HDL proteomics and functionality in diabetes mellitus chronic kidney disease: association with advanced glycation end products

Abstract

Advanced glycation products (AGEs) are prevalent in chronic kidney disease regardless of the presence of hyperglycemia. They are formed due to the failure to detoxify dicarbonyl compounds, precursors of AGEs, because of the gradual loss of renal function and oxidative stress. AGEs alter lipid and lipoprotein metabolism and are independently associated with cardiovascular risk. In addition, they favor inflammation and oxidative stress that aggravate the development of CKD. Advanced glycated albumin (AGE-albumin) isolated from poorly controlled diabetes mellitus (DM) patients alters lipid homeostasis in macrophages contributing to intracellular accumulation of cholesterol. The concentrations of cholesterol or apo A-I in HDL are used as metric for the quantification of the cardiovascular protection conferred by this lipoprotein Nonetheless, chemical changes in lipid or protein components of HDL and modification in its cargo proteins may induce, independently of cholesterol and apo A-I content, damage on its antiatherogenic function. Our hypothesis is that the evolution of the diabetic kidney disease (DKD), regardless of changes in glycemic control (glycated hemoglobin), may impair the antiatherogenic properties of HDL. Therefore, the objective of this project is to evaluate the effects of HDL from patients with DKD in different stages of renal function loss, in comparison with healthy control individuals (matched by age and sex) on HDL composition, proteomics and ability to remove cell cholesterol, inhibit inflammation and mediate vasodilation. HDL will be isolated from type 2 DM patients´plasma at different stages of DRD and tested, in comparison to that obtained from controls, for 14C-cholesterol removal, anti-inflammatory activity promoted by lipopolysaccharides in macrophages and vasodilation of mice aortic rings. The findings will help to elucidate HDL modification in DKD in association with its proteomics as a predictor of cardiovascular risk in the gradual loss of renal function. (AU)