Insight review articles

of the main AGE-modified proteins in endothelial cells
29
. Proteins
involved in macromolecular endocytosis are also modified by AGEs,
as the increase in endocytosis induced by hyperglycaemia is prevent-
ed by overexpression of the methylglyoxal-detoxifying enzyme 
glyoxalase I (ref. 30). Overexpression of glyoxalase I also completely
prevents the hyperglycaemia-induced increase in expression of
angiopoietin-2 in Muller cells (T. Matsumura et al., unpublished
results), a factor that has been implicated in both pericyte loss and
capillary regression
31
.
AGE formation alters the functional properties of several 
important matrix molecules. On type I collagen, intermolecular
crosslinking by AGEs induces an expansion of the molecular
packing
32
. These AGE-induced crosslinks alter the function of intact
vessels. For example, AGEs decrease elasticity in large vessels from
diabetic rats, even after vascular tone is abolished, and increase fluid
filtration across the carotid artery
33
. AGE formation on type IV colla-
gen from basement membrane inhibits lateral association of these
molecules into a normal network-like structure by interfering with
binding of the non-collagenous NC1 domain to the helix-rich
domain
34
. AGE formation on laminin causes decreased polymer 
self-assembly, decreased binding to type IV collagen, and decreased
binding to heparan sulphate proteoglycan
35
.
AGE formation on extracellular matrix not only interferes with
matrix–matrix interactions, but also interferes with matrix–cell
interactions. For example, AGE modification of type IV collagen’s
cell-binding domains decreases endothelial cell adhesion
36
, and AGE
modification of a growth-promoting sequence of six amino acids in
the A chain of the laminin molecule markedly reduces neurite 
outgrowth
37
.
Several cell-associated binding proteins for AGEs have been 
identified, including OST-48, 80K-H, galectin-3, the macrophage
scavenger receptor type II and RAGE
38–41
. Some of these are likely to
contribute to clearance of AGEs, whereas others may underlie the
sustained cellular perturbations mediated by binding of the AGE 
ligands. In cell-culture systems, the AGE receptors identified seem to
mediate long-term effects of AGEs on key cellular targets of diabetic
complications such as macrophages, glomerular mesangial cells and
vascular endothelial cells, although not all these receptors bind 
proteins with physiological AGE-modification levels. These effects
include expression of cytokines and growth factors by macrophages
and mesangial cells (interleukin-1, insulin-like growth factor-I,
tumour necrosis factor-
a, TGF-b, macrophage colony-stimulating
factor, granulocyte–macrophage colony-stimulating factor and
platelet-derived growth factor), and expression of pro-coagulatory
and pro-inflammatory molecules by endothelial cells (thrombo-
modulin, tissue factor and the cell adhesion molecule VCAM-1)
42–47
.
In addition, binding of ligands to endothelial AGE receptors seems to
mediate in part the hyperpermeability of the capillary wall induced
by diabetes, probably through the induction of VEGF
48
.
Consistent with this concept, blockade of one such receptor,
RAGE, a member of the immunoglobulin superfamily with three
immunoglobulin-like regions on a single polypeptide chain, 
suppressed macrovascular disease in an atherosclerosis-prone type 1
diabetic mouse model in a glucose- and lipid-independent fashion
49
.
Blockade of RAGE has also been shown to inhibit the development of
diabetic nephropathy and periodontal disease, and to enhance
wound repair in murine models. RAGE has been shown to mediate
signal transduction, through generation of reactive oxygen species,
which activates both the transcription factor NF-
kB, and p21
Ras
(refs 50, 51). AGE signalling is blocked in cells by expression of RAGE
antisense cDNA
52
or an anti-RAGE ribozyme
53
.

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