Department of Endocrinology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, China.
State Key Laboratory of Bioelectronics, School of Biological Science and Medical Engineering, Southeast University, Nanjing, China.
Front Immunol. 2022 Sep 23;13:1006137. doi: 10.3389/fimmu.2022.1006137. eCollection 2022.
Diabetic nephropathy (DN) is the leading cause of death and the greatest risk to the lives of people with advanced diabetes. Yet, the molecular mechanisms underlying its development and progression remain unknown. In this research, we studied the primary pathways driving DN using transcriptome sequencing and immune repertoire analysis. Firstly, we found that the diversity and abundance of the immune repertoire in late DN were significantly increased, while there was no significant change in early DN. Furthermore, B cell-mediated antibody responses may be the leading cause of DN progression. By analyzing master regulators, we found the key DN-driving transcription factors. In the late stage of DN, immune cells, fibroblasts, and epithelial cells were abundant, but other stromal cells were few. Early DN kidneys had a higher tissue stemness score than normal and advanced DN kidneys. We showed that DN progression involves proximal tubular metabolic reprogramming and stemness restoration using Monocle3. Through WGCNA, we found that co-expression modules that regulate DN progression and immune repertoire diversity mainly regulate immune-related signaling pathways. In addition, we also found that early DN had apparent activation of immune-related signaling pathways mainly enriched in immune cells. Finally, we found that activation of fibroblasts is typical of early DN. These results provide a research basis for further exploring the molecular biology and cellular mechanisms of the occurrence and development of DN and provide a theoretical basis for the prevention and treatment of DN.
糖尿病肾病（DN）是导致糖尿病患者死亡的主要原因，也是其生命健康的最大威胁。然而，其发病和进展的分子机制尚不清楚。本研究通过转录组测序和免疫受体库分析，研究了导致 DN 的主要途径。首先，我们发现晚期 DN 中免疫受体库的多样性和丰度显著增加，而早期 DN 则没有明显变化。此外，B 细胞介导的抗体反应可能是 DN 进展的主要原因。通过分析主要调控因子，我们发现了关键的 DN 驱动转录因子。在 DN 的晚期阶段，免疫细胞、成纤维细胞和上皮细胞丰富，但其他基质细胞较少。早期 DN 肾脏的组织干性评分高于正常和晚期 DN 肾脏。我们通过 Monocle3 显示，DN 进展涉及近端肾小管的代谢重编程和干性恢复。通过 WGCNA，我们发现调节 DN 进展和免疫受体库多样性的共表达模块主要调节免疫相关信号通路。此外，我们还发现早期 DN 中明显激活了免疫相关信号通路，主要富集在免疫细胞中。最后，我们发现早期 DN 中存在典型的成纤维细胞激活。这些结果为进一步探索 DN 的发生发展的分子生物学和细胞机制提供了研究基础，并为 DN 的防治提供了理论依据。
