Alterations in nonenzymatic biochemistry in uremia: Origin and significance of “carbonyl stress” in long-term uremic complications

Abstract

Advanced glycation end products (AGEs), formed during Maillard or browning reactions by nonenzymatic glycation and oxidation (glycoxidation) of proteins, have been implicated in the pathogenesis of several diseases, including diabetes and uremia. AGEs, such as pentosidine and carboxymethyllysine, are markedly elevated in both plasma proteins and skin collagen of uremic patients, irrespective of the presence of diabetes. The increased chemical modification of proteins is not limited to AGEs, because increased levels of advanced lipoxidation end products (ALEs), such as malondialdehydelysine, are also detected in plasma proteins in uremia. The accumulation of AGEs and ALEs in uremic plasma proteins is not correlated with increased blood glucose or triglycerides, nor is it determined by a decreased removal of chemically modified proteins by glomerular filtration. It more likely results from increased plasma concentrations of small, reactive carbonyl precursors of AGEs and ALEs, such as glyoxal, methylglyoxal, 3-deoxyglucosone, dehydroascorbate, and malondialdehyde. Thus, uremia may be described as a state of carbonyl overload or "carbonyl stress" resulting from either increased oxidation of carbohydrates and lipids (oxidative stress) or inadequate detoxification or inactivation of reactive carbonyl compounds derived from both carbohydrates and lipids by oxidative and nonoxidative chemistry. Carbonyl stress in uremia may contribute to the long-term complications associated with chronic renal failure and dialysis, such as dialysis-related amyloidosis and accelerated atherosclerosis. The increased levels of AGEs and ALEs in uremic blood and tissue proteins suggest a broad derangement in the nonenzymatic biochemistry of both carbohydrates and lipids.

Increased Expression of Adhesion Molecules in Uremic Atherosclerosis in Apolipoprotein-E–Deficient Mice

“…We suspect that NF-B activation is involved in mediating the increase of ICAM-1 expression in the nonlesioned intima because the above-mentioned stimuli are all characteristically in excess in uremia. Uremic patients often have elevated plasma or tissue concentrations of proinflammatory cytokines (IL-6, TNF␣, and IL-1) (35,36), advanced glycation end products (37), and of angiotensin II (38), and they frequently display evidence of increased oxidative stress (39,40). NF-B also controls VCAM-1 expression (41).…”

Endothelial dysfunction in diabetes

“…Through a series of oxidative and non-oxidative reactions, AGEs are formed irreversibly and accumulate in tissues over time. Recently, the concept of non-enzymatic protein modi®cation by glucose has been broadened to include a variety of reactive carbonyl compounds that are capable of AGE formation, and the term carbonyl stress' has been put forward (Miyata et al, 1999). Although AGE formation occurs during the normal ageing process, it is markedly accelerated during diabetes, as a consequence of an increase in substrate, e.g.…”

A Post-Amadori Inhibitor Pyridoxamine Also Inhibits Chemical Modification of Proteins by Scavenging Carbonyl Intermediates of Carbohydrate and Lipid Degradation

“…Non-enzymatic modifications of proteins have been implicated in the pathogenesis of diabetes, atherosclerosis, and neurodegenerative diseases as well as in normal aging (1)(2)(3)(4). These modifications can arise from direct exposure to reactive oxygen, chlorine, or nitrogen species or from reaction with low molecular weight reactive carbonyl compounds derived from carbohydrates, lipids, or amino acids (5-7).…”

“…Because carbonyl modification reactions can alter protein structure and function and cause the formation of high molecular weight protein aggregates, they have been implicated in the development of a number of pathologies via a condition known as "carbonyl stress" (4,19,20). Therefore, inhibition of synthesis and/or trapping of free and protein-bound carbonyls presents an important avenue for drug development.…”