Site-specific AGE modifications in the extracellular matrix: a role for glyoxal in protein damage in diabetes

Abstract

Non-enzymatic modification of proteins in hyperglycemia is a major proposed mechanism of diabetic complications. Specifically, advanced glycation end products (AGEs) derived from hyperglycemia-induced reactive carbonyl species (RCS) can have pathogenic consequences when they target functionally critical protein residues. Modification of a small number of these critical residues, often undetectable by the methodologies relying on measurements of total AGE levels, can cause significant functional damage. Therefore, detection of specific sites of protein damage in diabetes is central to understanding molecular basis of diabetic complications and for identification of biomarkers which are mechanistically linked to the disease. The current paradigm of RCS-derived protein damage places the major focus on methylglyoxal (MGO), an intermediate of cellular glycolysis. We propose that glyoxal (GO) is a major contributor to extracellular matrix (ECM) damage in diabetes. Here, we review the current knowledge and provide new data about GO-derived site-specific ECM modification in experimental diabetes.

Diabetic nephropathy induces alterations in the glomerular and tubule lipid profiles

“…We utilized a set of experimental tools: a robust DN mouse model, which develops renal lesions comparable to those found in human disease ( 12 ); a high spatial resolution MALDI IMS technology; and pyridoxamine (PM), which was employed to elucidate whether hyperglycemia-induced oxidative pathways play a role in phospho-and glycolipid changes relevant to DN. PM is an inhibitor of oxidative and glycoxidative reactions and has been shown to act via sequestration of redox active metal ions, scavenging of reactive carbonyl compounds, and scavenging of hydroxyl radical both in vitro and in vivo (13)(14)(15)(16)(17)(18). We determined molecular changes at the level of a single glomerulus or tubule, which has not been achieved in the previous studies of renal tissues using MALDI IMS (19)(20)(21).…”

Carnosine metabolism in diabetes is altered by reactive metabolites

“…This post-translational modification controls protein function Hartmanova et al 2013). Excessive production of reactive carbonyl species (RCS) and oxygen species (ROS) is another important mechanism underlying the pathogenesis of diabetic complication (Voziyan et al 2014) such as cardiovascular and renal sequelae (Cheang et al 2011;Forstermann and Sessa 2012). ROS such as hydrogen peroxide (H 2 O 2 ) are known to lead to post-translational modifications by oxidizing amino acids in proteins.…”

“…RCS react preferentially with arginine residues. The current paradigm of RCS-derived protein damage places the focus on methylglyoxal (MG), a spontaneous decomposition product of dihydroxyacetone phosphate and gylderaldehyde-3-phosphate, which contributes to extracellular matrix damage in diabetes (Voziyan et al 2014).…”

Correlations between Photodegradation of Bisretinoid Constituents of Retina and Dicarbonyl Adduct Deposition

“…In addition, extracellular deposition of MG and GO adducts contributes to tissue damage with the modified proteins having relatively long lifetimes (52). Thus, to determine whether the photooxidation/photodegradation of bisretinoid in RPE cells can result in the deposition of carbonyls on extracellular proteins, A2E-containing cultured RPE cells that had been grown on a substrate of collagen IV were irradiated at 430 nm (1.5 milliwatts/cm 2 , 20 min), and after a 6-h incubation, the collagen was harvested.…”