Role of Galectin-3 in Diabetic Nephropathy

Abstract

Abstract. 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 ␤-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-R1and 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 AGEreceptor 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.Diabetic nephropathy is a major cause of morbidity and mortality in patients with both type 1 and type 2 diabetes. It is characterized by predominant glomerular involvement with expansion of the mesangial region and glomerular basement membrane (GBM) thickening, associated with ialinosis of the afferent and efferent arterioles and tubulointerstitial sclerosis. The enlargement of the mesangium seems to play a major role in the progression of glomerulopathy, for it is initially accommodated by an overall growth of the glomerulus but later impinges on the glomerular capillary lumen and diminishes the filtration surface. The increase in mesangial volume is linked predominantly to increased deposition of the extracellular matrix (ECM) and possibly to an expansion of the cell compartment (1).Hyperglycemia plays a central role in the pathogenesis of diabetic nephropathy, as shown by its prevention by strict metabolic control (2,3). The injurious effects of hyperglycemia have been attributed to its biochemical and metabolic consequences, including the increased glucose flux through the polyol and hexosamine pathways, activation of protein kinase C, enhanced nonenzymatic glycation, and oxidative stress (1).

Galectin-3 Gene Inactivation Reduces Atherosclerotic Lesions and Adventitial Inflammation in ApoE-Deficient Mice

“…27 GaL3 was shown to mediate the endocytotic uptake of modified lipoproteins 15 and to be a component of the AGE-receptor complex expressed in macrophages. 16 The functional interaction of GaL3 (AGE-R3) with AGE-R1 and AGE-R2 receptors 28 suggested the possible interaction with AGEbinding proteins. 29 Thus a putative sequence of events may start with the migration of monocytes into the artery wall, triggering GaL3 up-regulation in these cells.…”

Galectin-3 in diabetic patients

“…Maeda et al showed that galectin-3 induced hepatic stellate cells transdifferentiation into myofibroblasts via the mitogenactivated protein kinase/extracellular signal-regulated kinase (ERK)-ERK 1/2 signaling pathway and, at variance with galectin-1, in a protein kinase C-and A-dependent manner [53], whereas MacKinnon et al showed that galectin-3 ablation reduced alveolar epithelial cell EMT in response to TGF-β1 [50]. In addition, galectin-3 plays a complex role in the modulation of immune/inflammatory function, with distinct pro-inflammatory actions, but also with relevant anti-inflammatory effects which predominate under chronic conditions [7]. In acute settings, galectin-3 favors the inflammatory response against microbial infections.…”

“…Extracellular galectin-3 interacts via the CRD [5] with the β-galactoside residues of several extracellular matrix (ECM) and cell surface glycoproteins [6]; this is the classical lectin-glycoconjugate interaction. Conversely, interactions of intracellular galectin-3 occur via peptide-peptide associations mediated by its N-terminus domain, though also the CRD may be involved at this level [7]. These structural properties enable galectin-3 to bind several proteins, thus exerting multiple functions which make it a broad-spectrum biological response modifier involved in several disease conditions [8] (Figure 1).…”

“…In fact, under conditions of increased AGE/ALE levels, galectin-3 ablation was associated with tissue-specific outcomes, reflecting the AGE/ALE-receptor function and possibly the direct anti-inflammatory effects of this lectin [7]. Conversely, in experimental models of acute inflammation and fibrosis, deletion of Lgals3 gene resulted in prevention or attenuation of target tissue injury [21].…”

Polarization of Macrophages in Metabolic Diseases

“…We recently demonstrated in two pre-clinical models of advanced DN that macrophages indeed had re-polarized locally in the tissue towards a phenotype more resembling a mixed M2 to M1/M2-like phenotype with significantly reduced CD11c in combination with enhanced galectin-3 expression [69]. Macrophage galectin-3 strengthen TGFβR signalling by retaining cell surface expression of TGF-β receptors and thus the newly polarized diabetic kidney macrophage might provide novel insight to understand the tissue remodelling processes occurring in DN [133,134]. …”