National Clinical Research Center for Kidney Disease, Affiliated Jinling Hospital, Medical School, Nanjing University, Nanjing, China.
Department of Nephrology, the First Affiliated Hospital of University of Science and Technology of China, Hefei, China.
BMC Nephrol. 2023 Jun 19;24(1):180. doi: 10.1186/s12882-023-03239-6.
Diabetic kidney disease (DKD) is the most common complication of diabetes mellitus and a leading cause of kidney failure worldwide. Despite its prevalence, the mechanisms underlying early kidney damage in DKD remain poorly understood. In this study, we used single nucleus RNA-seq to construct gene regulatory networks (GRNs) in the kidney cortex of patients with early DKD. By comparing these networks with those of healthy controls, we identify cell type-specific changes in genetic regulation associated with diabetic status. The regulon activities of FXR (NR1H4) and CREB5 were found to be upregulated in kidney proximal convoluted tubule epithelial cells (PCTs), which were validated using immunofluorescence staining in kidney biopsies from DKD patients. In vitro experiments using cultured HK2 cells showed that FXR and CREB5 protected cells from apoptosis and epithelial-mesenchymal transition. Our findings suggest that FXR and CREB5 may be promising targets for early intervention in patients with DKD.
糖尿病肾病（DKD）是糖尿病最常见的并发症，也是全球范围内导致肾衰竭的主要原因。尽管其发病率很高，但 DKD 早期肾脏损伤的机制仍知之甚少。在这项研究中，我们使用单细胞 RNA-seq 构建了早期 DKD 患者肾脏皮质的基因调控网络（GRNs）。通过将这些网络与健康对照组进行比较，我们确定了与糖尿病状态相关的遗传调控的细胞类型特异性变化。在肾脏近端曲管上皮细胞（PCTs）中，FXR（NR1H4）和 CREB5 的调控子活性被发现上调，这在 DKD 患者的肾脏活检免疫荧光染色中得到了验证。使用培养的 HK2 细胞进行的体外实验表明，FXR 和 CREB5 可保护细胞免于凋亡和上皮-间充质转化。我们的研究结果表明，FXR 和 CREB5 可能是 DKD 患者早期干预的有前途的靶点。
