Kidney Disease in Diabetes Mellitus: Cross-Linking between Hyperglycemia, Redox Imbalance and Inflammation

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.

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; H₂O₂: hydrogen peroxide; NRF2: nuclear erythroid 2-related factor 2; O₂: molecular oxygen; NOX: NADPH oxidase; O₂^•-: superoxide anion radical; ^•OH: hydroxyl radical; SOD: superoxide dismutase. Adapted from Bhargava.

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

Figure 3

Mediators of kidney injury induced by chronic hyperglycemia via redox imbalance and inflammation in the pathogenesis of diabetic kidney disease. ROS: reactive oxygen species; ERK: extracellular signal-related kinases; TNF- α: tumor necrosis factor alpha; NF-κB: nuclear factor-kappa B; VEGF: the vascular endothelial growth factor; IL-1: interleukin 1; IL-6: interleukin 6; IL-18: interleukin 18; ECM: extracellular matrix; NOX: NADPH oxidase; -O-GLaNAc: O-glycosylated into N-acetylglucosamine; PAI-1: plasminogen activator inhibitor-1; AGE: advanced glycation end-products; PKC: protein kinase C; MCP-1: monocyte chemotactic protein-1; RPGA: receptor for advanced glycation end products; RAAS: renin-angiotensin aldosterone system; TGF-β: transforming growth factor-beta.