Gaudet Alexandre, Zheng Xiaoyi, Kambham Neeraja, Bhalla Vivek
bioRxiv. 2023 Mar 2:2023.03.01.530562. doi: 10.1101/2023.03.01.530562.
Esm-1, endothelial cell-specific molecule-1, is a susceptibility gene for diabetic kidney disease (DKD) and is a cytokine- and glucose-regulated, secreted proteoglycan, that is notably expressed in kidney and attenuates inflammation and albuminuria. has restricted expression at the vascular tip during development but little is known about its expression pattern in mature tissues, and its precise effects in diabetes.
We utilized publicly available single-cell RNA sequencing data to explore the characteristics of expression in 27,786 renal endothelial cells obtained from four adult human and three mouse databases. We validated our findings using bulk transcriptome data from an additional 20 healthy subjects and 41 patients with DKD and using RNAscope. Using correlation matrices, we relate Esm1 expression to the glomerular transcriptome and evaluated these matrices with systemic over-expression of Esm-1.
In both mice and humans, is expressed in a subset of all renal endothelial cell types and represents a minority of glomerular endothelial cells. In patients, (+) cells exhibit a highly conserved enrichment for blood vessel development genes. With diabetes, these cells are fewer in number and profoundly shift expression to reflect chemotaxis pathways. Analysis of these gene sets highlight candidate genes such as for cross talk between cell types. We also find that diabetes induces correlations in the expression of large clusters of genes, within cell type-enriched transcripts. significantly correlates with a majority genes within these clusters, delineating a glomerular transcriptional polarization reflected by the magnitude of deficiency. In diabetic mice, these gene clusters link expression to albuminuria, and over-expression of Esm-1 reverses the expression pattern in many of these genes.
A comprehensive analysis of single cell and bulk transcriptomes demonstrates that diabetes correlates with lower expression and with changes in the functional characterization of (+) cells. is both a marker for glomerular transcriptional polarization, and a mediator that re-orients the transcriptional program in DKD.
Esm-1，即内皮细胞特异性分子-1，是糖尿病肾病（DKD）的一个易感基因，是一种受细胞因子和葡萄糖调节的分泌型蛋白聚糖，在肾脏中显著表达，可减轻炎症和蛋白尿。它在发育过程中在血管顶端表达受限，但对其在成熟组织中的表达模式及其在糖尿病中的精确作用知之甚少。
我们利用公开的单细胞RNA测序数据，探索从四个成人和三个小鼠数据库获得的27786个肾内皮细胞中Esm-1的表达特征。我们使用另外20名健康受试者和41名DKD患者的批量转录组数据以及RNAscope验证了我们的发现。使用相关矩阵，我们将Esm1表达与肾小球转录组相关联，并通过Esm-1的全身过表达评估这些矩阵。
在小鼠和人类中，Esm-1在所有肾内皮细胞类型的一个子集中表达，占肾小球内皮细胞的少数。在患者中，Esm-1（+）细胞在血管发育基因方面表现出高度保守的富集。糖尿病时，这些细胞数量减少，表达发生深刻变化以反映趋化途径。对这些基因集的分析突出了细胞类型间相互作用的候选基因，如Cxcl12。我们还发现糖尿病会诱导细胞类型富集转录本中大量基因簇表达的相关性。Esm-1与这些簇中的大多数基因显著相关，描绘了由Esm-1缺乏程度反映的肾小球转录极化。在糖尿病小鼠中，这些基因簇将Esm-1表达与蛋白尿联系起来，Esm-1的过表达逆转了许多这些基因的表达模式。
对单细胞和批量转录组的综合分析表明，糖尿病与Esm-1表达降低以及Esm-1（+）细胞功能特征的变化相关。Esm-1既是肾小球转录极化的标志物，也是在DKD中重新定向转录程序的介质。
