Accelerated diabetic glomerulopathy in galectin-3/AGE receptor 3 knockout mice.
Several molecules were shown to bind advanced glycation end products (AGEs) in vitro, but it is not known whether they all serve as AGE receptors and which functional role they play in vivo. We investigated the role of galectin-3, a multifunctional lectin with (anti)adhesive and growth-regulating properties, as an AGE receptor and its contribution to the development of diabetic glomerular disease, using a knockout mouse model. Galectin-3 knockout mice obtained by gene ablation and the corresponding wild-type mice were rendered diabetic with streptozotocin and killed 4 months later, together with age-matched nondiabetic controls. Despite a comparable degree of metabolic derangement, galectin-3-deficient mice developed accelerated glomerulopathy vs. the wild-type animals, as evidenced by the more pronounced increase in proteinuria, extracellular matrix gene expression, and mesangial expansion. This was associated with a more marked renal/glomerular AGE accumulation, indicating it was attributable to the lack of galectin-3 AGE receptor function. The galectin-3-deficient genotype was associated with reduced expression of receptors implicated in AGE removal (macrophage scavenger receptor A and AGE-R1) and increased expression of those mediating cell activation (RAGE and AGE-R2). These results show that the galectin-3-regulated AGE receptor pathway is operating in vivo and protects toward AGE-induced tissue injury in contrast to that through RAGE.
Pugliese
G
G
Department of Clinical Sciences, 'La Sapienza' University, 00161 Rome, Italy. giuseppe.pugliese@uniroma1.it
Pricci
F
F
Iacobini
C
C
Leto
G
G
Amadio
L
L
Barsotti
P
P
Frigeri
L
L
Hsu
D K
DK
Vlassara
H
H
Liu
F T
FT
Di Mario
U
U
D000818:Animals; D000943:Antigens, Differentiation / Q000235:genetics / Q000378:metabolism*; D001786:Blood Glucose / Q000378:metabolism; D001835:Body Weight; D024141:Collagen Type IV / Q000235:genetics; D003921:Diabetes Mellitus, Experimental / Q000150:complications; D003928:Diabetic Nephropathies / Q000209:etiology* / Q000235:genetics / Q000503:physiopathology; D005353:Fibronectins / Q000235:genetics; D037502:Galectin 3; D015870:Gene Expression; D005838:Genotype; D006442:Glycated Hemoglobin / Q000378:metabolism; D007668:Kidney / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D051379:Mice; D018345:Mice, Knockout; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000235:genetics; D053773:Transforming Growth Factor beta1
D000943:Antigens, Differentiation; D001786:Blood Glucose; D024141:Collagen Type IV; D005353:Fibronectins; D037502:Galectin 3; D006442:Glycated Hemoglobin; D012333:RNA, Messenger; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; C508961:Tgfb1 protein, mouse