1375 BLADDER DYSFUNCTION ASSOCIATED WITH TYPE 2 DIABETES IS IMPROVED BY INHIBITION OF INFLAMMATORY AND APOPTOTIC MEDIATORS

Abstract

You have accessJournal of UrologyInfections/Inflammation of the Genitourinary Tract: Kidney & Bladder1 Apr 20111375 BLADDER DYSFUNCTION ASSOCIATED WITH TYPE 2 DIABETES IS IMPROVED BY INHIBITION OF INFLAMMATORY AND APOPTOTIC MEDIATORS Zongwei Wang, Zhiyong Cheng, Vivian Cristofaro, Jijun Li, Edward Gong, Klemen Strle, Maryrose Sullivan, Rosalyn Adam, Morris White, and Aria Olumi Zongwei WangZongwei Wang Boston, MA More articles by this author , Zhiyong ChengZhiyong Cheng Boston, MA More articles by this author , Vivian CristofaroVivian Cristofaro Boston, MA More articles by this author , Jijun LiJijun Li Boston, MA More articles by this author , Edward GongEdward Gong Boston, MA More articles by this author , Klemen StrleKlemen Strle Boston, MA More articles by this author , Maryrose SullivanMaryrose Sullivan Boston, MA More articles by this author , Rosalyn AdamRosalyn Adam Boston, MA More articles by this author , Morris WhiteMorris White Boston, MA More articles by this author , and Aria OlumiAria Olumi Boston, MA More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2011.02.1199AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Diabetic bladder dysfunction in type 2 diabetes mellitus (DM2) affects up to 80% of individuals, however, its underlying pathophysiology is poorly understood. Here we demonstrate a genetic mouse model with DM2 with hepatocyte-specific double knockout of Insulin receptor substrates 1 & 2 (DKO), which mimics the diabetic bladder dysfunction in humans. We wish to examine the molecular pathways that lead to diabetic induced cystopathy. METHODS Bladders from 6, 12, 16 and 20 week old DKO/control mice were harvested and functional alterations were evaluated by muscle strip experiment ex vivo and cystometric experiment in vivo. Affymetrix mouse gene chip was employed to evaluate the expression of 45,000 genes. The level of 10 cytokines in serum was determined using the Multiplex kit. The ultrastructure was evaluated by electron microscopy (EM). Cultured Bladder Smooth Muscle Cell (BSMC) contraction in vitro was assayed by collagen gel retraction. The presence of macrophages, extent of apoptosis and expression of specific proteins were assessed with IHC and western blot respectively. RESULTS Young DKO mice exhibited higher amplitudes of tension to different stimuli relative to age-matched controls, while older mice demonstrated lower amplitudes. Bladder baseline pressure and peak voiding pressure was elevated in DKO mice, whereas contractile pressure was maintained. Over 20 inflammatory genes were up-regulated 1.5 fold or greater, most of which belonged to the TNF superfamily. ATPase, Rho GTPase, Rho kinase and other metabolic genes, Caspase-3 and other apoptosis genes were upregulated. In serum, four cytokines, TNF-á, IL-1beta, IL-5 and GMCSF were significantly upregulated. Mitochondria of BSMC in DKO mice were significantly shrunken in older mice, suggesting abnormal energy metabolism in the mice suffering from late stage diabetic cystopathy. TNF-á directly stimulated the contraction of BSMC, and this contraction was inhibited by ROCK inhibitor, MLCK inhibitor or anti-inflammatory agent. Systemic treatment with neutralizing TNFR1 in DKO mice corrected the diabetic cystopathy without affecting serum glucose levels. CONCLUSIONS Our findings demonstrate that hyperactive bladder dysfunction occurs in early/middle aged animals whereas the bladder is hypoactive in older animals. Inhibition of the inflammatory/apoptotic pathways improves bladder function, without alteration of serum glucose. © 2011 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 185Issue 4SApril 2011Page: e549 Advertisement Copyright & Permissions© 2011 by American Urological Association Education and Research, Inc.MetricsAuthor Information Zongwei Wang Boston, MA More articles by this author Zhiyong Cheng Boston, MA More articles by this author Vivian Cristofaro Boston, MA More articles by this author Jijun Li Boston, MA More articles by this author Edward Gong Boston, MA More articles by this author Klemen Strle Boston, MA More articles by this author Maryrose Sullivan Boston, MA More articles by this author Rosalyn Adam Boston, MA More articles by this author Morris White Boston, MA More articles by this author Aria Olumi Boston, MA More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...