Murine glomerular transcriptome links endothelial cell-specific molecule-1 deficiency with susceptibility to diabetic nephropathy

Abstract

Diabetic nephropathy (DN) is the leading cause of kidney disease; however, there are no early biomarkers and no cure. Thus, there is a large unmet need to predict which individuals will develop nephropathy and to understand the molecular mechanisms which govern this susceptibility. We compared the glomerular transcriptome from mice with distinct susceptibilities to DN, and identified differential regulation of genes that modulate inflammation. From these genes, we identified endothelial cell specific molecule-1 (Esm-1), as a glomerular-enriched determinant of resistance to DN. Glomerular Esm-1 mRNA and protein were lower in DN-susceptible, DBA/2, compared to DN-resistant, C57BL/6, mice. We demonstrated higher Esm-1 secretion from primary glomerular cultures of diabetic mice, and high glucose was sufficient to increase Esm-1 mRNA and protein secretion in both strains of mice. However, induction was significantly attenuated in DN-susceptible mice. Urine Esm-1 was also significantly higher only in DN-resistant mice. Moreover, using intravital microscopy and a biomimetic microfluidic assay, we showed that Esm-1 inhibited rolling and transmigration in a dose-dependent manner. For the first time we have uncovered glomerular-derived Esm-1 as a potential non-invasive biomarker of DN. Esm-1 inversely correlates with disease susceptibility and inhibits leukocyte infiltration, a critical factor in protecting the kidney from DN.

Gene expression profiles of diabetic kidney disease and neuropathy in eNOS knockout mice: Predictors of pathology and RAS blockade effects

“…A role for activated immune and inflammatory responses with increases in pro‐inflammatory mediators such as Tnf has also been reported in other mouse models of DKD including the Akita‐RenTg mice that develop both type 1 diabetes and a robust kidney disease phenotype 49 . Similar transcriptomic data were also observed in the glomeruli of streptozotocin‐induced type 1 diabetic mice 50 . In addition, we previously compared the glomerular transcriptomic changes in three of the best murine DKD models (C57BLKS db/db eNOS−/− , streptozotocin DBA/2, and C57BLKS db/db ) to early human DKD and found consistent increases in inflammatory pathways in all 3 models that overlapped with those in humans.…”

“…49 Similar transcriptomic data were also observed in the glomeruli of streptozotocininduced type 1 diabetic mice. 50 In addition, we previously compared the glomerular transcriptomic changes in three of the best murine DKD models (C57BLKS db/db eNOS−/−, streptozotocin DBA/2, and C57BLKS db/db) to early human DKD and found consistent increases in inflammatory pathways in all 3 models that overlapped with those in humans. This was despite the fact that pathway overlap in general with the human disease transcriptome was only moderately good.…”

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“…This leads to inhibition of leukocyte diapedesis, which explains the potential anti-inflammatory effect of endocan during acute lung injury. 9–11…”

Targeting Endothelial Cell-Specific Molecule 1 Protein in Cancer: A Promising Therapeutic Approach

“…However, leukocyte-to-endothelial cell adhesion was not reduced by ESM-1 in a biomimetic microfluidic assay by Zheng et al. ( 44 ). This data suggests that LFA-1 is not the only adhesion molecule on leukocytes that binds to ICAM-1 ( 44 ).…”

“…( 44 ). This data suggests that LFA-1 is not the only adhesion molecule on leukocytes that binds to ICAM-1 ( 44 ). To further investigate the impact of ESM-1 on leukocyte in vivo , researchers performed peritonitis assays on ESM-1 knockout mice and wild type mice.…”