442 A GENETIC ANIMAL MODEL FOR BLADDER DYSFUNCTION ASSOCIATED WITH TYPE 2 DIABETES

Abstract

You have accessJournal of UrologyBladder and Urethra: Anatomy, Physiology and Pharmacology II1 Apr 2010442 A GENETIC ANIMAL MODEL FOR BLADDER DYSFUNCTION ASSOCIATED WITH TYPE 2 DIABETES Zongwei Wang, Vivian Cristofaro, Maryrose Sullivan, Zhiyong Cheng, Morris White, and Aria Olumi Zongwei WangZongwei Wang More articles by this author , Vivian CristofaroVivian Cristofaro More articles by this author , Maryrose SullivanMaryrose Sullivan More articles by this author , Zhiyong ChengZhiyong Cheng More articles by this author , Morris WhiteMorris White More articles by this author , and Aria OlumiAria Olumi More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2010.02.513AboutPDF 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 conditional knockout of Insulin receptor substrates 1 & 2 (Irs1, Irs2), which mimic the diabetic bladder dysfunction in humans. METHODS Conditional hepatocyte knockout Irs1/Irs2 (DKO) mice develop DM2 with hyperglycemia after 5 weeks of age and remain hyperglycemic through 30 weeks of age. Bladders from 6, 10, 14 and 20 week old mice were harvested and bladder muscle strips were analyzed for spontaneous contraction, electrical field stimulation (EFS), and carbachol and KCl stimulation assays. The expression of TNF-alpha, Tumor Necrosis Factor-related apoptosis-inducing ligand (TRAIL), and phosphorylated myosin light chain (pMLC) protein were assessed by Western blot and immunohistochemistry. RESULTS Bladder of 6-week and 10-week old mice demonstrated hyperactivity compared to controls by spontaneous contraction (p<0.001), EFS (p<0.001), carbachol (p<0.01) and KCl (p<0.01) stimulation assays. In contrast, bladder of 14- and 20-week old Irs1/Irs2 DKO mice demonstrated hypoactivity (p<0.05) and under-stimulated (p<0.05) compared to controls The pMLC protein in DKO mice bladder was highly expressed in 6 and 10 week old mice, and significantly reduced in 20-week old mice, which correlates with the hyper- and hypoactivities observed in DKO bladders. Levels of apoptotic mediators, TNF-alpha and TRAIL, were increased in an age-dependent manner, and sustained a higher level in DKO bladders than that in age-matched control. Correction of type 2 diabetes in a triple conditional knockout model (Irs1/Irs2 & FOXO1 conditional hepatocyte knockout animal) restored the spontaneous bladder contractions in elderly animals (p<0.01). CONCLUSIONS DKO mice develop DM2 and their bladder dysfunctions are associated with hyperactivity in early/mid life of the mice, and hypoactivity in late adult life, findings that mimic DM2 in humans. Gradual increase in apoptotic mediators, TNF and TRAIL, in the bladder of DKO mice may account for the progressive bladder dysfunction in DM2. Genetic correction of type 2 diabetes restores spontaneous contractions in the bladder of older mice, suggesting that the secondary complications associated with type 2 diabetes can be corrected. Boston, MA© 2010 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 183Issue 4SApril 2010Page: e175 Advertisement Copyright & Permissions© 2010 by American Urological Association Education and Research, Inc.MetricsAuthor Information Zongwei Wang More articles by this author Vivian Cristofaro More articles by this author Maryrose Sullivan More articles by this author Zhiyong Cheng More articles by this author Morris White More articles by this author Aria Olumi More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...