Advanced glycation end products (AGE) contribute to diabetic tissue injury by two major mechanisms, i.e., the alteration of extracellular matrix architecture through nonenzymatic glycation, with formation of
protein crosslinks, and the modulation of cellular functions through interactions with specific
cell surface receptors, the best characterized of which is the receptor for AGE (RAGE). Recent evidence suggests that the AGE-RAGE interaction may also be promoted by inflammatory processes and oxidative cellular injury. To characterize the distributions of AGE and RAGE in diabetic kidneys and to determine their specificity for
diabetic nephropathy, an immunohistochemical analysis of renal biopsies from patients with
diabetic nephropathy (n = 26), hypertensive
nephrosclerosis (n = 7), idiopathic
focal segmental glomerulosclerosis (n = 11), focal
sclerosis secondary to
obesity (n = 7), and
lupus nephritis (n = 11) and from normal control subjects (n = 2) was performed, using affinity-purified
antibodies raised to RAGE and two subclasses of AGE, i.e.,
N(epsilon)-(carboxymethyl)-lysine (CML) and
pentosidine (PENT). AGE were detected equally in diffuse and nodular
diabetic nephropathy. CML was the major AGE detected in diabetic mesangium (96%), glomerular basement membranes (GBM) (42%), tubular basement membranes (85%), and vessel walls (96%). In
diabetic nephropathy, PENT was preferentially located in interstitial
collagen (90%) and was less consistently observed in vessel walls (54%), mesangium (77%), GBM (4%), and tubular basement membranes (31%). RAGE was expressed on normal podocytes and was upregulated in
diabetic nephropathy. The restriction of RAGE
mRNA expression to glomeruli was confirmed by reverse transcription-PCR analysis of microdissected renal tissue compartments. The extent of mesangial and GBM immunoreactivity for CML, but not PENT, was correlated with the severity of
diabetic glomerulosclerosis, as assessed pathologically. CML and PENT were also identified in areas of glomerulosclerosis and
arteriosclerosis in idiopathic and secondary
focal segmental glomerulosclerosis, hypertensive
nephrosclerosis, and
lupus nephritis. In active
lupus nephritis, CML and PENT were detected in the proliferative glomerular tufts and crescents. In conclusion, CML is a major AGE in renal basement membranes in
diabetic nephropathy, and its accumulation involves upregulation of RAGE on podocytes. AGE are also accumulated in acute inflammatory
glomerulonephritis secondary to
systemic lupus erythematosus, possibly via enzymatic oxidation of glomerular matrix
proteins.