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The effect of rapamycin on TGFβ1 and MMP1 expression in a rabbit model of urethral stricture
1Department of Urology, the Second Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an City, 710004, Shaanxi Province, People's Republic of China.
Purpose:
To investigate the effect of rapamycin on TGFβ1 and MMP1 expression in a rabbit model of urethral stricture.
Methods:
Twenty-four adult New Zealand male rabbits underwent an electrocoagulation of the bulbar urethra with a 13Fr pediatric resectoscope. Then rabbits were randomly divided into three groups: (1) normal control group: normal saline (NS), (2) the vehicle control group: dimethyl sulfoxide (DMSO), and (3) the treatment group: effective-dose rapamycin in DMSO (Ra), with 12, 6, and 6 rabbits in each group, respectively. Drugs were given by urethral irrigation daily for 4 weeks. Urethral tissue was harvested for histological and molecular analyses. TGFβ1 and MMP1 expression levels were evaluated by real-time quantitative PCR and immunohistochemistry.
Results:
Ten, six, and six rabbits were evaluated finally in Ra, DMSO, and NS group, respectively. Histological examination revealed the distribution of fibrosis and the degree of collagen deposition in the Ra group were smaller and slighter than the two control groups. Collagen content was significantly less in the Ra group than in the DMSO group (P < 0.001) and the NS group (P < 0.001). qRT-PCR analysis showed a higher expression of MMP1 mRNA in the Ra group than in the DMSO group (P < 0.001) and the NS group (P < 0.001). Immunohistochemistry showed the protein levels of MMP1 in the Ra group were significantly increased when compared with the DMSO group (P < 0.01) and the NS group (P < 0.01). On the other hand, no statistical difference could be found between every two groups in both mRNA and protein levels of TGFβ1.
Conclusions:
Rapamycin enhances the expression of MMP1 in a rabbit model of urethral stricture, but has no direct effect on the expression of TGFβ1.
Insights
Rapamycin reduced fibrosis in a rabbit urethral stricture model. It increased matrix metalloproteinase-1 (MMP1) but did not affect transforming growth factor-beta 1 (TGFβ1) levels.
Area of Science:
- Urology
- Pharmacology
- Biochemistry
Background:
- Urethral stricture is a significant cause of morbidity.
- Fibrosis and collagen deposition are key pathological features.
- Investigating novel therapeutic targets is crucial for treatment.
Purpose of the Study:
- To evaluate the therapeutic potential of rapamycin in a rabbit model of urethral stricture.
- To determine the effect of rapamycin on transforming growth factor-beta 1 (TGFβ1) and matrix metalloproteinase-1 (MMP1) expression.
Main Methods:
- A rabbit model of urethral stricture was established via electrocoagulation.
- Rabbits were randomized into three groups: normal saline, dimethyl sulfoxide (vehicle), and rapamycin.
- Histological, qRT-PCR, and immunohistochemical analyses were performed on urethral tissues.
Main Results:
- Rapamycin treatment significantly reduced fibrosis and collagen deposition compared to control groups.
- MMP1 mRNA and protein expression were significantly upregulated by rapamycin.
- No significant changes in TGFβ1 mRNA or protein levels were observed with rapamycin treatment.
Conclusions:
- Rapamycin demonstrates antifibrotic effects in a rabbit urethral stricture model.
- The antifibrotic mechanism involves upregulation of MMP1 expression.
- Rapamycin does not directly influence TGFβ1 expression in this model.
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