Esm-1 mediates transcriptional polarization associated with diabetic kidney disease

• Published in: American journal of physiology. Renal physiology Vol. 326; no. 6; pp. F1016 - F1031
• Main Authors: Gaudet, Alexandre, Zheng, Xiaoyi, Kambham, Neeraja, Bhalla, Vivek
• Format: Journal Article
• Language: English
• Published: United States American Physiological Society 01.06.2024
• Subjects: Animals; Case-Control Studies; Chemotaxis; Diabetes; Diabetes mellitus; Diabetic Nephropathies - genetics; Diabetic Nephropathies - metabolism; Diabetic Nephropathies - pathology; Endothelial cells; Endothelial Cells - metabolism; Extracellular Matrix Proteins - genetics; Extracellular Matrix Proteins - metabolism; Humans; Kidney diseases; Kidney Glomerulus - metabolism; Kidney Glomerulus - pathology; Mice; Neoplasm Proteins; Polarization; Proteoglycans; Proteoglycans - genetics; Proteoglycans - metabolism; Transcription; Transcription, Genetic; Transcriptome; Transcriptomes; diabetic kidney disease; inflammation; immunology; angiogenesis; single-cell RNA
• ISSN: 1931-857X; 1522-1466; 1522-1466
• DOI: 10.1152/ajprenal.00419.2023

Esm-1 is primarily expressed in glomerular endothelium in humans. Cells expressing Esm1 exhibit a high degree of conservation in the enrichment of genes related to blood vessel development. In the context of diabetes, these cells are reduced in number and show a significant transcriptional shift toward the chemotaxis pathway. In diabetes, there is a transcriptional polarization in the glomerulus that is reflected by the degree of Esm1 deficiency. Esm-1, endothelial cell-specific molecule-1, is a susceptibility gene for diabetic kidney disease (DKD) and is a secreted proteoglycan, with notable expression in kidney, which attenuates inflammation and albuminuria. However, little is known about Esm1 expression in mature tissues in the presence or absence of diabetes. We utilized publicly available single-cell RNA sequencing data to characterize Esm1 expression in 27,786 renal endothelial cells (RECs) obtained from three mouse and four human databases. We validated our findings using bulk transcriptome data from 20 healthy subjects and 41 patients with DKD and using RNAscope. In both mice and humans, Esm1 is expressed in a subset of all REC types and represents a minority of glomerular RECs. In patients, Esm1(+) cells exhibit conserved enrichment for blood vessel development genes. With diabetes, these cells are fewer in number and shift expression toward chemotaxis pathways. Esm1 correlates with a majority of genes within these pathways, delineating a glomerular transcriptional polarization reflected by the magnitude of Esm1 deficiency. Diabetes correlates with lower Esm1 expression and with changes in the functional characterization of Esm1(+) cells. Thus, Esm1 appears to be a marker for glomerular transcriptional polarization in DKD. NEW & NOTEWORTHY Esm-1 is primarily expressed in glomerular endothelium in humans. Cells expressing Esm1 exhibit a high degree of conservation in the enrichment of genes related to blood vessel development. In the context of diabetes, these cells are reduced in number and show a significant transcriptional shift toward the chemotaxis pathway. In diabetes, there is a transcriptional polarization in the glomerulus that is reflected by the degree of Esm1 deficiency.