Advanced glycation end products (AGEs) are a heterogeneous group of protein and lipids to which sugar residues are covalently bound. AGE formation is increased in situations with hyperglycemia (e.g., diabetes mellitus) and is also stimulated by oxidative stress, for example in uremia. It appears that activation of the renin-angiotensin system may contribute to AGE formation through various mechanisms. Although AGEs could nonspecifically bind to basement membranes and modify their properties, they also induce specific cellular responses including the release of profibrogenic and proinflammatory cytokines by interacting with the receptor for AGE (RAGE). However, additional receptors could bind AGEs, adding to the complexity of this system. The kidney is both: culprit and target of AGEs. A decrease in renal function increases circulating AGE concentrations by reduced clearance as well as increased formation. On the other hand, AGEs are involved in the structural changes of progressive nephropathies such as glomerulosclerosis, interstitial fibrosis, and tubular atrophy. These effects are most prominent in diabetic nephropathy, but they also contribute to renal pathophysiology in other nondiabetic renal diseases. Interference with AGE formation has therapeutic potential for preventing the progression of chronic renal diseases, as shown from data of animal experiments and, more recently, the first clinical trials.
Methylglyoxal hydroimidazolones are quantitatively major AGEs of human lens proteins. These substantial modifications of lens proteins may stimulate further glycation, oxidation, and protein aggregation leading to the formation of cataract.
Background Advanced glycation end-products (AGEs) are increased in situations with hyperglycemia and oxidative stress such as diabetes mellitus. They are products of nonenzymatic glycation and oxidation of proteins and lipids. The kidney plays an important role in clearance and metabolism of AGEs.
Data from a group consisting of patients with CRF, patients undergoing maintenance hemodialysis treatment, and renal transplant recipients provide evidence that conventional risk factors such as the presence of diabetes, ESRD, as well as elevated levels of the considered risk factor CRP, seem to play a more important role for cardiovascular outcome in patients with chronic kidney disease than elevated levels of AGEs, tHcy, and related metabolites. The evidence suggests that routine CRP measurement can be recommended in cases of chronic renal insufficiency.
Advanced glycation end products (AGEs) have been linked to the pathogenesis of diabetic nephropathy. Here we tested the effect of AGE-modified bovine serum albumin (AGE-BSA) on differentiated mouse podocytes in culture. Differential display and real-time PCR analyses showed that in addition to neuropilin-1, the entire signaling receptor complex of neuropilin-2, semaphorin-3A, and plexin-A1, was significantly reduced by AGE-BSA as was neuropilin-1 protein. The effect was specific for podocytes compared to isolated mesangial and tubular epithelial cells. Further, AGE-BSA was not toxic to podocytes. Neuropilin-1 expression was decreased in glomeruli of diabetic db/db mice compared to their non-diabetic littermates. Transcripts of both neuropilins were found to be decreased in renal biopsies from patients with diabetic nephropathy compared to transplant donors. Podocyte migration was inhibited by AGE-BSA with similar results found in the absence of AGE-BSA when neuropilin-1 expression was down-regulated by siRNA. In contrast, podocyte migration was stimulated by overexpression of neuropilin-1 even in the presence of AGE-BSA. Our study shows that AGE-BSA inhibited podocyte migration by down-regulating neuropilin-1. The decreased migration could lead to adherence of uncovered areas of the glomerular basement membrane to Bowman's capsule contributing to focal glomerulosclerosis.
The pentosidine levels but not BMD are independently associated with prevalent fractures. Impaired bone quality in T1D may result from increased AGE formation.
Advanced glycation end products formed oxidatively and nonoxidatively occurred to a higher degree in cataractous lenses than in noncataractous lenses. The strong relationship between the lenses' AGE content, color/opacity, and the state of the cataract may indicate that advanced glycation plays a pivotal role in cataract formation.
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