Diabetes causes NLRP3-dependent barrier dysfunction in mice with detrusor overactivity but not underactivity.
Diabetes causes NLRP3-dependent barrier dysfunction in mice with detrusor overactivity but not underactivity.
复制标题
糖尿病会导致逼尿肌过度活动但不活动不足的小鼠的 NLRP3 依赖性屏障功能障碍。
DOI：
10.1152/ajprenal.00047.2022
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发表时间：
2022
期刊：
影响因子：
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通讯作者：
Purves,JTodd
中科院分区：
文献类型：
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作者：
Odom,MichaelR;HughesJr,FrancisM;Jin,Huixia;Purves,JTodd
大约一半的糖尿病患者会发生糖尿病膀胱功能障碍（DBD）。DBD的开始和进展主要归因于由于葡萄糖失调引起的炎症以及激活含NOD、LRR和pyrin结构域的蛋白3（NLRP 3）炎性体的毒性代谢物的产生。NLRP 3激活导致促炎细胞因子的产生和释放，并导致尿路上皮焦亡，一种程序性细胞坏死的形式，我们假设这会损害尿路上皮屏障的完整性。在这里，我们研究了NLRP 3依赖性炎症如何影响糖尿病进展过程中的屏障功能，使用1型糖尿病雌性秋田小鼠模型，从早期过度活动的逼尿肌表型进展到晚期活动不足，在15和30周，分别。为了确定NLRP 3的特定作用，将秋田小鼠与缺乏NLRP 3基因的小鼠杂交。为了确定屏障功能，使用伊文思蓝染料离体和使用磺基-NHS-生物素体内评估对小分子的渗透性。在15周时，糖尿病小鼠的离体和体内渗透性均增加。尿斑蛋白和紧密连接组分的表达在15周时也显著下调。有趣的是，缺乏NLRP 3基因的糖尿病小鼠没有表现出屏障损伤或屏障基因和蛋白质下调的证据。在30周的时间点，离体和体内屏障损伤以及屏障组分下调在糖尿病小鼠中不再明显，表明在DBD的过度活跃和不活跃阶段之间发生尿路上皮修复或重塑。总的来说，这些发现证明了NLRP 3介导的炎症在与逼尿肌过度活动相关的尿路上皮屏障损伤中的作用，但不是活动不足。新&值得注意的是，这是第一项研究证明NLRP 3介导的炎症是1型糖尿病女性秋田小鼠膀胱过度活动导致尿路上皮屏障损伤的原因。在这些糖尿病小鼠中消除NLRP 3基因可以防止糖尿病导致的屏障损伤。当雌性秋田小鼠发展为活动不足表型时，尿路上皮屏障已经恢复，表明炎症是糖尿病膀胱功能障碍发展早期的关键致病因素。
Approximately half of the patients with diabetes develop diabetic bladder dysfunction (DBD). The initiation and progression of DBD is largely attributed to inflammation due to dysregulated glucose and the production of toxic metabolites that activate the NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) inflammasome. NLRP3 activation leads to the production and release of proinflammatory cytokines and causes urothelial pyroptosis, a form of programmed cell necrosis, which we hypothesize compromises urothelial barrier integrity. Here, we investigated how NLRP3-dependent inflammation impacts barrier function during the progression of diabetes using a type 1 diabetic female Akita mouse model that progresses from an early overactive to a late underactive detrusor phenotype at 15 and 30 wk, respectively. To determine the specific role of NLRP3, Akita mice were crossbred with mice lacking theNLRP3gene. To determine barrier function, permeability to small molecules was assessed, ex vivo using Evans blue dye and in vivo using sulfo-NHS-biotin. Both ex vivo and in vivo permeabilities were increased in diabetic mice at 15 wk. Expression of uroplakin and tight junction components was also significantly downregulated at 15 wk. Interestingly, diabetic mice lacking theNLRP3gene showed no evidence of barrier damage or downregulation of barrier genes and proteins. At the 30-wk time point, ex vivo and in vivo barrier damage as well as barrier component downregulation was no longer evident in diabetic mice, suggesting urothelial repair or remodeling occurs between the overactive and underactive stages of DBD. Collectively, these findings demonstrate the role of NLRP3-mediated inflammation in urothelial barrier damage associated with detrusor overactivity but not underactivity.NEW & NOTEWORTHYThis is the first study to demonstrate that NLRP3-mediated inflammation is responsible for urothelial barrier damage in type 1 diabetic female Akita mice with an overactive bladder. Eliminating the NLRP3 gene in these diabetic mice prevented barrier damage as a result of diabetes. By the time female Akita mice develop an underactive phenotype, the urothelial barrier has been restored, suggesting that inflammation is a critical causative factor early in the development of diabetic bladder dysfunction.