Research Institutions)
ALEXANDRE, Eduardo Costa. Lower urinary tract dysfunction in obese mice and new therapeutic alternatives: resveratrol and mirabegron. 2017. Doctoral Thesis - Universidade Estadual de Campinas (UNICAMP). Faculdade de Ciências Médicas Campinas, SP.

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