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Department of Clinical Sciences and
Department of Experimental Medicine and Pathology, ‘La Sapienza’ University, 00161 Rome, Italy;
* Laboratory of Metabolism and Biochemical Pathology, Istituto Superiore di Sanità, 00161 Rome Italy;
Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla 92037;
The La Jolla Institute for Allergy and Immunology, La Jolla 92121, California, USA; and
¶ The Mount Sinai School of Medicine, New York 10029, New York, USA
1Correspondence: Dipartimento di Scienze Cliniche (Endocrinologia), Viale del Policlinico, 155, 00161 Rome, Italy. E-mail: giuseppe.pugliese{at}uniroma1.it
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.—Pugliese, G., Pricci, F., Iacobini, C., Leto, G., Amadio, L., Barsotti, P., Frigeri L., Hsu, D. K., Vlassara, H., Liu, F.-T., Di Mario, U. Accelerated diabetic glomerulopathy in galectin-3/AGE receptor 3 knockout mice.
Key Words: diabetic nephropathy • advanced glycation end products • advanced glycation end product receptors • extracellular matrix
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