ABC | Volume 112, Nº5, May 2019

Review Article Amorim et al Kidney disease in diabetes Arq Bras Cardiol. 2019; 112(5):577-587 Figure 2 – Schematic representation of the pathways preceding glycolysis and induction of oxidative stress. ETC: electron transport chain; 1,3-BPG: bisphosphoglycerate; G6P: glucose 6-phosphate; G3P: glyceraldehyde-3-phosphate; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; F6P: fructose-6-phosphate; F-1,6-P: fructose‑1,6- phosphate; PKC: protein kinase C; AGE; advanced glycation end-products HYPERGLYCEMIA GLUCOSE G-6-P F-6-P F-1,6-P G-3-P 1,3-B PIRUVATE LACTATE AGE PKC ETC HESOXAMINES POLYOL OXIDATIVE STRESS After AGEs’ metabolism and removal from the tissues, the low molecular weight, soluble peptides and the second generation AGEs need to be excreted in the urine. Second generation AGEs can be highly reactive products, but their effects are limited by renal excretion. However, in renal failure, AGEs excretion is impaired, contributing to the increased levels in serum and tissues. 38 Such increase in the endogenous pool of AGEs causes direct damage to the cells by interaction of extracellular proteins with cellular components (proteins, carbohydrates, lipids and nucleotides), affecting cellular structure and functions. These modified proteins have decreased enzymatic hydrolysis, resulting in excessive accumulation of extracellular matrix proteins, glomerulosclerosis, and consequently, renal fibrosis. 34 In addition to direct extra- and intracellular damage, AGEs interact with their transmembrane receptor – the receptor for advanced glycation end products (RAGE), which are expressed in many types of renal and inflammatory cells. 40 Following the substrate/receptor interaction, a cascade of reactions inside the cell is initiated. These reactions regulate the transcription of proteins, adhesion molecules and proinflammatory cytokines, such as IL-1, IL-6 e TNF- α , mediated by the activation of macrophages via NF- κ B, exacerbating subclinical tissue inflammation associated with DM in DKD. 41,42 The AGEs/RAGEs interaction is associated with increased production of RONs; it contributes to the OS by direct activation of NOX (by mitochondrial activation through the RAGEs in renal cells and infiltrated immune cells). Also, AGs reduces the expression of eNOS and increases the expression of inducible NOS (iNOS), triggering OS by increased ONOO - production and reducing NO availability. Consequently endothelial dysfunction occurs by synthesis of vascular cell adhesion molecule 1 (VCAM-1), intercellular adhesion molecule 1 (ICAM-1), monocyte chemotactic protein-1 (MCP-1) and TGF- β . 38,39 NADPH-oxidases The NOX family of NADPH oxidases is an important source of ROS in DM. There are seven different NOX isoforms: NOX1, NOX2, NOX3, NOX4 (formerly known as “renox” due to its high expression in renal tissue), NOX5 and the 580