Department of Gynecology and Obstetrics, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei Province, China.
Department of Anesthesiology, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430014, Hubei Province, China.
Int Urogynecol J. 2022 May;33(5):1231-1242. doi: 10.1007/s00192-021-05061-w. Epub 2022 Jan 4.
Mechanical trauma and oxidative injury are involved in the pathogenesis of stress urinary incontinence (SUI), and oxidative stress (OS) is considered a potential therapeutic target. The antioxidant properties of dimethyl fumarate (DMF), a potent activator of Nrf2, have been highlighted recently. We therefore predicted that DMF might have therapeutic effects on mechanical trauma-induced SUI.
The SUI mice model was established by vaginal distension (VD). Leak point pressure (LPP), serum OS biomarkers, cell proliferation and apoptosis, collagen, elastin, matrix metalloproteinases (MMP), Nrf2, the TGF-β1/Smad3 signaling pathway, and the associated tissue growth factors in the anterior vaginal wall were measured in either wild-type or Nrf2-knockout (Nrf2/) female C57BL/6 mice.
The results showed that DMF improved the VD-induced LPP reduction, alleviated oxidative injury, stimulated cell proliferation and inhibited apoptosis in the anterior vaginal wall tissue of mice. Moreover, DMF treatment reduced the hydrolysis of ECM proteins by MMP2 and MMP9. The above effects may be mediated by a series of tissue growth factors, including α-SMA, PAI-1, and TIMP-2, with the TGF-β1/Smad3 signaling pathway as the core regulatory mechanism. In further study, Nrf2/ mice were used to replicate the SUI model. And the difference is that DMF failed to reactivate the TGF-β1/Smad3 pathway, nor did it improve LPP.
Dimethyl fumarate can ameliorate urethra closure dysfunction in the VD-induced SUI mice model, and the therapeutic effect of DMF is mediated by the Nrf2-dominated antioxidant system and its downstream TGF-β1/Smad3 signaling pathway.
机械性损伤和氧化损伤与压力性尿失禁（SUI）的发病机制有关，氧化应激（OS）被认为是一个潜在的治疗靶点。富马酸二甲酯（DMF）是 Nrf2 的有效激活剂，具有抗氧化特性。因此，我们预测 DMF 可能对机械性损伤引起的 SUI 具有治疗作用。
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 小鼠中测量漏点压（LPP）、血清 OS 生物标志物、细胞增殖和凋亡、胶原蛋白、弹性蛋白、基质金属蛋白酶（MMP）、Nrf2、TGF-β1/Smad3 信号通路以及前阴道壁的相关组织生长因子。
结果表明，DMF 改善了 VD 引起的 LPP 降低，减轻了氧化损伤，刺激了小鼠前阴道壁组织的细胞增殖并抑制了细胞凋亡。此外，DMF 治疗降低了 MMP2 和 MMP9 对 ECM 蛋白的水解。上述作用可能是通过一系列组织生长因子介导的，包括α-SMA、PAI-1 和 TIMP-2，以 TGF-β1/Smad3 信号通路为核心调节机制。在进一步的研究中，使用 Nrf2/小鼠复制 SUI 模型。不同的是，DMF 未能重新激活 TGF-β1/Smad3 通路，也未能改善 LPP。
富马酸二甲酯可改善 VD 诱导的 SUI 小鼠模型中的尿道闭合功能障碍，DMF 的治疗作用是通过 Nrf2 主导的抗氧化系统及其下游 TGF-β1/Smad3 信号通路介导的。
