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- Title
Nonenzymatic glycation of type IV collagen and matrix metalloproteinase susceptibility.
- Authors
Mott, Joni D.; Khalifah, Raja G.; Nagase, Hideaki; Shield III, Charles F.; Hudson, Julie K.; Hudson, Billy G.
- Abstract
Nonenzymatic glycation of type IV collagen and matrix metalloproteinase susceptibility. The glomerular basement membrane (GBM) is damaged in diabetes through complex mechanisms that are not fully understood. Prominent among them is nonenzymatic protein glycation leading to the formation of so-called advanced glycation end products (AGEs). We examined the effects of <em>in vitro</em> glycation of intact collagen type IV in bovine lens capsule (LBM) and kidney glomerular (GBM) basement membranes on their susceptibility to matrix metalloproteinases, using stromelysin 1 (MMP-3) and gelatinase B (MMP-9). Sites of cleavage of unmodified LBM collagen were located in the triple helical region. <em>In vitro</em> glycation by glucose severely inhibited the release of soluble collagen cleavage peptides by MMP-3 and MMP-9. The distribution of AGEs within the three domains of collagen IV (7S, triple helical, and noncollagenous NCl) were compared for LBM glycation using AGE fluorescence, pentosidine quantitation, and immunoreactivity towards anti-AGE antibodies that recognize the AGE carboxymethyllysine (CML). Marked asymmetry was observed, with the flexible triple helical domain having the most pentosidine and fluorescent AGEs but the least CML. The <em>in vivo</em> relevance of these findings is supported by preliminary studies of AGE distribution in renal basement membrane (RBM) collagen IV domains from human kidneys of two insulin-dependent diabetics and one normal subject. Pentosidine and fluorescent AGE distributions of diabetic RBM were similar to LBM, but the CML AGE in diabetic kidney was less in the triple helical domain than in NCL. Our results support the hypothesis that nonenzymatic glycation of collagen IV contributes to the thickening of basemeat membranes, a hallmark of diabetic nephropathy.
- Subjects
EXTRACELLULAR matrix proteins; KIDNEY glomerulus; PEOPLE with diabetes; ENDOCRINE diseases; CARBOHYDRATE intolerance; HYPOGLYCEMIC agents
- Publication
Kidney International, 1997, Vol 52, Issue 5, p1302
- ISSN
0085-2538
- Publication type
Article
- DOI
10.1038/ki.1997.455