Advanced Glycosylation Endproducts in Diabetic Renal Disease: Clinical Measurement, Pathophysiological Significance, and Prospects for Pharmacological Inhibition

Abstract

Glucose reacts nonenzymatically with amino groups to produce a class of stable, crosslinking moieties termed advanced glycosylation endproducts (AGEs). These products act to increase vascular permeability, enhance subintimal protein and lipoprotein deposition, inactivate nitric oxide, and exert a number of toxic effects on endothelial cells. Loss of normal renal function has been found recently to cause a marked increase in the circulating levels of plasma AGEs, suggesting that these moieties may comprise one component of the so-called uremic ‘middle molecules’. AGEs also form on the lipid and the protein components of LDL, forming a modified form of LDL (AGE-LDL) which is not taken up by tissue LDL receptors. Aminoguanidine offers a specific therapeutic modality for inhibiting advanced glycosylation in vivo and has been observed recently to reduce both hemoglobin-AGE and circulating LDL levels.

Carbamylated low-density lipoprotein induces death ofendothelial cells: A link to atherosclerosis in patients with kidney disease

“…Although different modified LDLs were found in uremic patients [15,16], and oxLDL was shown to be elevated in uremic patients [17][18][19], no mechanistic studies to establish a cause-effect relationship between oxLDL or another modified LDL and atherosclerosis during uremia were performed. Urea is a normal component of human blood plasma where it undergoes spontaneous transformation to cyanate.…”

Circulating endothelial nitric oxide synthase inhibitory factor in some patients with chronic renal disease

“…Another reason for reduced NOS activity in CRD relates to increased oxidant stress in which oxygen free radicals inactivate newly formed NO and prevent the normal vasodilatory response [28]. Over time, oxidative stress leads to nonenzymatic glycation and oxidation and the accumulation of advanced glycosylated end products (AGEs) [29]. AGEs modify the vascular wall so as to "quench" NO and thus reduce the vasodilatory action of NO (and other agonists) [29].…”

“…Over time, oxidative stress leads to nonenzymatic glycation and oxidation and the accumulation of advanced glycosylated end products (AGEs) [29]. AGEs modify the vascular wall so as to "quench" NO and thus reduce the vasodilatory action of NO (and other agonists) [29]. AGEs also down-regulate eNOS in cultured vascular endothelial cells [30].…”

Protein oxidative damage in the stratum corneum: evidence for a link between environmental oxidants and the changing prevalence and nature of atopic dermatitis in Japan

“…These oxidative changes result in functional changes in structural or enzymatic proteins 20,21 . Protein oxidation has been pathogenetically correlated with diabetes mellitus, emphysema, atherosclerosis, certain degenerative neurological diseases, certain ageing effects, and premature ageing diseases such as Werner's syndrome 23–27 …”