ABC | Volume 112, Nº5, May 2019

Review Article Amorim et al Kidney disease in diabetes Arq Bras Cardiol. 2019; 112(5):577-587 Figure 1 – Oxidative stress and enzymatic antioxidant defense system in diabetic renal cells. CAT: catalase; ROS: reactive oxygen species; GPx: glutathione peroxidase; GSH: glutathione; GSSG: oxidized glutathione; RG: reduced glutathione; H 2 O 2 : hydrogen peroxide; NRF2: nuclear erythroid 2-related factor 2; O 2 : molecular oxygen; NOX: NADPH oxidase; O 2 •- : superoxide anion radical; • OH: hydroxyl radical; SOD: superoxide dismutase. Adapted from Bhargava. 28 Extracellular OXIDATIVE STRESS ENZYMATIC ANTIOXIDANTE DEFENSE SYSTEMS Stress O 2 Intracellular A B C ROS ROS NRF2 NRF2 NOX • OH H 2 O 2 H 2 O 2 H 2 O 2 NADPH NADPH + + + = + H 2 O Nucleus + O 2 = H 2 O Fe 2+/ Cu + + = H 2 O + Damage to proteins, lipids and DNA O 2 •– GSH GSH GSSG GSSG GSSG SOD GPx GPx RG GSH CAT CAT GPx SOD SOD In renal cells, increased PKC stimulates several mechanisms involved in the development of kidney injury. The induction and activation of endothelial nitric oxide synthase (eNOS) by PKC increases the availability of nitric oxide (NO) in diabetic kidney in the first stages of DKD. 32 Increased NO contributes to elevation of prostaglandin E1 levels, Ang II activity, and activation of the vascular endothelial growth factor (VEGF), resulting in increased permeability, endothelial dysfunction, glomerular hyperfiltration and albuminuria. 33,34 In prolonged diabetes, persistent hyperglycemia reduces the levels of tetrahydrobiopterin (BH4), an eNOS cofactor, with proportional reduction in NO synthesis in vascular endothelium, leading to vasoconstriction and glomerular and systemic hypertension. 34 Hyperglycemia-related endothelial damage is caused by a nitroso-redox imbalance, by increased RONs (resulting from the interaction between O2•- and NO, which leads to increased ONOO- and decreased vascular NO), leading to endothelial dysfunction and DKD progression. 35 Increased expression of PKC leads to activation of the transforming growth factor-beta (TGF- β ) and the plasminogen activator inhibitor-1 (PAI-1), resulting in increased deposition of fibronectin, collagen types I and IV and extracellular matrix deposition, and consequently, renal hypertrophy, glomerulosclerosis and renal fibrosis. 30 Hexosamines The hyperfunction of this pathway, stimulated by hyperglycemia, promotes the conversion of fructose 6-phosphate, and the synthesis of uridine diphosphate N-acetylglucosamine (UDP-GlcNAc) as end product, which is O -glycosylated into N-acetylglucosamine ( O -GlcNAc) by the O -GlcNAc transferase. 29,30 The excess of O -GlcNAc is responsible for stimulating and modifying cell protein. In DKD, changes in genetic expression increase TNF- α transcription, thereby inducing renal damage via OS, and overproduction of extracellular matrix proteins. 20,29,36 Advanced glycation end products (AGEs) AGEs are uremic toxins and their involvement in the development of renal damage may be partially explained by increased endogenous synthesis resulting from hyperglycemia, diet and insufficient clearance of these products due to reduced GFR. 37 AGEs are formed through non-enzymatic amino-carbonyl reactions, or Maillard reaction between the carbonyl group of glucose, fructose, galactose and ribose, or intermediates of glucose metabolism (glucose-6-phosphate, fructose-6- phosphate, ribose-5-phosphate, deoxyribose-5-phosphate and glyceraldehyde), with an amine group and other molecules, to form a reversible Schiff base, and subsequently, Amadori products, which are initial products of the Maillard reaction. 13 Synthesis of the Amadori products is accelerated in hyperglycemic conditions, and these compounds are highly reactive with amine groups and metal ions through glycoxidation of biological molecules, forming glyoxal (GO), methylglyoxal (MGO), and malondialdehyde (MDA). 38,39 579