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

Abstract

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 GalNAcbeta1-4(NeuAcalpha2-3)Galbeta1-4GlcNAcbeta1-3Gal (Sd(a) determinant) carried by human THGP in protecting the distal nephron from colonization of type-S fimbriated E. coli which recognise NeuAcalpha2-3Gal, (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.

Interstitial calcinosis in renal papillae of genetically engineered mouse models: relation to Randall’s plaques

“…Mis-sense mutations that abrogate an existing cysteine or create a de novo cysteine in THP have been causatively linked to certain hereditary hyperuricemic patients, and they cause THP to misfold and be trapped in the rER leading to cytotoxity and failed apical targeting [36–39]. THP also contains eight asparagine-linked glycosylation consensus sites, but only seven are in a good context and were shown to be actually glycosylated [40]. Of these, asparagine 251 is modified by a high-mannose chain that is highly conserved across the species and is responsible for specific interactions between urinary THP and FimH adhesin of type 1-fimbriated E. coli [41–44].…”

“…Unless more reproducible sample preparation, storage and quantitation methodologies become a gold standard for different laboratories, such as the one recently published [77], it would be premature and misleading to conclude that quantitative defects of THP do not exist in stone formers. Finally, qualitative deficiencies such as insufficient sialylation of THP have been suggested to cause a functional defect in the inhibition of stone formation [40, 54, 78, 79]. These human-relevant topics are undoubtedly worthy of further exploration.…”

Tamm-Horsfall Protein Regulates Circulating and Renal Cytokines by Affecting Glomerular Filtration Rate and Acting as a Urinary Cytokine Trap

“…In vitro studies showed that the high-mannose moieties of THP are required for its interaction with IL1 and TNF, because de-glycosylation or inclusion of free mannoses effectively blocks the THP-cytokine interaction (65,66). Interestingly, high-mannose glycosylation of THP is extremely conserved, being present in THP isolated from all mammals studied to date (67,68). This suggests a strong structural/functional relationship in the THP-cytokine interaction and adds to the functional importance of THP-cytokine binding as an evolutionarily conserved mechanism in renal protection.…”

The Sda/GM2-glycan is a carbohydrate marker of porcine primordial germ cells and of a subpopulation of spermatogonia in cattle, pigs, horses and llama

“…and is possibly involved in protecting the human urinary tract from pathogenic Escherichia coli (Serafini-Cessi et al 2005).…”