Murine glomerular transcriptome links endothelial cell-specific molecule-1
deficiency with susceptibility to diabetic nephropathy.
Authors Zheng X, Soroush F, Long J, Hall ET, Adishesha PK, Bhattacharya S, Kiani MF,
Bhalla V
Submitted By Vivek Bhalla on 9/25/2017
Status Published
Journal PLoS ONE
Year 2017
Date Published
Volume : Pages 12 : e0185250
PubMed Reference 28934365
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 that govern this susceptibility. We compared the glomerular
transcriptome from mice with distinct susceptibilities to DN at four weeks after
induction of diabetes, but before histologic injury, 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.