New Pathogenic Concepts and Therapeutic Approaches to Oxidative Stress in Chronic Kidney Disease

Abstract

In chronic kidney disease inflammatory processes and stimulation of immune cells result in overproduction of free radicals. In combination with a reduced antioxidant capacity this causes oxidative stress. This review focuses on current pathogenic concepts of oxidative stress for the decline of kidney function and development of cardiovascular complications. We discuss the impact of mitochondrial alterations and dysfunction, a pathogenic role for hyperuricemia, and disturbances of vitamin D metabolism and signal transduction. Recent antioxidant therapy options including the use of vitamin D and pharmacologic therapies for hyperuricemia are discussed. Finally, we review some new therapy options in diabetic nephropathy including antidiabetic agents (noninsulin dependent), plant antioxidants, and food components as alternative antioxidant therapies.

Figure 1

Integrative scheme of the mechanisms that cause kidney and heart damage secondary to mitochondrial dysfunction. Mitochondrial dysfunction represented by mitochondrial permeability transition pore opening, mitochondrial uncoupling/fragmentation, mitochondrial membrane potential loss, cytochrome C release, and decreased ATP synthesis, among other mitochondrial alterations, causes oxidative stress that leads to inflammatory state. Both conditions result in renal and cardiac damage that often occurs at the same time and establishes a intercommunication through hemodynamic and nonhemodynamic mechanisms.

Figure 2

Role of sodium-glucose cotransporter 2 in blood glucose control in basal and hyperglycemic conditions and effects on blood glucose.

Figure 3

The pathophysiological mechanism of diabetic nephropathy and targets for emerging therapies. Advanced glycation end products (AGEs), endothelin-1 (ET-1), receptor for AGEs (RAGES), superoxide dismutase (SOD), catalase (CAT), nicotinamide adenine dinucleotide phosphate oxidase (NADPHox), glutathione (GSH), glutathione peroxidase (GPX), glutathione reductase (GR) and glutathione-s-transferase (GST), transforming growth factor-β1 (TGF-β1), tumor necrosis factor-α (TNF-α), reactive oxygen species (ROS), sodium-glucose cotransporter 2 (SGLT2), nuclear transcription factor-kappa-B (NF-κB), vascular endothelial growth factor (VEGF), Monocyte Chemoattractant Protein (MCP-1), connective tissue growth factor (CTGF), fibronectin (FN), vascular cell adhesion molecule-1 (VCAM-1), intracellular adhesion molecule-1 (ICAM-1), heme oxygenase-1 (HO-1), NF-E2-related factor-2 (Nrf2), and collagen type IV (col IV).