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

Abstract

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.

DDOST, PRKCSH and LGALS3, which encode AGE-receptors 1, 2 and 3, respectively, are not associated with diabetic nephropathy in type 1 diabetes

“…Moreover, an increased amount of AGE-R1 suppresses AGE-mediated mesangial cell inflammatory injury through negative regulation of RAGE signalling [10]. AGE-R3, which is encoded by LGALS3, also seems to participate in the degradation of AGEs, since knockout mice for AGE-R3 have higher AGE levels in the kidneys and a higher incidence of age-related glomerular lesions [11]. The clustering of genetic risk factors for many autoimmune diseases suggests that these diseases share similar underlying causal mechanisms [12].…”

Increased glomerular cell (podocyte) apoptosis in rats with streptozotocin-induced diabetes mellitus: role in the development of diabetic glomerular disease

“…Glomerular cell apoptosis Glomerular cell death rate was assessed by immunohistochemistry, as previously reported [11,31]. Sections were sequentially treated with: (1) Triton X-100 (0.1%, vol./vol.)…”

“…Serum AGE levels were assessed by competitive ELISA, using a mouse monoclonal antibody against AGE-modified bovine serum albumin [11,31].…”

The Two Faces of Galectin-3: Roles in Various Pathological Conditions

“…Metaflammation precedes the development of metabolic abnormalities such as insulin resistance, type 2 diabetes and nonalcoholic fatty liver disease. Despite the fact that Galectin-3 exhibits deleterious effects under inflammatory conditions, various studies have demonstrated its protective role in the pathogenesis of obesity-induced inflammation triggered by accumulation of different metabolic stressors, such as advanced glycation end products (AGEs) (28). Namely, AGEs and the receptor for AGEs (RAGE) have been linked to enhanced apoptosis and dysfunction of pancreatic β cells and also to the pathogenesis of diabetic complications (29).…”