Structural and Functional Biology Department, Biology Institute, University of Campinas, PO Box 6109, 13083-970 Campinas, Sao Paulo, Brazil.
Structural and Functional Biology Department, Biology Institute, University of Campinas, PO Box 6109, 13083-970 Campinas, Sao Paulo, Brazil.
Life Sci. 2018 Jul 15;205:54-62. doi: 10.1016/j.lfs.2018.05.016. Epub 2018 May 9.
Peripheral diabetic neuropathy (DN) manifests in nearly 60% of diabetic patients, being pain its most debilitating symptom. Although electrophysiological and morphological aspects are well described, little is known about its development and progression, undermining effective therapies. Hyperglycemia and insulin signaling impairment are considered the triggering events of oxidative stress observed in the dying nerves, however there are still many gaps in the knowledge of intracellular plastic changes it generates.
In this study we aimed to evaluate the early transcriptome changes in DN when the first symptoms of the disease start to appear.
Next-Generation Sequencing of messenger RNA (RNA-Seq) of L4 and L5 dorsal root ganglia (DRG) four weeks post-diabetes induction in a rat model for type 1 diabetes.
RNA sequencing found 66 transcripts differentially expressed between diabetic and control groups, related mainly to the following biological processes: inflammation, hyperalgesia/analgesia, cell growth and cell survival. Given their roles, the differentially expressed genes suggest an attempt to switch to a survival/regenerative program.
Our results show that changes in the transcriptome profile start to appear early in the course of DN and might be related to secure cell homeostasis. Hence, the present data may indicate how DRG cells are responding to hyperglycemia in its early stages and which mechanisms first fail to respond, further leading to cell damage and cell death. Early screening of cell alterations in DN might lead to more concrete targets for pharmaceutical interventions, which could more efficiently delay cell damage.
周围性糖尿病神经病变（DN）在近 60%的糖尿病患者中表现出来，其最具致残性的症状是疼痛。尽管电生理学和形态学方面的研究已经很充分，但对于其发展和进展知之甚少，这阻碍了有效的治疗方法的出现。高血糖和胰岛素信号转导受损被认为是垂死神经中观察到的氧化应激的触发事件，然而，对于它产生的细胞内可塑性变化的认识仍然存在许多空白。
在本研究中，我们旨在评估当糖尿病开始出现最初症状时，DN 的早期转录组变化。
在 1 型糖尿病大鼠模型中，在糖尿病诱导后 4 周时，对 L4 和 L5 背根神经节（DRG）的信使 RNA（RNA-Seq）进行下一代测序。
RNA 测序发现，糖尿病组和对照组之间有 66 个转录本表达差异，主要与以下生物学过程有关：炎症、痛觉过敏/镇痛、细胞生长和细胞存活。鉴于它们的作用，差异表达的基因表明试图切换到生存/再生程序。
我们的结果表明，DN 病程早期转录组谱的变化就开始出现，这可能与细胞内稳态的安全有关。因此，目前的数据可能表明 DRG 细胞对高血糖的早期反应以及哪些机制首先无法响应，进一步导致细胞损伤和细胞死亡。早期筛查 DN 中的细胞变化可能会为药物干预提供更具体的靶点，从而更有效地延迟细胞损伤。
