The diabetic milieu modulates the advanced glycation end product-receptor complex in the mesangium by inducing or upregulating galectin-3 expression

Nonenzymatic glycation has been implicated in the pathogenesis of the dysre gulated tissue remodeling that characterizes diabetic glomerulopathy, via t he formation of advanced glycation end products (AGEs) and their binding to cell surface receptors. Several AGE-binding proteins have been identified so far, including p60, p90, and the adhesive and growth-regulating lectin g alectin-3 (Gal-3), the components of the so-called AGE-receptor complex. Th is study aimed to evaluate the mesangial expression of the AGE-receptor com plex and its modulation by the diabetic milieu, both in vivo, in nondiabeti c versus streptozotocin-induced diabetic rats, and in vitro, in mesangial c ells exposed to either normal glucose (NG) levels (5.5 mmol/l), as compared with high glucose (HG) levels (30 mmol/l) and iso-osmolar mannitol (M), or to native bovine serum albumin (BSA), as compared with glycated BSA with A GE formation (BSA-AGE) and glycated BSA in which AGE formation was prevente d by aminoguanidine (BSA-AM). In vivo, Gal-3 protein and mRNA were not dete ctable in glomeruli from nondiabetic rats until 12 months after initiating the study. On the contrary, in diabetic rats, Gal-3 expression was observed at 2 months of disease duration, and it increased thereafter. Both p60 and p90 immunoreactivities were observed at the glomerular level with slightly increased expression of p90, but not p60, :in diabetic versus nondiabetic animals. In vitro, Gal-3 was not detectable in mesangial cells cultured in NG (although it became evident after a certain number of passages in cultur e), whereas Gal-3 was detectable in cells grown on BSA. Prolonged exposure (2-4 weeks) of mesangial cells to HG but not to M, as well as growing cells on BSA-AGE and, to a lesser extent, BSA-AM, induced or significantly incre ased the expression of Gal-3, both protein (up to 2.65-fold) and mRNA (up t o 3.10-fold) and its secretion in the medium (by similar to 50%). Both p60 and p90 were demonstrated in mesangial cells under NG conditions, and the e xpression of p90, but not p60, was upregulated by similar to 20% by HG or B SA-AGE. These results indicate that 1) under basal conditions, Gal-3, unlik e p90 and p60, is not detectable in the mesangium but becomes expressed wit h aging and 2) the diabetic milieu induces or upregulates Gal-3 production, whereas it increases only slightly the expression of p90, but not p60. Gal -3 expression or overexpression may modulate the AGE-receptor-mediated even ts by modifying the function of the AGE-receptor complex. Additionally, it may exert direct effects on tissue remodeling by virtue of its adhesive and growth-regulating properties.