Esm-1 mediates transcriptional polarization associated with diabetic kidney disease

Abstract

AbstractBackgroundEsm-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.Esm1has 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.MethodsWe utilized publicly available single-cell RNA sequencing data to explore the characteristics ofEsm1expression 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.ResultsIn both mice and humans,Esm1is expressed in a subset of all renal endothelial cell types and represents a minority of glomerular endothelial cells. In patients,Esm1(+) 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 asIgfbp5for 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.Esm1significantly correlates with a majority genes within these clusters, delineating a glomerular transcriptional polarization reflected by the magnitude ofEsm1deficiency. In diabetic mice, these gene clusters linkEsm1expression to albuminuria, and over-expression of Esm-1 reverses the expression pattern in many of these genes.ConclusionsA comprehensive analysis of single cell and bulk transcriptomes demonstrates that diabetes correlates with lowerEsm1expression and with changes in the functional characterization ofEsm1(+) cells.Esm1is both a marker for glomerular transcriptional polarization, and a mediator that re-orients the transcriptional program in DKD.