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Aldose Reductase and RAGE Promote Key Mechanisms in the Pathogenesis of Diabetic Renal Disease in a Murine Model (LB711)
Author(s) -
Manigrasso Michaele,
Ganda Anjali,
Rosario Rosa,
Ananthakrishnan Radha,
D'Agati Vivette,
Ramasamy Ravichandran,
Schmidt Ann Marie
Publication year - 2014
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.28.1_supplement.lb711
Subject(s) - glycation , endocrinology , aldose reductase , medicine , diabetic nephropathy , rage (emotion) , diabetes mellitus , advanced glycation end product , pathogenesis , polyol pathway , oxidative stress , glomerular basement membrane , kidney , biology , proteinuria , neuroscience
Aldose reductase (AR) is the rate‐limiting enzyme in the polyol pathway and imparts multiple metabolic consequences in diabetes; among these is the generation of advanced glycation end‐product precursors (pre‐AGEs) from glucose metabolism. AR generates oxidative stress and stimulates pro‐fibrotic mechanisms in the diabetic kidney. Previous studies have shown that AR‐inhibitors suppress albuminuria, mesangial expansion and glomerular basement thickening (GBM) in animal models and reduce microalbuminuria in humans with type 1 diabetes. We tested the hypothesis that the receptor for advanced glycation end‐products (RAGE) gene deletion in type 1 diabetic transgenic mice expressing human levels of AR (TghAR+) will exert protection against indices of DN, as deletion of RAGE has been shown to protect against the pathogenesis of diabetic renal disease in an animal models, at least in part by blocking the adverse effects of AGEs and oxidative stress. TghAR+ male mice (C57BL/6) were bred into the RAGE‐expressing (+) or RAGE‐null (TghAR‐RKO) background and rendered diabetic at 6 weeks of age with streptozotocin. Wild‐type (WT) and RAGE‐null animals (RKO) were used as controls and rendered diabetic at the same age. After 3 months of diabetes, animals were sacrificed and kidneys were harvested and processed for histology and gene expression. Kidney sections were stained with periodic‐acid Schiff (PAS) and semi‐quantitative scoring was used to determine the degree of mesangial sclerosis by average findings in >100 glomeruli/mouse (scale 0‐3+; 0=absent, 1=mild, 2=moderate, 3=severe). GBM thickness and foot process effacement mere measured by ultrastructural analysis (>8 glomeruli/mouse). Gene expression of inflammatory markers (interleukin 6; Il6, tumor necrosis factor alpha; Tnfα, and monocyte chemoattractant protein 1; Ccl2) was assessed using whole kidney cortex and normalized to β‐actin.This preliminary study suggests that deletion of RAGE in the TghAR+ background in mice results in a substantial protection against indices of DN by reducing inflammation in type 1 DM. Furthermore, these preliminary results suggest that in the diabetic kidney, these AR actions are mediated through the RAGE pathway. Grant Funding Source : JDRF