Insight review articles
Increased intracellular formation of advanced glycation end-products
tải về 382.68 Kb. Chế độ xem pdf
|
Điều trị THA cấp cứu
| Increased intracellular formation of advanced glycation end-products
AGEs are found in increased amounts in diabetic retinal vessels 20 and renal glomeruli 21 . They were originally thought to arise from non- enzymatic reactions between extracellular proteins and glucose. But the rate of AGE formation from glucose is orders of magnitude slow- er than the rate of AGE formation from glucose-derived dicarbonyl precursors generated intracellularly, and it now seems likely that intracellular hyperglycaemia is the primary initiating event in the formation of both intracellular and extracellular AGEs 22 . AGEs can arise from intracellular auto-oxidation of glucose to glyoxal 23 , decomposition of the Amadori product (glucose-derived 1-amino- 1-deoxyfructose lysine adducts) to 3-deoxyglucosone (perhaps accelerated by an amadoriase), and fragmentation of glyceraldehyde- 3-phosphate and dihydroxyacetone phosphate to methylglyoxal 24 . These reactive intracellular dicarbonyls — glyoxal, methylglyoxal and 3-deoxyglucosone — react with amino groups of intracellular and extracellular proteins to form AGEs. Methylglyoxal and glyoxal are detoxified by the glyoxalase system 24 . All three AGE precursors are also substrates for other reductases 25 . The potential importance of AGEs in the pathogenesis of diabetic complications is indicated by the observation in animal models that two structurally unrelated AGE inhibitors partially prevented various functional and structural manifestations of diabetic microvascular disease in retina, kidney and nerve 26–28 . In a large randomized, double-blind, placebo-controlled, multi-centre trial in type 1 diabetic patients with overt nephropathy, the AGE inhibitor aminoguanidine lowered total urinary protein and slowed progres- sion of nephropathy, over and above the effects of existing optimal care. In addition, aminoguanidine reduced the progression of diabetic retinopathy (K. K. Bolton et al., submitted). Production of intracellular AGE precursors damages target cells by three general mechanisms (Fig. 2). First, intracellular proteins modified by AGEs have altered function. Second, extracellular matrix components modified by AGE precursors interact abnormal- ly with other matrix components and with the receptors for matrix proteins (integrins) on cells. Third, plasma proteins modified by AGE precursors bind to AGE receptors on endothelial cells, mesan- gial cells and macrophages, inducing receptor-mediated production of reactive oxygen species. This AGE receptor ligation activates the pleiotropic transcription factor NF- kB, causing pathological changes in gene expression. In endothelial cells exposed to high glucose, intracellular AGE formation occurs within a week. Basic fibroblast growth factor is one tải về 382.68 Kb. Chia sẻ với bạn bè của bạn:
|