Increased carbonyl modification by lipids and carbohydrates in diabetic nephropathy.
BACKGROUND
In diabetic nephropathy (DN), possible mediators of untoward effects of hyperglycemia include the advanced glycation end products (AGEs). Indeed, an AGE, carboxymethyllysine (CML), accumulates in expanded mesangial matrix and nodular lesions. An advanced lipoxidation end product (ALE), malondialdehyde-lysine (MDA-lysine), generated on proteins during lipid peroxidation also accumulates in these lesions. As both ALEs and AGEs are formed by carbonyl amine chemistry between protein and carbonyl compounds derived from autoxidation of lipids and carbohydrates, their colocalization suggests an increased carbonyl modification of proteins.


METHODS
To address this hypothesis, human diabetic renal tissues were examined to characterize carbonyl modification of proteins by lipids and carbohydrates: (a) ALEs, MDA-lysine and 4-hydroxynonenal (HNE) protein adduct, derived from lipids, and (b) AGEs, pentosidine and CML, derived from carbohydrates. Furthermore, to elucidate the biological effect of carbonyl modification on primary cultured human and rat mesangial cells, the intracellular protein phosphorylation was examined in the presence of various kinds of carbonyl compounds.


RESULTS
The ALE and AGE adducts examined were identified in expanded mesangial matrix and nodular lesions. The exposure of cultured mesangial cells to carbonyl compounds resulted in phosphorylation of tyrosine residues of a number of intracellular proteins.


CONCLUSIONS
These data suggest a broad derangement in nonenzymatic biochemistry involving both lipids and carbohydrates exists in diabetic glomerular lesions ("carbonyl stress").
Miyata
T
T
Institute of Medical Sciences, Tokai University School of Medicine, Isehara, Japan.
Sugiyama
S
S
Suzuki
D
D
Inagi
R
R
Kurokawa
K
K
D000818:Animals; D050260:Carbohydrate Metabolism; D002478:Cells, Cultured; D003928:Diabetic Nephropathies / Q000378:metabolism* / Q000473:pathology; D017127:Glycation End Products, Advanced / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D007678:Kidney Glomerulus / Q000737:chemistry / Q000166:cytology / Q000473:pathology; D050356:Lipid Metabolism; D015227:Lipid Peroxidation; D008239:Lysine / Q000031:analogs & derivatives / Q000737:chemistry / Q000378:metabolism; D008315:Malondialdehyde / Q000737:chemistry / Q000378:metabolism; D010084:Oxidation-Reduction; D051381:Rats
D017127:Glycation End Products, Advanced; D008315:Malondialdehyde; C048496:N(6)-carboxymethyllysine; D008239:Lysine