Advanced glycation end products and diabetic nephropathy.
Chronic hyperglycemia and oxidative stress in diabetes results in the formation and accumulation advanced glycation end products (AGEs). AGEs have a wide range of chemical, cellular, and tissue effects that contribute to the development of microvascular complications. In particular, AGEs appear to have a key role in the diabetic nephropathy. Their importance as downstream mediators of tissue injury in diabetic kidney disease is demonstrated by animal studies using inhibitors of advanced glycation to retard the development of nephropathy without directly influencing glycemic control. AGE modification of proteins may produce in changes charge, solubility, and conformation leading to molecular dysfunction as well as disrupting interactions with other proteins. AGEs also interact with specific receptors and binding proteins to influence the renal expression of growth factors and cytokines, implicated in the progression of diabetic renal disease. The effects of AGEs appears to be synergistic with other pathogenic pathways in diabetes including oxidative stress, hypertension, and activation of the renin-angiotensin system. Each of these pathways may be activated by AGEs, and each may promote the formation of AGEs in the vicious cycle associated with progressive renal damage. It is likely that therapies that inhibit the formation of AGEs or remove established AGE modifications will form an important component part of future therapy in patients with diabetes, acting in concert with conventional approaches to prevent diabetic renal injury.
Thomas
Merlin C
MC
Danielle Alberti Memorial Centre for Diabetes Complications, Baker Medical Research Institute, Melbourne, Victoria, Australia.
Forbes
Josephine M
JM
Cooper
Mark E
ME
D000818:Animals; D003928:Diabetic Nephropathies / Q000209:etiology* / Q000517:prevention & control; D004791:Enzyme Inhibitors / Q000378:metabolism / Q000627:therapeutic use*; D017127:Glycation End Products, Advanced / Q000009:adverse effects* / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D006146:Guanidines / Q000378:metabolism / Q000627:therapeutic use*; D006801:Humans; D018384:Oxidative Stress
D004791:Enzyme Inhibitors; D017127:Glycation End Products, Advanced; D006146:Guanidines; C004479:pimagedine