Xu Yao, Zheng Zhihuang, Oswald Marleen Silke, Cheng Guozhe, Liu Jun, Zhai Qidi, Kruegel Ute, Schaefer Michael, Gerhardt Holger, Endlich Nicole, Gollasch Maik, Simm Stefan, Tsvetkov Dmitry
Department of Internal Medicine and Geriatrics, University Medicine Greifswald, 17487, Greifswald, Germany.
Department of Nephrology, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200080, China.
Adv Sci (Weinh). 2025 Sep;12(33):e01175. doi: 10.1002/advs.202501175. Epub 2025 Jun 17.
Chronic kidney disease (CKD) is characterized by persistent inflammation and tubulointerstitial fibrosis leading to end-stage renal disease. Transient receptor potential canonical 6 (TRPC6) channel inhibition mitigates tubular injury and renal fibrosis in murine models of unilateral ureteral obstruction (UUO) and 2-month chronic post-ischemia-reperfusion injury (2m post-I/R). Through integrated analysis of single-cell-RNA-sequencing (scRNA-Seq) data from UUO mice treated with the selective TRPC6 inhibitor SH045, here the renoprotective cell composition and cell type-specific transcriptional programs are defined. We explored translational aspects by conducting an in-depth scRNA-Seq analysis of kidney samples from patients with CKD. These results reveal global transcriptional shifts with a dramatic diversification of inflammatory cells, endothelial cells and fibroblasts. Notably, a distinct subpopulation of novel endothelial cells is delineated, which is termed ECRIN, that regulate inflammatory networks implicating VEGF and GAS signaling pathways. The data also indicates that inhibition of TRPC6 channels triggers a Prnp transcription factor regulatory network, which contributes to the alleviation of renal fibrosis. The key findings are supported at the protein level by immunofluorescence and western blot analysis. We observed similar patterns in the chronic 2m postI/R injury model. These findings provide novel insights into the potential therapeutic benefits of TRPC6 inhibition in CKD.
慢性肾脏病（CKD）的特征是持续炎症和肾小管间质纤维化，最终导致终末期肾病。在单侧输尿管梗阻（UUO）和2个月慢性缺血再灌注损伤（缺血再灌注损伤后2个月）的小鼠模型中，瞬时受体电位阳离子通道亚家族C成员6（TRPC6）通道抑制可减轻肾小管损伤和肾纤维化。通过对用选择性TRPC6抑制剂SH045治疗的UUO小鼠的单细胞RNA测序（scRNA-Seq）数据进行综合分析，确定了肾脏保护细胞组成和细胞类型特异性转录程序。我们通过对CKD患者的肾脏样本进行深入的scRNA-Seq分析来探索转化方面的问题。这些结果揭示了全局转录变化，炎症细胞、内皮细胞和成纤维细胞出现了显著的多样化。值得注意的是，我们划定了一种新的内皮细胞亚群，称为ECRIN，它调节涉及血管内皮生长因子（VEGF）和GAS信号通路的炎症网络。数据还表明，TRPC6通道的抑制触发了一种朊蛋白（Prnp）转录因子调控网络，这有助于减轻肾纤维化。免疫荧光和蛋白质印迹分析在蛋白质水平上支持了这些关键发现。我们在慢性缺血再灌注损伤后2个月的损伤模型中观察到了类似的模式。这些发现为TRPC6抑制在CKD中的潜在治疗益处提供了新的见解。
