Esm‐1 Protects Mice from Glomerular Macrophage Infiltration and Macroalbuminuria in Diabetic Nephropathy

Diabetic nephropathy (DN) is the most common cause of kidney failure in the world, but only a minority of individuals with diabetes develop nephropathy. Extending this observation to mice, different mouse strains are susceptible or resistant to DN. In comparing glomerular transcriptome profiles, we published that DN‐susceptible mice up‐regulate pro‐inflammatory pathways and have diminished expression of endothelial cell‐specific molecule‐1 (Esm‐1) mRNA and protein. Esm‐1 is a secreted glycoprotein that is enriched within kidneys and specifically, in glomeruli. We now test the hypothesis that Esm‐1 over‐expression would inhibit inflammation and rescue DN‐susceptible mice and conversely, Esm‐1 deletion would promote nephropathy in DN‐resistant mice. We first confirmed that Esm‐1 is enriched in glomerular endothelial cells by single cell qPCR. Esm‐1 expression was restricted to Cdh5 (+) or CD31 (+) cells and absent in cells enriched for podocyte or mesangial cell markers. We demonstrate by flow cytometry that in diabetic mice, endogenous, plasma Esm‐1 inversely correlates with glomerular leukocyte infiltration (R 2 = 0.61). Next, by hydrodynamic tail‐vein injection in DN‐susceptible mice, we increased circulating Esm‐1 and demonstrate diminished albumin‐to‐creatinine ratio vs. saline‐injected controls (1.0 ± 0.5 mg/mL vs. 3.6 ± 1.4 mg/mL, p = 0.008). Interestingly, over‐expression of non‐glycosylated Esm‐1 did not decrease albuminuria. In a corollary experiment, genetic deletion of Esm‐1 in DN‐resistant mice, increases urine albumin‐to‐creatinine ratio vs. wild‐type controls (806.5 ± 332.0 ug/mL vs. 1.4 ± 0.29 ug/mL, p < 0.001). In mechanistic studies, we previously published that Esm‐1 decreases leukocyte transmigration across endothelium in vitro . We now demonstrate by flow cytometry that increasing circulating Esm‐1 decreases glomerular macrophage infiltration (0.9 ± 0.5 % vs. 3.1 ± 0.7 % of total single cells, p = 0.002) in diabetic mice in vivo . Neutrophil and lymphocyte infiltration were not significantly different between groups. In conclusion, glycosylated Esm‐1, an endothelial cell‐specific inhibitor of leukocyte infiltration, protects mice from macroalbuminuria, possibly through inhibiting glomerular macrophage infiltration. Support or Funding Information Larry L. Hillblom Foundation; Holmgren Family Fund; NIH/NIDDK This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .