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.
Highlights
Diabetic nephropathy (DN) is the most common cause of chronic kidney disease and endstage renal disease in the developed and developing world[1]
While inflammation is a known component of DN[29,30,31,32,33], we discovered that early expression of glomerular genes related to inflammation is a differentiating marker of susceptibility to DN
These differences were examined at a late stage of disease, and importantly, compared the response to diabetes in DN-susceptible groups but not the genetic background between susceptible and resistant groups
Summary
Diabetic nephropathy (DN) is the most common cause of chronic kidney disease and endstage renal disease in the developed and developing world[1]. An increased prevalence of type 2 diabetes[2] and the high. Institutes of Health Grant (1R01GM114359) to Mohammad F. Kiani; The Shriners Hospitals for Children (86400); National Institutes of Health, National Institute of Diabetes and Digestive Kidney Diseases - Pilot and Feasbility Grant sponsored by the Diabetic Complications Consortium (3U24DK076169-08S4) to Vivek Bhalla; Holmgren Family Foundation Philanthropic gift for diabetes research in the Division of Nephrology, Department of Medicine, Stanford University School of Medicine. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript
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