Pd12-02 Necroptosis of Schwann Cells Contributes to Bladder Dysfunction in Diabetic Male Akita Mice

You have accessJournal of UrologyBladder & Urethra: Anatomy, Physiology & Pharmacology (PD12)1 May 2024PD12-02 NECROPTOSIS OF SCHWANN CELLS CONTRIBUTES TO BLADDER DYSFUNCTION IN DIABETIC MALE AKITA MICE Francis M. Hughes, Michael R. Odom, Aydin A. Gultekin, Janhvi Parsai, Huixia Jin, and J. Todd Purves Francis M. HughesFrancis M. Hughes , Michael R. OdomMichael R. Odom , Aydin A. GultekinAydin A. Gultekin , Janhvi ParsaiJanhvi Parsai , Huixia JinHuixia Jin , and J. Todd PurvesJ. Todd Purves View All Author Informationhttps://doi.org/10.1097/01.JU.0001008772.30001.48.02AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Diabetic bladder dysfunction (DBD) is the most common diabetic complication and it can manifest as bladder overactivity or underactivity. In the Akita mouse model (type 1) females develop inflammation-dependent overactivity while the males develop inflammation-independent underactivity. We have shown the underactivity in the males is due to a decrease in efferent neurotransmitter release. Retraction, or "dying back" of nerve terminals is well-known in diabetic neuropathy which new studies suggest is due to a programmed form of necrosis, known as necroptosis, of Schwann cells. Thus, we hypothesize that necroptosis of Schwann cells in the bladder leads to retraction of cholinergic nerve terminals which causes underactive-like bladder dysfunction in male Akita mice. METHODS: Male Akita mice (diabetics) and strain-matched controls (nondiabetics) were aged to 15 weeks when UAB is evident. Bladders underwent immunocytochemistry for vesicular acetylcholine transporter (VACHT, a marker for cholinergic nerve terminals) or were co-stained for mixed lineage kinase domain-like (MLKL, a marker of necroptosis) and myelin (a marker of Schwann cells), and quantitated. Beginning at 6 weeks of age, groups of diabetic male mice were given an inhibiter of necroptosis (Necrostatin-1) (1.65 mg/kg/day, i.p.) or vehicle. On week 15 urodynamics was performed and compared to age-matched nondiabetic mice. RESULTS: Diabetic male Akita mice demonstrated a significant decrease in the density of cholinergic nerve terminals in the bladder wall (A), consistent with retraction of nerve terminals. Wildtype bladders stained for myelin fibers (a marker of Schwann cells) with a small portion co-staining with MLKL. Co-staining was dramatically increased in the diabetic bladders (B), suggesting increased necroptosis of Schwann cells. To examine the effect of necroptosis on bladder dysfunction, this death process was interrupted by Necrostatin-1 and urodynamics performed. Necrostatin-1 significantly attenuated the diabetic bladder underactivity (increased void volume, decreased frequency; C and D) suggesting necroptosis is playing a critical role in bladder dysfunction in the male Akita mice. CONCLUSIONS: Diabetic bladder dysfunction in male Akita mice is caused, in part, by necroptosis occurring in the Schwann Cells. Download PPT Source of Funding: NIH-RO1 DK117890, NIH-K12 DK100024 © 2024 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 211Issue 5SMay 2024Page: e256 Advertisement Copyright & Permissions© 2024 by American Urological Association Education and Research, Inc.Metrics Author Information Francis M. Hughes More articles by this author Michael R. Odom More articles by this author Aydin A. Gultekin More articles by this author Janhvi Parsai More articles by this author Huixia Jin More articles by this author J. Todd Purves More articles by this author Expand All Advertisement PDF downloadLoading ...