MP30-18 ENHANCED ATP RELEASE AND P2X1R EXPRESSION CONTRIBUTE TO BLADDER DYSFUNCTION IN TYPE 2 DIABETES

Abstract

You have accessJournal of UrologyBladder & Urethra: Anatomy, Physiology & Pharmacology II1 Apr 2016MP30-18 ENHANCED ATP RELEASE AND P2X1R EXPRESSION CONTRIBUTE TO BLADDER DYSFUNCTION IN TYPE 2 DIABETES Zongwei Wang, Vivian Cristofaro, Hongying Cao, Rongbin Ge, Maryrose Sullivian, and Aria Olumi Zongwei WangZongwei Wang More articles by this author , Vivian CristofaroVivian Cristofaro More articles by this author , Hongying CaoHongying Cao More articles by this author , Rongbin GeRongbin Ge More articles by this author , Maryrose SullivianMaryrose Sullivian More articles by this author , and Aria OlumiAria Olumi More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2016.02.1250AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Diabetes bladder dysfunction (DBD) is one of the major urologic complications associated with type 2 diabetes (DM2). We have shown specific molecular alterations in a mouse model that harbors hepatic insulin receptor substrate 1 and 2 deletions (double knockout: DKO) which develops type 2 diabetes. Previously, we have shown that DBD occurs progressively with hyperactivity in the early stage and hypoactivity in late stage of DBD. Here we demonstrate that there is significant ATP release in the early stage of DBD, with an associated increase of the purinergic receptor, P2X1R, in the detrusor muscle. METHODS The functional alterations of bladders from 12 week old DKO and control mice were evaluated by in vivo cystometry, ex vivo cystometry of intact bladder, and ex vivo muscle strip contraction measurement. The ATP release in the lumen of intact bladder during ex vivo cystometry was measured. Bladder histological changes were observed after H&E staining, Masson Trichrome staining and immunohistochemistry (IHC). The purinergic receptors were detected with qPCR at mRNA level and western blot at protein level. RESULTS In anesthetic cystometry test, the post void residual (PVR) urine volume was elevated, the voiding efficiency and bladder compliance were lowered in DKO mice. Urothelium-denuded strips had significantly higher tension than urothelium-intact bladder smooth muscle strips in DKO diabetic animals responding to electrical field stimulation (EFS) and carbachol. There was more ATP released in the lumen of bladder in DKO animals upon EFS and exogenous αβ-meATP stimulation. Bladder compliance upon filling was negatively correlated with ATP release. Evaluation of the purinergic receptors, P2X1, P2X2, P2X3, P2X4, P2X5, P2X6, P2X7, in the detrusor muscle revealed that P2X1R mRNA was increased by 10-folds in the DKO animals compared to age matched control animals. Surprisingly, there was no expression of P2X1R in the urothelium. The P2X1R protein levels were also elevated. P2X1R inhibitor NF279 dramatically suppressed the contractility of bladder strip in DKO animal. No histological alteration was found in DKO bladder. CONCLUSIONS During the hyperactive phase of DBD, reduced bladder compliance is associated with significant ATP release. The purinergic receptor, P2X1R, was selectively expressed in the detrusor muscle and not in the urothelial layer. Our findings signify the importance of the purinergic receptors, particularly P2X1R, which may be considered as a target for therapy during the hyperactive phase of diabetic bladder dysfunction associated with DM2. © 2016FiguresReferencesRelatedDetails Volume 195Issue 4SApril 2016Page: e417-e418 Advertisement Copyright & Permissions© 2016MetricsAuthor Information Zongwei Wang More articles by this author Vivian Cristofaro More articles by this author Hongying Cao More articles by this author Rongbin Ge More articles by this author Maryrose Sullivian More articles by this author Aria Olumi More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...