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Urothelium released ATP is increased in bladder dysfunction associated with type 2 diabetes
Zongwei Wang, PhD1, Vivian Cristofaro, PhD2, Zhiyong Cheng, PhD3, Xingyuan Xiao, M.D, PhD.1, Rongbin Ge, M.D, PhD.1, Maryrose Sullivan, PhD2, Morris White, PhD3, Aria F. Olumi, M.D.1.
1MGH, Boston, MA, USA, 2VA Boston Healthcare System, Boston, MA, USA, 3Children's Hospital, Boston, MA, USA.

BACKGROUND:
Diabetes bladder dysfunction is one of the major urologic complications associated with type 2 diabetes (DM2). However, the molecular mechanisms underlying diabetic bladder dysfunction are poorly understood. Here, we demonstrate that in the early stage of diabetic cystopathy, there is increased release of ATP from urothelial cells.
METHODS:
Bladders from 12 and 20 week old DKO/ floxed control mice were harvested and functional alterations were evaluated by in vivo cystometry, ex vivo cystometry of intact bladder, and ex vivo muscle strip contraction measurement. Urothelial ATP release was determined in ex vivo whole bladders.
RESULTS:
The DKO mice developed insulin resistance and systemic hyperglycemia starting from 5 weeks old, and growth retardation and decreased bladder weight, but the ratio of bladder weight/body weight was similar to control. The post void residual (PVR) urine volume in in vivo cystometry was elevated, the voiding efficiency was lowered in DKO animals both at the age of 12 week and 20 week in DKO mice compared with age matched controls. The bladder compliance of 12 week but not 20 week DKO mice was lower than age-matched controls. Similar bladder capacity was found in both groups. Bladder strip contractility assays showed that urothelium-intact bladder smooth muscle strips had higher tension than urothelium-denuded strips in DKO animal upon stimulation with electrical field (EFS) or carbachol, whereas there was no significant difference for control group. Ex vivo cystometry on whole bladders showed that EFS and exogenous α-β-meATP stimulation resulted in more ATP release in 12 week DKO animal than that in age-matched control. The amount of released ATP was inversely correlated with bladder compliance.

CONCLUSIONS:
Urothelial ATP release is significantly increased during the excitatory (hyperactive) phase of diabetic bladder dysfunction.
Funding: AUA, NIH


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