Oxidative stress, AGE, and atherosclerosis E. Schleicher, U. Friess  Kidney International  Volume 72, Pages S17-S26 (August 2007) DOI: 10.1038/sj.ki.5002382 Copyright © 2007 International Society of Nephrology Terms and Conditions

Figure 1 Working hypothesis for the accelerated atherosclerosis in diabetes. Reactive ROS and AGEs that react via the RAGE are generated if the vascular wall is stressed. Because all three partners are linked a vicious cycle is induced. This cycle is enhanced by further stress factors occurring in diabetes. Kidney International 2007 72, S17-S26DOI: (10.1038/sj.ki.5002382) Copyright © 2007 International Society of Nephrology Terms and Conditions

Figure 2 Vascular cells are protected from excessive glucose uptake. Vascular cells express GLUTs with Km between 2 and 5 mM (e.g. GLUT 1 and GLUT 4), whereas the Km of GLUT 2, which is expressed in liver and the pancreatic β-cell, is 22 mM. The graphs show the dependency of the relative glucose transport rate from glucose concentration. Vertical lines indicate glucose concentrations of 4, 7.5, and 15 mM (80, 135, and 270 mg/dl), respectively, to indicate the ranges of daily variations of blood glucose levels in nondiabetic and diabetic subjects. Kidney International 2007 72, S17-S26DOI: (10.1038/sj.ki.5002382) Copyright © 2007 International Society of Nephrology Terms and Conditions

Figure 3 Effects of ROS in vascular cells. Numerous inducers and metabolic conditions associated with atherogenesis add up to increase intracellular ROS from enzymatic and mitochondrial sources. Once enhanced ROS formation is started, subsequent activation of signaling pathways and the redox-sensitive transcription factors NF-κB and AP-1 has been shown to modulate the expression of proinflammatory cytokines and other genes relevant to vascular pathology such as RAGE, VCAM, or monocyte chemoattractant protein-1. Upregulated cytokine expression and accumulating AGEs may, in turn, provide potent feedback loops to sustain cellular oxidative stress and proinflammatory response. Kidney International 2007 72, S17-S26DOI: (10.1038/sj.ki.5002382) Copyright © 2007 International Society of Nephrology Terms and Conditions

Figure 4 The physiological vascular stress induced by hemodynamic and metabolic factors can readily be counteracted by low-grade production of ROS and/or cytokines. However, when sustained stress induced by cytokine generation in ectopic fat, or by hypertension, hyperglycemia, etc. chronically challenges the vascular wall a vicious cycle is induced consisting of elevated and sustained activation of ROS, RAGE/NF-κB activation, and cytokines. Subsequent changes in the vascular wall, for example endothelial dysfunction and intima media thickening (IMT) indicate early changes possibly leading to atherosclerosis. Kidney International 2007 72, S17-S26DOI: (10.1038/sj.ki.5002382) Copyright © 2007 International Society of Nephrology Terms and Conditions