Galectin-3/AGE-receptor 3 knockout mice show accelerated AGE-induced glomerular injury: evidence for a protective role of galectin-3 as an AGE receptor.
We previously showed that mice lacking galectin-3/AGE-receptor 3 develop accelerated diabetic glomerulopathy. To further investigate the role of galectin-3/AGE-receptor function in the pathogenesis of diabetic renal disease, galectin-3 knockout (KO) and coeval wild-type (WT) mice were injected for 3 months with 30 microg/day of N(epsilon)-carboxymethyllysine (CML)-modified or unmodified mouse serum albumin (MSA). Despite receiving equal doses of CML, KO had higher circulating and renal AGE levels and showed more marked renal functional and structural changes than WT mice, with significantly higher proteinuria, albuminuria, glomerular, and mesangial area and glomerular sclerosis index. Renal 4-hydroxy-2-nonenal content and NFkappaB activation were also more pronounced in KO-CML vs. WT-CML. Kidney mRNA levels of fibronectin, laminin, collagen IV, and TGF-beta were up-regulated, whereas those of matrix metalloproteinase-2 and -14 were down-regulated, again more markedly in KO-CML than WT-CML mice. Basal and CML-induced RAGE and 80K-H mRNA levels were higher in KO vs. WT mice. MSA injection did not produce any significant effect in both genotypes. The association of galectin-3 ablation with enhanced susceptibility to AGE-induced renal disease, increased AGE levels and signaling, and altered AGE-receptor pattern indicates that galectin-3 is operating in vivo as an AGE receptor to afford protection toward AGE-dependent tissue injury.
Iacobini
Carla
C
Department of Cell Biology and Neurosciences, Istituto Superiore di Sanità, Rome, Italy.
Menini
Stefano
S
Oddi
Giovanna
G
Ricci
Carlo
C
Amadio
Lorena
L
Pricci
Flavia
F
Olivieri
Antonella
A
Sorcini
Mariella
M
Di Mario
Umberto
U
Pesce
Carlo
C
Pugliese
Giuseppe
G
D000447:Aldehydes / Q000378:metabolism; D000818:Animals; D016923:Cell Death; D049109:Cell Proliferation; D016326:Extracellular Matrix Proteins / Q000096:biosynthesis / Q000235:genetics; D037502:Galectin 3 / Q000235:genetics / Q000502:physiology*; D017127:Glycation End Products, Advanced / Q000378:metabolism / Q000633:toxicity*; D007668:Kidney / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D007672:Kidney Cortex / Q000378:metabolism; D007674:Kidney Diseases / Q000139:chemically induced* / Q000473:pathology / Q000503:physiopathology; D007678:Kidney Glomerulus / Q000473:pathology*; D007700:Kinetics; D008239:Lysine / Q000031:analogs & derivatives* / Q000633:toxicity; D020782:Matrix Metalloproteinases / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism; D011507:Proteinuria / Q000139:chemically induced / Q000503:physiopathology; D012333:RNA, Messenger / Q000378:metabolism; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D016212:Transforming Growth Factor beta / Q000096:biosynthesis / Q000235:genetics
D000447:Aldehydes; D016326:Extracellular Matrix Proteins; D037502:Galectin 3; D017127:Glycation End Products, Advanced; D016328:NF-kappa B; D012333:RNA, Messenger; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; D016212:Transforming Growth Factor beta; C048496:N(6)-carboxymethyllysine; D020782:Matrix Metalloproteinases; C027576:4-hydroxy-2-nonenal; D008239:Lysine