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bioRxiv · 10.1101/143016

Murine Glomerular Transcriptome Links Endothelial Cell-Specific Molecule-1 Deficiency With Susceptibility To Diabetic Nephropathy

Zheng, X.·Soroush, F.·Long, J.·Hall, E. T.·Adishesha, P. K.·Bhattacharya, S.·Kiani, M. F.·Bhalla, V.
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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.

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Zheng, X., Soroush, F., Long, J., Hall, E. T., Adishesha, P. K., Bhattacharya, S., Kiani, M. F., Bhalla, V.. 2017-05-27. Murine Glomerular Transcriptome Links Endothelial Cell-Specific Molecule-1 Deficiency With Susceptibility To Diabetic Nephropathy. https://doi.org/10.1101/143016

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