Accelerated diabetic glomerulopathy in galectin‐3/AGE receptor 3 knockout mice

Abstract

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.

Advanced glycation end products regulate extracellular matrix protein and protease expression by human glomerular mesangial cells

“…Similar pathways have been implicated in the induction of cytokine adhesion molecules and growth factor synthesis by AGEs in various cell types (12,13,30). The pathways activated by the other receptors are less known, except for R3 which is involved in AGEs internalisation and clearance (31). Taken together, these results suggest that AGEs can activate human mesangial cells, mainly but not exclusively, through the binding to RAGE and its subsequent activation.…”

Regulation of Inducible Nitric Oxide Synthase Expression in Advanced Glycation End Product–Stimulated RAW 264.7 Cells

“…Diabetic nephropathy is developed in RAGE-overexpressed mice (34). Also, it has been reported that diabetic glomerulopathy is accelerated in gelactin-3-deficient mice, suggesting that the interaction between AGEs and gelactin-3 blocks the negative effects of AGEs (6). In vitro studies suggest that AGEs activate signaling pathways similar to those induced by inflammatory cytokines.…”

“…In addition, two binding proteins for AGEs were identified on the surface of endothelial cells, receptor for AGEs (RAGE) and lactoferrin-like polypeptide (homologous to lactoferrin) (4). The interaction between AGEs and their receptors plays a key role in the progression of diabetic atherosclerosis and glomerulopathy (5,6).…”

FEEL-1 and FEEL-2 Are Endocytic Receptors for Advanced Glycation End Products

“…For example, Park et al (24) have shown that intravenous administration of the soluble extracellular domain of RAGE, which was originally cloned from bovine pulmonary endothelial cells, efficiently suppressed diabetic atherosclerosis in apolipoprotein E-deficient mice. Second, Pugliese et al (25) have shown that diabetic glomerulopathy was rather accelerated in mice lacking galectin-3, a critical component of OST-48/80-K-H/galectin-3 complex (11) phages obtained from SR-A knock-out mice had the reduced capacity for endocytic degradation of AGE-BSA, which was 30% of that in wild-type cells. However, liver sinusoidal endothelial cells obtained from SR-A knock-out mice had capacity for endocytic degradation of AGE-BSA, which was indistinguishable from that of wild-type liver sinusoidal endothelial cells (27).…”