N-Glycans carried by Tamm-Horsfall glycoprotein have a crucial role in the defense against urinary tract diseases

Tamm-Horsfall glycoprotein (THGP), produced exclusively by renal cells from the thick ascending limb of Henle's loop, is attached by a glycosyl-phosphatidylinositol (GPI)-anchor to the luminal face of the cells. Urinary excretion of THGP (50-100 mg/day) occurs upon proteolytic cleavage of the large ectodomain of the GPI-anchored form. N-Glycans, consisting of a large repertoire of sialylated polyantennary chains and high-mannose structures, account for approximately 30% of the weight of human urinary THGP. We describe: (i) the involvement of urinary THGP high-mannose glycans in defense against infections of the urinary tract, caused by type-1 fimbriated Escherichia coli, which recognize high-mannose structures, (ii) the role of GalNAc beta 1-4(NeuAc alpha 2-3)Gal beta 1-4GlcNAc beta 1-3Gal (Sd(a) determinant) carried by human THGP in protecting the distal nephron from colonization of type-S fimbriated E. coli which recognise NeuAc alpha 2-3Gal, (iii) the inhibitory effect of sialylated THGP on crystal aggregation of calcium oxalate and calcium phosphate, thus preventing nephrolithiasis. Finally, we outline the importance of N-glycans in promoting the polymerization of THGP, a process resulting in the formation of homopolymers with an M-r of several million in urine. Since THGP defense against diseases of the urinary tract mainly consists in binding damaging agents, its ability to behave as a multivalent ligand significantly enhances this protective role.