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Dimethyl fumarate ameliorates stress urinary incontinence by reversing ECM remodeling via the Nrf2-TGF-β1/Smad3 pathway in mice

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Abstract

Introduction and hypothesis

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.

Methods

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.

Results

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.

Conclusions

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.

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Abbreviations

ARE:

Antioxidant response elements

α-SMA:

Alfa-smooth muscle actin

CAT:

Catalase activity

CMS:

Cyclic mechanical strain

DMF:

Dimethyl fumarate

ECM:

Extracellular matrix

Keap1:

Kelch-like ECH-associated protein 1

LPP:

Leak point pressure

MDA:

Malondialdehyde

MMP:

Matrix metalloproteinase

Nrf2:

Nuclear factor erythroid-2-related factor 2

OS:

Oxidative stress

PAI-1:

Plasminogen activator inhibitor-1

PCNA:

Proliferating cell nuclear antigen

ROS:

Reactive oxygen species

SUI:

Stress urinary incontinence

TGF-β1:

Transforming growth factor-beta1

TIMP:

Tissue inhibitor of metalloproteinase

tSOD:

Total superoxide dismutase

VD:

Vaginal distension

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Acknowledgements

The authors would like to thank all the teachers in the Department of Gynecology and Obstetrics, Central Laboratory and Experimental Animal Center of Renmin Hospital of Wuhan University for their assistance. Thanks to the National Natural Science Foundation of China for funding.

Funding

This study was funded by the National Natural Science Foundation of China (grant no: 81701424).

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Authors and Affiliations

  1. Department of Gynecology and Obstetrics, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei Province, China

    Cheng Liu, Yang Li, Jianming Tang, Shasha Hong & Li Hong

  2. Department of Anesthesiology, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430014, Hubei Province, China

    Ying Wang

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Contributions

Cheng Liu: investigation, data analysis, manuscript writing; Ying Wang: investigation, data analysis, manuscript writing; Yang Li: investigation, data collection; Jianming Tang: methodology; Shasha Hong: data collection; Li Hong: project development.

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Correspondence to Li Hong.

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Liu, C., Wang, Y., Li, Y. et al. Dimethyl fumarate ameliorates stress urinary incontinence by reversing ECM remodeling via the Nrf2-TGF-β1/Smad3 pathway in mice. Int Urogynecol J 33, 1231–1242 (2022). https://doi.org/10.1007/s00192-021-05061-w

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