The role of metabolic memory in the development of diabetic nephropathy

Abstract

Diabetes mellitus is considered a serious global health problem, and its complications have a major impact on population mortality. Diabetic nephropathy is a major complication of metabolic disease, characterized primarily by a progressive decline in the rate of glomerular filtration, persistent proteinuria, and hypertension. Several mechanisms have been proposed as important in the pathogenesis and progression of diabetic nephropathy. Hyperglycemia is closely associated with oxidative stress, with increase in pro-inflammatory cytokines such as IL-1, IL-6 and TNF-±, growth factors, such as TGF-², and formation of advanced glycation end products. Considering the fact that even after glycemic control there is the occurrence of diabetic complications, recent studies have proposed the phenomenon known as metabolic memory to explain this fact. From this perspective, this study will evaluate the modulation of a series of markers related or possibly related to diabetic nephropathy in conditions of hyperglycemia and early and late glycemic control by the oral antidiabetic agent metformin. Markers related to oxidative stress (protein expression of SIRT-1, AMPK, Bax, TGF-b, MKK 3/6, MKP-1 and p38), inflammation (IL-6, TNF-a, NF-kB) and the advanced glycation process (glycated hemoglobin and N-(carboxymethyl)lysine) will be evaluated in a model of diabetic rats, as well as the expression of target genes (PPARGC1A, TGF-², TSP-1, MKP-1 and UNC13B) and their possible epigenetic regulation (methylation of CpG islands) with or without control of hyperglycemia. The aim here is thus to elucidate new pathways involved in the process of metabolic memory that have an important role in the development of diabetic nephropathy, in order to contribute to its control. (AU)