Metformin ameliorates bladder dysfunction in a rat model of partial bladder outlet obstruction
Metformin ameliorates bladder dysfunction in a rat model of partial bladder outlet obstruction
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二甲双胍改善部分膀胱出口梗阻大鼠模型的膀胱功能障碍
DOI：
10.1152/ajprenal.00625.2020
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发表时间：
2021-05-01
影响因子：
4.2
通讯作者：
Shi, Benkang
中科院分区：
文献类型：
--
作者：
Chen, Lipeng;Lv, Linchen;Shi, Benkang
膀胱出口梗阻（BOO）最重要的后果是膀胱形态和功能的改变。使用部分BOO（pBOO）大鼠模型，我们发现二甲双胍治疗的大鼠在pBOO后早期（2周）表现出较低的基线压力和较低的炎症反应。二甲双胍在早期阶段治疗pBOO大鼠膀胱中抑制了含有3个炎性体的NLR家族pyrin结构域途径。二甲双胍降低了原代尿路上皮细胞中NLR家族pyrin结构域3的活性。在慢性期（pBOO后9周），二甲双胍治疗可改善膀胱纤维化并改善依从性下降。二甲双胍治疗抑制了Smad3的激活，并补偿了9周pBOO大鼠膀胱中减少的自噬。慢性pBOO膀胱原代成纤维细胞中促纤维化蛋白的上调抑制了自噬，二甲双胍可恢复自噬。沉默AMP活化蛋白激酶或轻链3B后，二甲双胍对成纤维细胞的抗纤维化作用减弱。总之，本研究阐明了口服二甲双胍可缓解pBOO早期膀胱炎症。长期口服二甲双胍可预防pBOO大鼠膀胱的功能和组织学变化。目前的研究表明，二甲双胍可用于预防继发于BOO.NEW & NOTEWORTHY膀胱功能障碍的发展目前在大鼠模型中的研究表明，口服二甲双胍缓解炎症后，部分膀胱出口梗阻在早期阶段和改善膀胱纤维化以及膀胱功能障碍的长期治疗。我们的研究表明二甲双胍是一种潜在的抑制膀胱重塑和缓解膀胱功能障碍的药物。二甲双胍治疗膀胱功能障碍和膀胱纤维化的疗效有待进一步临床试验验证。
Alteration of bladder morphology and function was the most important consequence of bladder outlet obstruction (BOO). Using a rat model of partial BOO (pBOO), we found that rats treated with metformin showed lower baseline pressures with a reduced inflammatory reaction in the early phase (2 wk) after pBOO. The NLR family pyrin domain containing 3 inflammasome pathway was inhibited in pBOO rat bladders with treatment of metformin in the early phase. Metformin reduced the activity of NLR family pyrin domain containing 3 in primary urothelial cells. In the chronic phase (9 wk after pBOO), metformin treatment ameliorated bladder fibrosis and improved the reduced compliance. Treatment with metformin suppressed the activation of Smad3 and compensated the diminished autophagy in 9-wk pBOO rat bladders. Autophagy was inhibited with upregulation of profibrotic proteins in primary fibroblasts from chronic pBOO bladders, which could be restored by administration of metformin. The antifibrotic effects of metformin on fibroblasts were diminished after silencing of AMP-activated protein kinase or light chain 3B. In summary, this study elucidates that oral administration of metformin relieves inflammation in the bladder during the early phase of pBOO. Long-term oral administration of metformin can prevent functional and histological changes in the pBOO rat bladder. The current study suggests that metformin might be used to prevent the development of bladder dysfunction secondary to BOO.NEW & NOTEWORTHY The present study in a rat model showed that oral administration of metformin alleviated inflammation following partial bladder outlet obstruction in the early phase and ameliorated bladder fibrosis as well as bladder dysfunction by long-term treatment. Our study indicated that metformin is a potential drug to inhibit bladder remodeling and alleviate bladder dysfunction. Clinical trials are needed to validate the effect of metformin on the bladder dysfunction and bladder fibrosis in the future.