Department of Nephrology, Fourth Hospital of China Medical University, Shenyang, China.
Department of Nephrology, Shenyang Seventh People's Hospital, Shenyang, China.
Acta Diabetol. 2024 Nov;61(11):1455-1474. doi: 10.1007/s00592-024-02312-2. Epub 2024 Jun 19.
Diabetic Kidney Disease (DKD) is a complex disease associated with circadian rhythm and biological clock regulation disorders. Melatonin (MT) is considered a hormone with renal protective effects, but its mechanism of action in DKD is unclear.
We used the GSE151325 dataset from the GEO database for differential gene analysis and further explored related genes and pathways through GO and KEGG analysis and PPI network analysis. Additionally, this study used a type 2 diabetes db/db mouse model and investigated the role of melatonin in DKD and its relationship with clock genes through immunohistochemistry, Western blot, real-time PCR, ELISA, chromatin immunoprecipitation (ChIP), dual-luciferase reporter technology, and liposome transfection technology to study DEC1 siRNA.
Bioinformatics analysis revealed the central position of clock genes such as CLOCK, DEC1, Bhlhe41, CRY1, and RORB in DKD. Their interaction with key inflammatory regulators may reveal melatonin's potential mechanism in treating diabetic kidney disease. Further experimental results showed that melatonin significantly improved the renal pathological changes in db/db mice, reduced body weight and blood sugar, regulated clock genes in renal tissue, and downregulated the TLR2/MyD88/NF-κB signaling pathway. We found that the transcription factor DEC1 can bind to the TLR2 promoter and activate its transcription, while CLOCK's effect is unclear. Liposome transfection experiments further confirmed the effect of DEC1 on the TLR2/MyD88/NF-κB signaling pathway.
Melatonin shows significant renal protective effects by regulating clock genes and downregulating the TLR2/MyD88/NF-κB signaling pathway. The transcription factor DEC1 may become a key regulatory factor for renal inflammation and fibrosis by activating TLR2 promoter transcription. These findings provide new perspectives and directions for the potential application of melatonin in DKD treatment.
糖尿病肾病（DKD）是一种与昼夜节律和生物钟调节紊乱相关的复杂疾病。褪黑素（MT）被认为是一种具有肾脏保护作用的激素，但它在 DKD 中的作用机制尚不清楚。
我们使用 GEO 数据库中的 GSE151325 数据集进行差异基因分析，并通过 GO 和 KEGG 分析以及 PPI 网络分析进一步探讨相关基因和途径。此外，本研究还使用了 2 型糖尿病 db/db 小鼠模型，通过免疫组化、Western blot、实时 PCR、ELISA、染色质免疫沉淀（ChIP）、双荧光素酶报告基因技术和脂质体转染技术，研究了褪黑素在 DKD 中的作用及其与时钟基因的关系，以研究 DEC1 siRNA。
生物信息学分析揭示了时钟基因如 CLOCK、DEC1、Bhlhe41、CRY1 和 RORB 在 DKD 中的中心位置。它们与关键炎症调节因子的相互作用可能揭示了褪黑素在治疗糖尿病肾病中的潜在机制。进一步的实验结果表明，褪黑素显著改善了 db/db 小鼠的肾脏病理变化，降低了体重和血糖，调节了肾脏组织中的时钟基因，并下调了 TLR2/MyD88/NF-κB 信号通路。我们发现转录因子 DEC1 可以与 TLR2 启动子结合并激活其转录，而 CLOCK 的作用尚不清楚。脂质体转染实验进一步证实了 DEC1 对 TLR2/MyD88/NF-κB 信号通路的影响。
褪黑素通过调节时钟基因和下调 TLR2/MyD88/NF-κB 信号通路，显示出显著的肾脏保护作用。转录因子 DEC1 可能通过激活 TLR2 启动子转录成为肾脏炎症和纤维化的关键调节因子。这些发现为褪黑素在 DKD 治疗中的潜在应用提供了新的视角和方向。
