Cldn4 overexpression promotes penile cavernous smooth muscle cell fibrotic response via the JNK signaling pathway.

IF 4.3 3区 材料科学 Q1 ENGINEERING, ELECTRICAL & ELECTRONIC
Huang Jie, Wang Jie, Guo Yingxue, Zhang Xin, Xu Runnan, Huang Wenjie, Ma Jianxiong, Lv Bodong
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引用次数: 0

Abstract

Background: Erectile dysfunction (ED), defined as the inability to achieve or maintain a penile erection sufficient to satisfy sexual behavior, is prevalent worldwide.

Aim: Using previous research, bioinformatics, and experimental confirmation, we aimed to discover genes that contribute to ED through regulating hypoxia in corpus cavernosum smooth muscle cells (CCSMCs).

Methods: We used the Gene Expression Omnibus to acquire the sequencing data of the corpus cavernosum transcriptome for diabetic ED and nerve injury type ED rats. We intersected the common differentially expressed genes. Further verification was performed using single cell sequencing. Real-time quantitative polymerase chain reaction and immunofluorescence were used to investigate whether the differentially expressed genes are found in the corpus cavernosum. We used induced hypoxia to assess cell viability changes, and we developed a lentivirus overexpressing Cldn4 for in vitro and in vivo experiments to measure changes in JNK signaling, fibrosis, hypoxia, and erectile function.

Outcomes: Our results indicate that targeting the JNK pathway and decreasing local hypoxia may be better options for therapeutic intervention to improve erectile function.

Results: We identified Cldn4 and found its expression increased in the corpora cavernosa of the 2 datasets. In addition, we found that hypoxia can increase the expression of Cldn4, activate the JNK signaling pathway, and exacerbate fibrosis in CCSMCs. Cldn4 overexpression in CCSMCs activated the JNK signaling pathway and increased fibrotic protein expression. Last, rat corpus cavernosum overexpressing Cldn4 activated the JNK signaling pathway, increased local fibrosis, and impaired erectile function.

Clinical implications: Through bioinformatics and in vitro and in vivo experiments, we found that Cldn4 has a negative effect on ED, and targeting Cldn4 may provide new ideas for ED treatment.

Strengths and limitations: Although we have identified Cldn4 as a potential target for ED treatment, we have only conducted preliminary validation on CCMSCs, and we still need to further validate in other cell lines.

Conclusion: CCSMC hypoxia leads to increased Cldn4, in both nerve injury and diabetic ED rat models, and promotes fibrosis by activating the JNK signaling pathway.

Cldn4过表达会通过JNK信号通路促进阴茎海绵体平滑肌细胞纤维化反应。
背景:勃起功能障碍(ED)是指阴茎不能勃起或不能维持勃起以满足性行为,在全球范围内普遍存在。目的:利用以往的研究、生物信息学和实验证实,我们旨在发现通过调节阴茎海绵体平滑肌细胞(CCSMCs)缺氧而导致ED的基因:我们利用基因表达总库(Gene Expression Omnibus)获取了糖尿病 ED 大鼠和神经损伤型 ED 大鼠海绵体转录组的测序数据。我们对常见的差异表达基因进行了交叉分析。我们使用单细胞测序进行了进一步验证。我们使用实时定量聚合酶链反应和免疫荧光来研究差异表达基因是否存在于海绵体中。我们利用诱导缺氧来评估细胞活力的变化,并开发了一种过表达 Cldn4 的慢病毒,用于体外和体内实验,以测量 JNK 信号、纤维化、缺氧和勃起功能的变化:我们的结果表明,针对JNK通路和减少局部缺氧可能是改善勃起功能的更好治疗干预选择:我们发现了 Cldn4,并发现它在两个数据集的阴茎海绵体中表达增加。此外,我们还发现缺氧会增加 Cldn4 的表达、激活 JNK 信号通路并加剧海绵体细胞的纤维化。Cldn4在CCSMCs中的过表达激活了JNK信号通路,增加了纤维化蛋白的表达。最后,大鼠海绵体过表达 Cldn4 会激活 JNK 信号通路,增加局部纤维化,并损害勃起功能:通过生物信息学和体内外实验,我们发现Cldn4对ED有负面影响,靶向Cldn4可能为ED治疗提供新思路:虽然我们发现了Cldn4是治疗ED的潜在靶点,但我们只是在CCMSCs上进行了初步验证,还需要在其他细胞系上进一步验证:结论:在神经损伤和糖尿病 ED 大鼠模型中,CCSMC 缺氧会导致 Cldn4 增加,并通过激活 JNK 信号通路促进纤维化。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
CiteScore
7.20
自引率
4.30%
发文量
567
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