Role of galectin-3 in diabetic nephropathy.
The advanced glycosylation end products (AGE) participate in the pathogenesis of nephropathy and other diabetic complications through several mechanisms, including their binding to cell surface receptors. The AGE receptors include RAGE, the macrophage scavenger receptors, OST-48 (AGE-R1), 80K-H (AGE-R2), and galectin-3 (AGE-R3). Galectin-3 interacts with the beta-galactoside residues of cell surface and matrix glycoproteins via the carbohydrate recognition domain and with intracellular proteins via peptide-peptide associations mediated by its N-terminus domain. These structural properties enable galectin-3 to exert multiple functions, including the mRNA splicing activity, the control of cell cycle, the regulation of cell adhesion, the modulation of allergic reactions, and the binding of AGE. The lack of transmembrane anchor sequence or signal peptide suggests that it is associated with other AGE receptors, possibly AGE-R1 and AGE-R2, to form an AGE-receptor complex, rather than playing an independent role. In target tissues of diabetic vascular complications, such as the endothelium and mesangium, galectin-3 is weakly expressed under basal conditions and is markedly upregulated by the diabetic milieu (and to a lesser extent by aging). Galectin-3-deficient mice were found to develop accelerated diabetic glomerulopathy versus the wild-type animals, as evidenced by the more pronounced increase in proteinuria, mesangial expansion, and matrix gene expression. This was associated with a more marked renal/glomerular AGE accumulation, suggesting that it was attributable to the lack of galectin-3 AGE-receptor function. These data indicate that galectin-3 is upregulated under diabetic conditions and is operating in vivo to provide protection toward AGE-induced tissue injury, as opposed to RAGE.
Iacobini
Carla
C
Laboratory of Metabolism and Pathological Biochemistry, Section of Endocrine Biochemistry, Istituto Superiore di Sanità, Rome, Italy.
Amadio
Lorena
L
Oddi
Giovanna
G
Ricci
Carlo
C
Barsotti
Paola
P
Missori
Serena
S
Sorcini
Mariella
M
Di Mario
Umberto
U
Pricci
Flavia
F
Pugliese
Giuseppe
G
D000818:Animals; D019610:Cytoprotection; D003928:Diabetic Nephropathies / Q000473:pathology / Q000503:physiopathology*; D037502:Galectin 3 / Q000737:chemistry / Q000378:metabolism*; D017127:Glycation End Products, Advanced / Q000378:metabolism; D006801:Humans; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000378:metabolism; D013329:Structure-Activity Relationship
D037502:Galectin 3; D017127:Glycation End Products, Advanced; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic