Advanced glycated albumin and insulin resistance in rats: focus on periepididimal adipose tissue and N-acetylcysteine actions

Abstract

Advanced glycation end products (AGE) contribute to the pathogenesis of chronic complications in diabetes mellitus (DM). In macrophages, AGE enhance the uptake of cholesterol-enriched lipoproteins and diminish cholesterol efflux mediated by HDL. Besides AGE induce oxidative stress and inflammation in these cells which may contribute to the progression of atherosclerosis from the arterial wall and peripheral point of view considering that macrophage infiltration in different organs and tissues modulates the local inflammatory response and abnormal lipid metabolism. The objective of this project is to analyze the effect of chronic administration of AGE-albumin in rats associated or not with N-acetylcystein (NAC) treatment in the inflammatory status of peritoneal and adipose tissue macrophages. Our hypothesis is that AGE can increase the inflammatory status in macrophages independently of hyperglycemia and that NAC could prevent/revert this effect which was not evaluated in an in vivo model so far. Male Wistar rats will be randomically assigned to four experimental groups receiving: 1) control (C) albumin ; 2) C-albumin + NAC; 3) AGE-albumin and 4) AGE-albumin + NAC. Animals will receive C or AGE-albumin (20 mg/kg/dia) by daily intraperitoneal injections and NAC in the water, for 90 days. It will be determined the histological profile of periepididimal adipose tissue and M1 and M2 macrophage differentiation as well as the mRNA expression of inflammatory citokynes, RAGE, AGE-R1 and CD-36. In peritoneal macrophages it will be determined cytokines and ROS production, mRNA expression of inflammatory citokynes, RAGE, AGE-R1 and NF-kB as wells as the NF-kB binding to the promotor of Ager gene.Findings will help to elucidate the mechanisms involved in the progression of inflammation in peritoneal and adipose tissue macrophages that may contribute to long term complications in DM.