ABC | Volume 112, Nº5, May 2019

Review Article Kidney Disease in Diabetes Mellitus: Cross-Linking between Hyperglycemia, Redox Imbalance and Inflammation Rayne Gomes Amorim , Glaucevane da Silva Guedes, Sandra Mary de Lima Vasconcelos, Juliana Célia de Farias Santos Universidade Federal de Alagoas - Faculdade de Nutrição, Maceió, AL – Brazil Keywords DiabetesMellitus/complications; Kidney, Diseases; Oxidation- Reduction; Inflammation; Oxidative Stress; Renal Dialysis. Mailing Address: Juliana Célia de Farias Santos • Universidade Federal de Alagoas Ringgold standard institution - Faculdade de Nutrição - Avenida Lourival de Melo Mota, Km14, Postal Code 57072-970, Tabuleiro do Martins, Maceió, AL – Brazil E-mail: jcfsnut@hotmail.com Manuscript received August 29, 2019, revised manuscript December 19, 2018, accepted February 13, 2019 DOI: 10.5935/abc.20190077 Abstract Chronic hyperglycemia is the key point of macro- and microvascular complications associated with diabetes mellitus. Excess glucose is responsible for inducing redox imbalance and both systemic and intrarenal inflammation, playing a critical role in the pathogenesis of diabetic kidney disease, which is currently the leading cause of dialysis in the world. The pathogenesis of the disease is complex, multifactorial and not fully elucidated; many factors and mechanisms are involved in the development, progression and clinical outcomes of the disease. Despite the disparate mechanisms involved in renal damage related to diabetes mellitus, the metabolic mechanisms involving oxidative/inflammatory pathways are widely accepted. The is clear evidence that a chronic hyperglycemic state triggers oxidative stress and inflammation mediated by altered metabolic pathways in a self-perpetuating cycle, promoting progression of cell injury and of end-stage renal disease. The present study presents an update on metabolic pathways that involve redox imbalance and inflammation induced by chronic exposure to hyperglycemia in the pathogenesis of diabetic kidney disease. Introduction Diabetic kidney disease (DKD) is a devastating outcome of diabetes mellitus (DM), responsible for high morbidity and overall mortality. It is clinically characterized by persistent renal dysfunction for a period equal to or longer than three months, marked by urinary excretion of albumin >30 mg/24 h or an albumin/creatinine ratio (ACR) ≥ 30 mg/g or glomerular filtration rate (GFR) < 60 mL/min/1.73 m after a hyperfiltration phase, in addition to structural abnormalities (e.g. diabetic glomerulosclerosis) in individuals with previous diagnosis of DM. 1,2 It is estimated that approximately 425 million people have DM in the world, with a projected increase by 48% to the yar of 2045. Approximately 12.5 million people are diagnosed with DM in Brazil, which occupies the third position in number of individuals with DM in the world in 2017. 3 Nearly 90% of DM patients develop microvascular and macrovascular complications; DKD is considered one of the most severe clinical outcomes, affecting 20-40% of the patients, most of them type 2 DM patients. 1 DKD is currently the main cause of dialysis in developed countries, the second main cause in Brazil. 4-6 DKD is a progressive and irreversible condition, whose pathogenesis has been associated with functional and structural changes of renal cells in response to metabolic stress induced by excessive glucose inflow, by means of activation of specific metabolic pathways linked to redox imbalance and inflammation. 7 Although many classical mechanisms involved in the development and progression of DKD have been described, new molecular and epigenetic pathways have been suggested to be responsible for the early kidney functional loss and DKD‑related complications. 8 In this review we discuss current knowledge of metabolic pathways involving redox imbalance and inflammation induced by chronic exposure to hyperglycemia in the pathogenesis of DKD, aiming to propose new paradigms. Pathophysiology of DKD induced by hyperglycemia: new paradigms DKD is a chronic metabolic disease in which hyperglycemia causes dysfunction of renal and vascular cells. The pathophysiology of DKD and the consequent end‑stage renal disease requiring dialysis is caused by a chronic hyperglycemic state that leads to activation and changes of metabolic pathways and hemodynamic dysfunction. Some of these changes occur in an integrated way, leading to several other changes. Although diabetic hyperglycemia is an important but not crucial factor for the development of glomerular lesions in DKD, we will describe metabolic changes induced by intermittent and chronic exposure to hyperglycemia. The following topics will be discussed: glucose auto-oxidation, polyol and hexamine pathways, formation of advanced glycation end-products (AGEs), synthesis of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX), protein kinase C (PKC) activation, and abnormal activity of angiotensin II (Ang II). 9,10 Glucose uptake by diabetic kidney cells Hyperglycemia is the main clinical manifestation of DM, the main driving force for the development of chronic complications of the disease, including DKD. It is caused by two main mechanisms: the first involves dysfunction and apoptosis of pancreatic beta cells caused by an autoimmune abnormality (type 1 DM), and the second results from an 577