Protective Role of Nuclear Factor Erythroid-2-Related Factor 2 against Mechanical Trauma-Induced Apoptosis in a Vaginal Distension-Induced Stress Urinary Incontinence Mouse Model

Abstract

Apoptosis and oxidative damage are involved in the pathogenesis and progression of stress urinary incontinence (SUI). Our previous results indicate that cell apoptosis and oxidative damage increase in a mouse model of mechanical injury-induced SUI and in fibroblasts treated with excessive mechanical strain. Nuclear factor erythroid-2-related factor 2 (Nrf2) is a well-characterized global antioxidant gene inducer that can reduce oxidative damage and apoptosis. Therefore, we predicted that Nrf2 may have a protective role in mechanical trauma-induced SUI. To test this hypothesis, a mouse model of vaginal distension- (VD-) induced SUI was established. Leak point pressure (LPP); levels of apoptosis, apoptosis-related proteins, and peroxidation products; and the activities of antioxidative proteins in the anterior vaginal wall were measured in wild-type (Nfe2l2+/+) C57BL/6 mice and Nrf2-knockout mice (Nfe2l2-/-). The results showed that Nrf2 knockout aggravated VD-induced reduction in LPP, increase in cell apoptosis and peroxidation product levels, decrease in antioxidative protein activities, and alterations in apoptosis-related protein levels in the vaginal walls of mice. To further confirm the role of Nrf2 in mechanical trauma-induced apoptosis and SUI, VD was performed on mice overexpressing Nrf2 via in vivo transfection of LV-Nfe2l2. The results showed that Nrf2 overexpression significantly alleviated VD-induced abnormalities in the anterior vaginal wall. Taken together, our data suggested that Nrf2 is a potential protective factor in mechanical trauma-induced apoptosis in a mouse model of SUI. Antioxidative therapy may be a promising treatment for mechanical trauma-related SUI.

CACNA1H downregulation induces skeletal muscle atrophy involving endoplasmic reticulum stress activation and autophagy flux blockade

“…The preparation of total protein lysates and western blotting were performed as described previously 35 . The primary antibody information was as follows: anti-CACNA1H (1:1000, ImmunoWay, YT4773), anti-β-actin (1:1000, Proteintech, 20536-1-AP), anti-MyHC (1:300, RND, MAB4470), anti-GRP78 (1:1000, Proteintech, 11587-1-AP), anti-DDIT3 (1:1000, CST, #5554), anti-SQSTM1 (1:1000, MBL, M162-3), anti-Beclin-1(1:1000, Proteintech, 11306-1-AP), anti-LC3 (1:1000, Proteintech, 14600-1-AP), anti-cytochrome C (1:1000, CST, #11940).…”

Molecular Processes in Stress Urinary Incontinence: A Systematic Review of Human and Animal Studies

“…ECM-related protein expression and serum or urinary biomarkers were examined in 51 studies [ 22 , 23 , 24 , 25 , 26 , 27 , 28 , 30 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 41 , 42 , 45 , 47 , 56 , 59 , 65 , 67 , 70 , 73 , 74 , 75 , 76 , 77 , 78 , 81 , 82 , 85 , 93 , 94 , 96 , 97 , 98 , 99 , 108 , 109 , 111 , 112 , 113 , 114 , 119 , 121 , 122 , 126 , 127 ]. Figure 4 shows an overview of human [ 23 , 24 , 25 , …”

“…Oxidative stress and apoptosis-related genes and proteins were examined in 18 studies [ 31 , 64 , 66 , 94 , 103 , 105 , 106 , 112 , 113 , 114 , 115 , 117 , 119 , 122 , 123 , 126 , 127 , 128 ]. One animal study showed that Nfe2l2 -knockout mice had lower LPPs after vaginal dilatation compared to wild-type C57BL/6J mice and this suggests that this antioxidant gene inducer is a potential protective factor in the development of SUI [ 122 ].…”

Small extracellular vesicles secreted by vaginal fibroblasts exert inhibitory effect in female stress urinary incontinence through regulating the function of fibroblasts

“…It was reported that collagen I and III were reduced in fibroblasts from the SUI patients, and elevated collagen I and III in fibroblasts relieved symptoms of SUI [ 4 , 26 ]. In addition, by regulating proliferation, migration, apoptosis, differentiation and other functions, fibroblasts participated in pathogenesis of various diseases [ 27 – 30 ]. Recently, it was found that human circulating fibrocytes stimulated by PDGF BB (Platelet-derived growth factor-BB) and TGF - β1 (Transforming growth factor-β1) promoted proliferation and migration, and increased collagen I and III synthesis of human dermal fibroblasts [ 15 ].…”