Can advanced glycation end product inhibitors modulate more than one pathway to enhance renoprotection in diabetes?
Although advanced glycation end products (AGEs) have been postulated to contribute to diabetic nephropathy in their own right, advanced glycation is clearly only one pathway by which renal injury may be induced in diabetes. The interaction between metabolic and hemodynamic factors amplifies the deleterious effects of the diabetic milieu, thereby reducing the threshold for microvascular injury via common mechanisms. This includes interactions between AGE-mediated pathways and the renin angiotensin system, oxidative stress, protein kinase C, and growth factors, which play a significant role in the development and progression of diabetic renal disease. As it is likely that the future of preventive therapy will not involve a single "cure-all" agent, it seems that a highly relevant question in diabetic nephropathy should be, which pathogenic pathways are already addressed by currently available therapies? Combination therapies that target multiple pathways may ultimately be more successful than those that modify a single pathway. Therefore, research into synergistic interactions among the various pathogenic pathways leading to diabetic complications is critical in order to develop interventions that confer optimal end-organ protection.
Coughlan
Melinda T
MT
Danielle Alberti Memorial Centre for Diabetes Complications, Baker Heart Research Institute, P.O. Box 6492, St. Kilda Rd. Central, Melbourne 8008, Australia. melinda.coughlan@baker.edu.au
Cooper
Mark E
ME
Forbes
Josephine M
JM
D000818:Animals; D003928:Diabetic Nephropathies / Q000503:physiopathology* / Q000517:prevention & control*; D004195:Disease Models, Animal; D017127:Glycation End Products, Advanced / Q000037:antagonists & inhibitors*; D006146:Guanidines / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D011733:Pyridoxamine / Q000494:pharmacology / Q000627:therapeutic use; D012084:Renin-Angiotensin System / Q000502:physiology; D013830:Thiadiazoles / Q000494:pharmacology / Q000627:therapeutic use; D053778:Thiazolidines
D017127:Glycation End Products, Advanced; D006146:Guanidines; C105739:OPB 9195; D013830:Thiadiazoles; D053778:Thiazolidines; D011733:Pyridoxamine; C004479:pimagedine