Ziv Radisavljevic, Vivian Cristofaro, Tomasz Golabek, Subbarao V. Yalla and Maryrose P. Sullivan.

Urology Research, VA Boston Healthcare System, Harvard Medical School, Boston, MA

Introduction and Objectives: Signaling processes induced by Angiotensin II (AngII), the effector protein of the renin-angiotensin system, have been implicated in the hypertrophic response in many smooth muscle systems. Mechanical stretch of isolated bladder smooth muscle cells increases autocrine secretion of AngII. Previous studies have shown that caveolae, cholesterol enriched plasmalemmal microdomains involved in signal transduction regulation, mediate the contractile response to several agonists in bladder smooth muscle, including AngII. The goal of this study was to investigate the relationship between the AngII receptor activation and expression of caveolins, the structural proteins of caveolae.

Methods: Urinary bladders were obtained from anesthetized rats and the urothelium was carefully removed. Longitudinal strips were stretched with 1.5 grams of force in vitro in organ bath at 37ºC and equilibrated for 45 min. The amplitude and frequency of spontaneous and AngII (1 mM) induced activity were recorded for 8 hours. Control strips were similarly stretched and unstimulated force was recorded. After 8 hours, total RNA was isolated using RNeasy Kit and real-time PCR was performed to determine the expression of caveolin-1, 2, and 3 genes using Taq-Man probes and specific primers for each gene sequence.

Results: AngII (1 mM) induced a significant up-regulation of gene expression of caveolin-1 (6.6±1.8 fold), caveolin-2 (8.4±3.3 fold) and caveolin-3 (7.9±3.0 fold) in urinary bladder smooth muscle after 8 hours of stimulation in comparison with control non-stimulated samples. AngII significantly increased the amplitude of smooth muscle contraction of bladder tissue during 8 hours of stimulation. Contractile force of bladder tissue progressively and significantly increased during 8 hours of stimulation with AngII in comparison to the control bladder tissue.

Conclusions: AngII significantly increased bladder smooth muscle contraction during 8 hours of stimulation through up-regulation of caveolin-1, 2, and 3 gene expression. These findings may have important implications for pathophysiologic processes linked to alterations in AngII secretion such as the hypertrophic response to bladder outlet obstruction. Thus AngII induced upregulation of caveolin expression may play a substantial role in altered receptor-mediated signaling associated with bladder dysfunction.

Supported by Research Service, Department of Veterans Affairs, Washington, DC

UroToday.com Coverage of SUFU 2007

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