Role of Advanced Glycation End Products in Diabetic Nephropathy

Abstract

Abstract. Nonenzymatic reactions between sugars and the free amino groups on proteins, lipids, and nucleic acids result in molecular dysfunction through the formation of advanced glycation end products (AGE). AGE have a wide range of chemical, cellular, and tissue effects through changes in charge, solubility, and conformation that characterize molecular senescence. AGE also interact with specific receptors and binding proteins to influence the expression of growth factors and cytokines, including TGF-␤1 and CTGF, thereby regulating the growth and proliferation of the various renal cell types. It seems that many of the pathogenic changes that occur in diabetic nephropathy may be induced by AGE. Drugs that either inhibit the formation of AGE or break AGE-induced cross-links have been shown to be renoprotective in experimental models of diabetic nephropathy. AGE are able to stimulate directly the production of extracellular matrix and inhibit its degradation. AGE modification of matrix proteins is also able to disrupt matrix-matrix and matrix-cell interactions, contributing to their profibrotic action. In addition, AGE significantly interact with the renin-angiotensin system. Recent studies have suggested that angiotensin-converting enzyme inhibitors are able to reduce the accumulation of AGE in diabetes, possibly via the inhibition of oxidative stress. This interaction may be a particularly important pathway for the development of AGE-induced damage, as it also can be attenuated by antioxidant therapy. In addition to being a consequence of oxidative stress, it is now clear that AGE can promote the generation of reactive oxygen species. It is likely that therapies that inhibit the formation of AGE will form an important part of future therapy in patients with diabetes, acting synergistically with conventional approaches to prevent diabetic renal injury.

Potential reno-protective effects of a gluten-free diet in type 1 diabetes

“…A number of studies have demonstrated that AGEs are associated with the presence and severity of diabetic kidney disease, as well as its subsequent progression [2]. Circulating AGEs are also correlated with the dietary intake of modified protein [3].…”

“…AGEs play a significant role in the development of diabetic kidney disease [2]. Recent data suggest that AGEs can be acquired from the diet [3].…”

Renal accumulation and clearance of advanced glycation end-products in type 2 diabetic nephropathy: effect of angiotensin-converting enzyme and vasopeptidase inhibition

“…Increased production and tissue accumulation of AGEs have been linked to diabetic end organ damage including diabetic nephropathy [23]. Consequently, any intervention which decreases or prevents the deposition of AGEs in the diabetic kidney offers the potential to attenuate the progressive loss of kidney function in diabetic patients.…”

Effect of Nitric Oxide-cGMP-Dependent Protein Kinase Activation on Advanced Glycation End-Product–Induced Proliferation in Renal Fibroblasts

“…Several factors including hyperglycemia, AGE, increased oxidant stress, as well as activation of PKC and TGF-␤, contribute to decreased NO production and/or availability (38). These effects are mediated through multiple mechanisms such as glucose quenching, inhibition, and/or posttranslational modification of NOS activity of both inducible and endothelial isoforms (10). Gradual accumulation of AGE and induction of plasminogen activator inhibitor-1 (PAI-1), resulting in the decreased expression of iNOS and reduced generation of nitric oxide, are proposed to be pathophysiologically critical for the maintenance phase of renal tubulointerstitial dysfunction (39).…”