Overview of advanced glycation end-products (AGEs) Part 2

Complications of Advanced Glycation End-products (AGEs) in Diabetic Patients

AGEs in Diabetes Mellitus (DM) Cells have receptors for AGE products “RAGE” Normally present in low levels in the body In DM, upregulation of these receptors occurs Contributes to microvascular and macrovascular complications Vascular and inflammatory cells, Muller cells of the retina, podocytes of the kidney, neurons and microglial cells, epithelial cells, etc may have low levels of RAGE.

Retinopathy AGEs Cause pericyte cell death unprotected capillary Stimulate VEGF hyperpermeability Increase leukocyte adhesion inflammation Increase platelet activation microthrombosis Pericytes (a type of CNS cell) cover the retinal capillary and provide protection. AGEs bind to RAGE on pericytes causing production of reactive oxygen species (ROS) which leads to cell death and loss of pericyte (this leaves vessel more vulnerable to angiogenesis, thrombogenesis and endothelial cell injury) AGEs also stimulate vascular endothelial growth factor (VEGF) which leads hyperpermeability seen in retinopathy AGEs cause vascular inflammation by increasing leukocyte activation and adherence AGEs also cause platelet activation and aggregation and fibrin stabilization contributing to microthrombosis http://www.timothyjackson.net/disciform.JPG

Nephropathy Alter ECM biology Stimulate cytokines, adhesion molecules, chemokines, growth factors and increase oxidative stress Interact with renin- angiotensin system Mesangial cells (specialized cells around blood vessels in kidney) of kidney have RAGE on cell surface. AGE binds to receptors and following consequences occur: AGEs cross-link with extracellular matrix (ECM) proteins leading to development of diabetic glomerulosclerosis. These also accumulate in the extracellular space and cause basement membrane thickening and mesangial growth AGEs cause cell death and stimulate VEGF on mesangial cells (leads to glomelular hyperfiltration) AGEs stimulate growth factors on podocytes and proximal tubular cells too Growth factor stimulation part of glomerulosclerosis and tubulointerstitial fibrosis in pathogenesis of nephropathy

Neuropathy AGE products accumulate on cytoskeleton proteins and myelin components Causes axonal degeneration and demyelization AGE product may alter ECM protein Affects regeneration AGE-RAGE interaction promotes oxidative stress leading to neurovascular damage Not fully understood Pathogensis thought to develops due to glycation of cytoskeletal proteins & myelin components which causes structural and functional changes in nerve fibers AGE may alter extracellular matrix protein laminin damaging regeneration process

Neuropathy Sugimoto K, Yasujima M, Yagihashi S. Role of advanced glycation end products in diabetic neuropathy. Curr Pharm Des. 2008;14(10):953-61.

Neuropathy Sugimoto K, Yasujima M, Yagihashi S. Role of advanced glycation end products in diabetic neuropathy. Curr Pharm Des. 2008;14(10):953-61.

Macrovascular Disease AGE cross-links with matrix proteins in the vascular wall Increases vessel rigidity Decreases nitric oxide Traps lipoproteins in arterial wall AGE-RAGE interaction increases oxidative stress Also activates NF-κB in vascular wall cells, which stimulates the expression several atherosclerosis-related genes AGE interacts with renin-angiotensin system Enhances angiotensin II-induced smooth muscle cell proliferation and activation Lipoproteins enable to be cleared thus increases LDL and contributes to atherosclerosis Nitirc oxide important for vasodilation (this adverse effect on nitric oxide is seen in microvascular complications as well) Again the increase in oxidative stress will lead to endothelial cell injury and VEGF is also stimulated on endothelial cells