Shenzhen University South China Hospital, Shenzhen University, Shenzhen, 518111, People's Republic of China.
Department of Physiology, Shantou University of Medical College, Shantou, 515041, People's Republic of China.
Mol Med. 2021 Sep 8;27(1):104. doi: 10.1186/s10020-021-00370-8.
The number of patients with diabetes is increasing worldwide. Diabetic testicular damage can cause spermiogenesis disorders and sexual dysfunction. We thus explored the role of miRNAs in diabetic testicular damage, and revealed that they could serve as effective prevention and treatment therapeutic targets.
Streptozotocin (STZ) was used to generate a rat model of type 2 diabetes. Rat testicular tissues were used for miRNA and mRNA sequencing. Through bioinformatics analysis, we constructed an miRNA-mRNA diabetic testicular damage regulatory network and screened for key miRNAs. We also used Leydig cells to generate a diabetic cell model and detected the downstream target genes of miRNAs, secretion of testosterone, and proliferation and apoptotic levels to elucidate the role and mechanism of the selected miRNAs in diabetic testicular damage.
Using second-generation sequencing, we identified 19 differentially expressed miRNAs and 555 mRNAs in the testes of diabetic rats. Based on computational prediction of targets and negative regulation relationships, we constructed a miRNA-mRNA regulatory network, including 12 miRNAs and 215 mRNAs. KEGG enrichment analysis revealed that genes were more concentrated on the survival signalling pathway. Based on this, we screened 2 key miRNAs, miR-504 and miR-935. In vitro, glucose could induce an increase in miR-504 and miR-935, whereas a decrease in MEK5 and MEF2C in a dose-dependent manner. Overexpression of miR-504 and miR-935 led to the decreased expression of MEK5 and MEF2C, decreased proliferation rate of Leydig cells, increased apoptotic rate, and decreased secretion of testosterone. Whereas, knockdown of miR-504 and miR-935 displayed opposite tendencies.
miRNAs play important roles in diabetic testicular damage. miR-504 and miR-935 might regulate testicular damage through the classic survival pathway of MEK5-ERK5-MEF2C. Targeted inhibition of miR-504 and miR-935 could reverse the high-glucose-induced testicular complications, thus posing as a potential therapeutic approach in diabetic testicular injury.
全球范围内糖尿病患者数量不断增加。糖尿病引起的睾丸损伤可导致精子发生障碍和性功能障碍。因此，我们探索了 microRNA 在糖尿病性睾丸损伤中的作用，并揭示了它们可能作为有效的预防和治疗靶点。
采用链脲佐菌素（STZ）建立 2 型糖尿病大鼠模型。采用大鼠睾丸组织进行 microRNA 和 mRNA 测序。通过生物信息学分析，构建了 microRNA-mRNA 糖尿病睾丸损伤调控网络，并筛选关键 microRNA。还利用 Leydig 细胞建立糖尿病细胞模型，检测 microRNA 的下游靶基因、睾酮分泌以及增殖和凋亡水平，以阐明所选 microRNA 在糖尿病性睾丸损伤中的作用和机制。
利用第二代测序技术，我们在糖尿病大鼠睾丸组织中鉴定出 19 个差异表达的 microRNA 和 555 个 mRNA。基于靶基因和负调控关系的计算预测，构建了一个 microRNA-mRNA 调控网络，包括 12 个 microRNA 和 215 个 mRNA。KEGG 富集分析显示，基因更多地集中在生存信号通路。基于此，我们筛选出 2 个关键 microRNA，miR-504 和 miR-935。体外实验中，葡萄糖可呈剂量依赖性诱导 miR-504 和 miR-935 增加，同时导致 MEK5 和 MEF2C 减少。miR-504 和 miR-935 的过表达导致 MEK5 和 MEF2C 的表达减少，Leydig 细胞增殖率降低，凋亡率增加，睾酮分泌减少。相反，miR-504 和 miR-935 的敲低则显示出相反的趋势。
microRNA 在糖尿病性睾丸损伤中发挥重要作用。miR-504 和 miR-935 可能通过 MEK5-ERK5-MEF2C 经典生存途径调节睾丸损伤。靶向抑制 miR-504 和 miR-935 可逆转高葡萄糖诱导的睾丸并发症，因此可能成为糖尿病性睾丸损伤的潜在治疗方法。
