ABC | Volume 112, Nº5, May 2019

Review Article Amorim et al Kidney disease in diabetes Arq Bras Cardiol. 2019; 112(5):577-587 overstimulation of insulin synthesis and secretion in the presence of insulin resistance (IR), mostly associated with overweight/obesity, which characterizes type 2 DM. 11 In the context of obesity, which is common in patients at risk of type 2 DM, IR results from increased levels of free fatty acids (FFAs), and the FFA by-products pro-inflammatory cytokines and diacylglycerols (DAG), that inhibit phosphorylation of the insulin receptor substrate 1 (IRS-1) in phosphorylation domains (serine/threonine), preventing the propagation of signals to the translocation of the glucose transporter-4 (GLUT4) translocation to the plasma membrane. This affects the interaction between insulin and its receptor, leading to decreased glucose uptake by insulin-dependent cells, and ultimately hyperglycemia and hyperinsulinemia. 12,13 In additional, in obese diabetic individuals, excessive accumulation of fat causes stress of adipocytes by hyperplasia and hypertrophy, leading to hypoxia and subclinical inflammation, increased macrophage infiltration and release of pro-inflammatory cytokines – tumor necrosis factor alpha (TNF- α ), interleukin-6 (IL-6) and interleukin-1 (IL-1) – which, in turn, aggravates IR. 12,14 TNF- α stimulates the secretion of other cytokines and chemokines and directly activates the transcription factor-kappa B (NF-kappa B), thereby leading to maintenance of chronic hyperglycemia, by affecting glucose uptake and promoting IR. 15 In attempt to reestablish homeostasis, glucose uptake occurs in cells not dependent on GLUT4, and hence, non‑insulin-dependent, such as renal cells, that have GLUT 1 and GLU2 as glucose transporters. These glucose carriers do not regulate glucose entry into cells, leading to glucotoxicity. In this situation, there is elevated expression of these transporters, leading to increased entry of glucose into renal cells, as occurs with the high-affinity glucose transporter GLUT 2, stimulated by hyperglycemia, and the sodium‑glucose co-transporter (SGLT) 1 and SGLT 2, responsible for tubular reabsorption. 16,17 Thus, in DM patients, glucose reabsorption in the proximal tubule is increased, contributing to hyperglycemia and, consequently, hyperfiltration. 18 Generation of reactive oxygen and nitrogen species (RONS) induced by hyperglycemia Glucotoxicity is caused by an inability of the cells to compensate for the increased glucose uptake in case of IR/hyperglycemia, as in DM. Increased stimulation of glucose oxidation pathways in non-insulin-dependent cells leads to the activation of alternative pathways, increased production of RONS and oxidative stress (OS) in hyperglycemic state. 19 Glucose auto-oxidation In glycemic homeostasis and in the absence of oxygen, glycolysis is the primary energy source in the cells. By-products of these reactions are coenzymes responsible for the uptake of high energy electrons, released during oxidation-reduction (redox) reactions, that participate in additional energy pathways. 20 The synthesis of substrates by glycolysis activates two other energy pathways: the tricarboxylic acid cycle (or the Krebs cycle) and the electron transport chain (ETC) (or the oxidative phosphorylation) in the mitochondria through protein complexes. 20-22 In DM, the hyperglycemic state promotes the overactivation of the three main energy pathways previously described. The increased stimulation of glycolysis and Krebs cycle result in elevated production of reduced flavin adenine dinucleotide (FADH2) and reduced nicotinamide adenine dinucleotide (NADH), fed into the ETC. 23 The ETC is a source of reactive oxygen species (ROS), especially in renal cells, which have a large number of mitochondria. 24 In diabetic kidney cells, highly stimulated, hyperpolarized mitochondria with high redox potential, produce increased levels of adenosine triphosphate (ATP) and superoxide anion (O 2 -• ) through the complexes I and II. O2-• originates both radical and non-radical RONS, including hydrogen peroxide (H2O2), the hydroxyl radical (•OH) and the ONOO - , which may be involved in the genesis of the lesions (Figure 1). 25,26 In the kidney of diabetic or diabetic/obese individuals, mitochondrial energy, altered by hyperglycemia and hyperlipidemia, causes mitochondrial dysfunction and excess ROS, which are harmful to mitochondrial DNA (mtDNA) by inhibiting the mammalian target of rapamycin complex 1 (mTORC1) and the AMP-activated protein kinase (AMPK). These changes alter the activation of the peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1 α ), and thereby affect mitochondrial biogenesis, by increasing mitochondrial fission and the synthesis of defective mitochondria. This can lead to impairment of the ECT functions, with reduced synthesis of ATP, leading to renal cell lesion and apoptosis. 27 In addition, increased glycolysis causes hyperactivation of polyol and hexosamine metabolic pathways, and increases the synthesis of AGEs and activation of PKC. This also result in decreased ATP levels, contributing to mitochondrial dysfunction and fragmentation. 28 Polyol pathway One of the consequences of the increased glucose uptake by the cells is the increment in the NADPH-dependent conversion of glucose into sorbitol by aldose reductase. Sorbitol is then converted to fructose, by nicotinamide adenine dinucleotide (NAD). 29,30 NADPH is an important cofactor for regeneration of the antioxidant glutathione (GSH). Therefore, in light of increased aldose reductase activity, the low availability of NADPH affects the antioxidant defense, resulting in redox imbalance. 31 The increase in O2•- inhibits the activity of glyceraldehyde 3-phosphate dehydrogenase (GAPDH), which, in turn, inhibits glycolysis and activates alternative pathways. The increase in the NADH/NAD ratio increases the production of DAG, which activates PKC. Fructose, an end-product of the pathway, has been recently related to kidney injury markers. 20 Protein kinase C (PKC) Both hyperglycemia and increased stimulation of glycolysis by-products increase the synthesis of glyceraldehyde-3- phosphate and its conversion into dihydroxyacetone, and thereby promote the synthesis of DAG, a PKC-activating factor (Figure 2). 31 578