Research Area
Diabetes

Grant Type
Fellowship

Year
2014

Abstract

Diabetic nephropathy (DN) progresses to end-stage kidney failure and has no cure. Therefore, innovative approaches and mechanistic insights are needed to develop prevention and treatment strategies. Decreasing leukocyte infiltration is a viable therapeutic strategy in DN, but there are no available kidney-specific immune modulators. Using an unbiased screen to identify novel kidney-enriched molecular determinants of DN, we compared glomerular transcriptome profiles from two mice strains susceptible vs. resistant to DN. We showed that pro-inflammatory pathways were predominantly up-regulated in glomeruli from DN-susceptible mice. Our long-term goal is to utilize this differential susceptibility to elucidate candidate glomerular genes as therapeutic targets that influence immune-mediated glomerular and tubulointerstitial injury in DN. Thus, we further characterized endothelial cell-specific molecule-1, Esm-1, a glomerular-enriched secreted glycoprotein, and an endogenous inhibitor of leukocyte-free antigen-1 (LFA-1): intercellular adhesion molecule-1 (ICAM-1) interaction. With the generous support of the Larry L. Hillblom Foundation I demonstrated the following: (1) Esm-1 is decreased in DN-susceptible vs. DN-resistant glomeruli; (2) Esm-1 is decreased in glomeruli from individuals with DN; (3) Esm-1 reduces leukocyte transmigration in vitro and (4) rescue with glycosylated Esm-1 reduces leukocyte infiltration in DN-susceptible mice. Future studies will focus on elucidating the regulation of expression that specifically increases Esm-1 in glomerular endothelial cells.