Accumulation of fructosyl-lysine and advanced glycation end products in the kidney, retina and peripheral nerve of streptozotocin-induced diabetic rats

Abstract

The accumulation of AGEs (advanced glycation end products) in diabetes mellitus has been implicated in the biochemical dysfunction associated with the chronic development of microvascular complications of diabetes--nephropathy, retinopathy and peripheral neuropathy. We investigated the concentrations of fructosyl-lysine and AGE residues in protein extracts of renal glomeruli, retina, peripheral nerve and plasma protein of streptozotocin-induced diabetic rats and normal healthy controls. Glycation adducts were determined by LC with tandem MS detection. In diabetic rats, the fructosyl-lysine concentration was increased markedly in glomeruli, retina, sciatic nerve and plasma protein. The concentrations of N (epsilon)-carboxymethyl-lysine and N (epsilon)-carboxyethyl-lysine were increased in glomeruli, sciatic nerve and plasma protein, and N(epsilon)-carboxymethyl-lysine also in the retina. Hydroimidazolone AGEs derived from glyoxal, methylglyoxal and 3-deoxylglucosone were major AGEs quantitatively. They were increased in the retina, nerve, glomeruli and plasma protein. AGE accumulation in renal glomeruli, retina, peripheral nerve and plasma proteins is consistent with a role for AGEs in the development of nephropathy, retinopathy and peripheral neuropathy in diabetes. High-dose therapy with thiamine and Benfotiamine suppressed the accumulation of AGEs, and is a novel approach to preventing the development of diabetic complications.

A developmental nephron deficit in rats is associated with increased susceptibility to a secondary renal injury due to advanced glycation end-products

“…A number of studies have suggested that renal AGE accumulation is positively linked to renal dysfunction associated with diabetes and ageing [29,30]. Our findings demonstrate that the kidneys of LPD offspring, in which there was a 28% reduction in nephron number, are more susceptible to AGE accumulation during normal ageing and accumulate AGEs more rapidly following exposure to increased circulating levels of AGEs, possibly via changes in AGE clearance receptors [38].…”

“…The factors leading to increased AGE accumulation in animals with a reduced number of nephrons remain to be established. In previous studies in diabetes, reduced renal filtration of circulating AGEs and increased AGE formation associated with hyperglycaemia have been linked to renal AGE accumulation in patients with diabetic nephropathy [29,30]. However, mechanisms other than GFR and dysglycaemia appear to contribute to AGE accumulation in the LPD model.…”

Low-dose erythropoietin inhibits oxidative stress and early vascular changes in the experimental diabetic retina

“…N ε -(Carboxymethyl) lysine (CML) is one well characterised glycoxidation product, which serves as a biomarker of general oxidative stress, accumulates in tissues with age and whose rate of accumulation is accelerated in diabetes [6][7][8]. ROS, in particular superoxide anions, interact with nitric oxide, forming the strong cytotoxin, peroxynitrite, which attacks various biomolecules, leading to the production of a modified amino acid nitrotyrosine [9].…”

Glycated and Oxidized Protein Degradation Products Are Indicators of Fasting and Postprandial Hyperglycemia in Diabetes

“…Detection of protein glycation, oxidation, and nitration adducts by liquid chromatography with triple quadrupole mass spectroscopy (LC-MS/MS) has been reported previously in the quantitative screening of protein glycation, oxidation, and nitration adducts, measured as adduct residues in proteins and free adducts in physiological fluids (6). In diabetes, protein glycation adducts residues have been shown to be increased in cytosolic proteins at sites of development of vascular complications including renal glomeruli, retina, and nerves (6,19). Cells maintain the quality and functional integrity of proteins by degradation and replacement of proteins damaged by oxidation and glycation (6,20).…”