Department of Gynecology and Obstetrics, Renmin Hospital of Wuhan University, 238 Jiefang Road, Wuhan, 430060, Hubei Province, People's Republic of China.
Int Urogynecol J. 2022 Sep;33(9):2565-2576. doi: 10.1007/s00192-022-05325-z. Epub 2022 Aug 13.
Stress urinary incontinence (SUI) is the most common form of urinary incontinence in women, which affects women's quality of life worldwide. Mechanical injury of the pelvic floor may disrupt the pelvic supportive tissues and connections via the remodeling of extracellular matrix (ECM), which is supposed to be one of the main pathological mechanisms of SUI.
The SUI mouse model was established using vaginal distension (VD). Leak point pressure (LPP), maximum cystometric capacity (MCC), collagen, Nrf2 and TGF-β1 in the anterior vaginal wall were measured in either wild-type or Nrf2-knockout (Nrf2/) female C57BL/6 mice with or without puerarin treatment. Then, the mechanical stretching (MS) loaded on L929 cells was generated by a four-point bending device. mTGF-β1 or LY2109761 (an inhibitor of TGF-β1) was used to verify the protective effect of puerarin after Nrf2 knockdown or overexpression.
The collagen content of the anterior vaginal tissues in VD mice and LPP and MCC was decreased significantly. Besides, the expression levels of Nrf2, TGF-β1, collagen I and collagen III of MS group were downregulated in L929 cells. Puerarin pretreatment could reverse mechanical injury-induced collagen downregulation and Nrf2/TGF-β1 signaling inhibition. Moreover, both LY2109761 pretreatment and Nrf2 knockdown could attenuate the protective effect of puerarin in the mechanical injury-induced ECM remodeling, whereas exogenous TGF-β1 could counteract the effect of Nrf2 downregulation.
Puerarin protected fibroblasts from mechanical injury-induced ECM remodeling through the Nrf2/TGF-β1 signaling pathway. This might be a new strategy for the treatment of SUI.
压力性尿失禁（SUI）是全球女性最常见的尿失禁形式，影响着女性的生活质量。盆底组织的机械损伤可能通过细胞外基质（ECM）的重塑来破坏盆底支持组织和连接，这被认为是 SUI 的主要病理机制之一。
通过阴道扩张（VD）建立 SUI 小鼠模型。在野生型或 Nrf2 敲除（Nrf2/-）雌性 C57BL/6 小鼠中，无论是否用葛根素治疗，测量阴道前壁的漏点压力（LPP）、最大膀胱容量（MCC）、胶原蛋白、Nrf2 和 TGF-β1。然后，通过四点弯曲装置产生作用于 L929 细胞的机械拉伸（MS）。使用 mTGF-β1 或 LY2109761（TGF-β1 的抑制剂）来验证 Nrf2 敲低或过表达后葛根素的保护作用。
VD 小鼠阴道前壁组织胶原含量减少，LPP 和 MCC 显著降低。此外，MS 组 L929 细胞中 Nrf2、TGF-β1、胶原 I 和胶原 III 的表达水平下调。葛根素预处理可逆转机械损伤引起的胶原下调和 Nrf2/TGF-β1 信号抑制。此外，LY2109761 预处理和 Nrf2 敲低均可减弱葛根素在机械损伤诱导的 ECM 重塑中的保护作用，而外源性 TGF-β1 可拮抗 Nrf2 下调的作用。
葛根素通过 Nrf2/TGF-β1 信号通路保护成纤维细胞免受机械损伤诱导的 ECM 重塑。这可能是治疗 SUI 的一种新策略。
