III. Department of Medicine, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246, Hamburg, Germany.
Hamburg Center for Kidney Health (HCKH), University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Genome Med. 2023 Jan 10;15(1):2. doi: 10.1186/s13073-022-01145-4.
Diabetic nephropathy (DN) is the leading cause of end-stage renal disease, and histopathologic glomerular lesions are among the earliest structural alterations of DN. However, the signaling pathways that initiate these glomerular alterations are incompletely understood.
To delineate the cellular and molecular basis for DN initiation, we performed single-cell and bulk RNA sequencing of renal cells from type 2 diabetes mice (BTBR ob/ob) at the early stage of DN.
Analysis of differentially expressed genes revealed glucose-independent responses in glomerular cell types. The gene regulatory network upstream of glomerular cell programs suggested the activation of mechanosensitive transcriptional pathway MRTF-SRF predominantly taking place in mesangial cells. Importantly, activation of MRTF-SRF transcriptional pathway was also identified in DN glomeruli in independent patient cohort datasets. Furthermore, ex vivo kidney perfusion suggested that the regulation of MRTF-SRF is a common mechanism in response to glomerular hyperfiltration.
Overall, our study presents a comprehensive single-cell transcriptomic landscape of early DN, highlighting mechanosensitive signaling pathways as novel targets of diabetic glomerulopathy.
糖尿病肾病（DN）是终末期肾病的主要原因，肾小球的组织病理学病变是 DN 最早的结构改变之一。然而，启动这些肾小球改变的信号通路尚不完全清楚。
为了描绘 DN 起始的细胞和分子基础，我们对 2 型糖尿病小鼠（BTBR ob/ob）早期 DN 的肾脏细胞进行了单细胞和批量 RNA 测序。
差异表达基因分析显示，肾小球细胞类型存在葡萄糖非依赖性反应。肾小球细胞程序上游的基因调控网络提示，机械敏感转录途径 MRTF-SRF 的激活主要发生在系膜细胞中。重要的是，在独立的患者队列数据集中也发现了 DN 肾小球中 MRTF-SRF 转录途径的激活。此外，离体肾脏灌注提示 MRTF-SRF 的调节是肾小球高滤过的共同机制。
总的来说，我们的研究展示了早期 DN 的全面单细胞转录组图谱，强调了机械敏感信号通路是糖尿病肾小球病的新靶点。
