Albert Einstein College of Medicine/Montefiore Medical Center
Introduction: Several factors, including dysregulation of urothelial sensory function, have been implicated in the development of diabetic bladder dysfunction (DBD). In this study, we focused on the pannexin 1 (Panx1) channel, a key component of the urothelial mechanosensory-transduction system. We investigated the effects of type 1 diabetes mellitus (DM) on urothelial Panx1 expression and role of Panx1 channels in the characteristic early onset of bladder overactivity in diabetic mice.
Methods: Wildtype (WT) and Panx1-null (Panx1-KO) 3-5-month-old mice were divided into Streptozotocin-induced diabetic [WT(DM); Panx1-KO(DM)] and buffer-injected control [WT(Ctrl); Panx1-KO(Ctrl)] cohorts. The voided stain on paper (VSOP) method was used to assess bladder function longitudinally at baseline and at 1- and 2-weeks following diabetes induction. At VSOP conclusion, animals were euthanized, bladders harvested, and urothelial Panx1 mRNA levels quantified by real time qPCR. Additional cohorts underwent awake urodynamic assessment at 2-weeks following DM induction. Data is expressed as mean±SEM. Statistical differences were determined using the Mann-Whitney test.
Results: Panx1 expression was 30% higher in the bladder urothelium of 2-week WT(DM) compared to WT(Ctrl) (p < 0.05). Although voiding frequency (VF) assessed via VSOP was significantly increased in both WT(DM) and Panx1-KO(DM) mice at 1- and 2-weeks compared to respective controls, this change was 2 to 2.5-fold less in Panx1-KO mice. At 1- and 2-weeks, VF of WT(DM) was 19.0±5.8 (p < 0.01; n=7) and 19.4±3.7 (p < 0.01; n=5) fold higher than WT(Ctrl), whereas VF of Panx1-KO(DM) was 7.7±1.5 (p < 0.05; n=5) and 9.6±1.8 (p < 0.05; n=5) fold higher than Panx1-KO(Ctrl), respectively. Furthermore, urodynamic assessment of 2-week WT(DM) indicated significantly higher frequency [WT(DM): 6.7±0.3 vs WT(Ctrl): 4.2±0.2 void/hr; p<0.0001, n=6 and 5), lower voided volume [WT(DM): 0.2±0.01 vs WT(Ctrl): 0.4±0.04 mL, p<0.0001) and lower bladder capacity [WT(DM): 0.3±0.01 vs WT(Ctrl): 0.4±0.02 mL, p<0.0001) compared to WT(Ctrl). In contrast, urodynamic parameters of 2-week Panx1-KO(DM) compared to Panx1-KO(Ctrl) were not statistically different.
Conclusions: These findings indicate that the absence of Panx1 channels is protective against the early effects of diabetes on bladder function, and that diabetes-induced dysregulation of urothelial Panx1 channels plays a key role in mechanisms leading to bladder overactivity at early stages of diabetes.
Source of Funding: NIH R01 DK122153 (PI: Suadicani)
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