Review
Tamm-Horsfall glycoprotein: biology and clinical relevance

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Abstract

Tamm-Horsfall glycoprotein (THP) is the most abundant urinary protein in mammals. Urinary excretion occurs by proteolytic cleavage of the large ectodomain of the glycosyl phosphatidylinositol-anchored counterpart exposed at the luminal cell surface of the thick ascending limb of Henle's loop. We describe the physical-chemical structure of human THP and its biosynthesis and interaction with other proteins and leukocytes. The clinical relevance of THP reported here includes: (1) involvement in the pathogenesis of cast nephropathy, urolithiasis, and tubulointerstitial nephritis; (2) abnormalities in urinary excretion in renal diseases; and (3) the recent finding that familial juvenile hyperuricemic nephropathy and autosomal dominant medullary cystic kidney disease 2 arise from mutations of the THP gene. We critically examine the literature on the physiological role and mechanism(s) that promote urinary excretion of THP. Some lines of research deal with the in vitro immunoregulatory activity of THP, termed uromodulin when isolated from urine of pregnant women. However, an immunoregulatory function in vivo has not yet been established. In the most recent literature, there is renewed interest in the capacity of urinary THP to compete efficiently with urothelial cell receptors, such as uroplakins, in adhering to type 1 fimbriated Escherichia coli. This property supports the notion that abundant THP excretion in urine is promoted in the host by selective pressure to obtain an efficient defense against urinary tract infections caused by uropathogenic bacteria.

Section snippets

Physical-chemical structure of urinary THP and its renal glycosyl phosphatidylinositol-anchored counterpart

The primary structure of human-THP has been predicted by sequencing the cDNA.13, 14 On the basis of the N-terminal sequence (Asp-Thr-Ser-Glu-Ala) found in urinary THP, Pennica et al13 assigned 616 amino acids to THP, in that the first 24 N-terminal amino acids predicted by cDNA represent the signal peptide lacking in the mature protein (we have used amino acid-mapping according to Pennica et al,13 to indicate both the N-glycosylation sites and all cited amino acids throughout the text). The

The glycomoiety structure of THP

Carbohydrates account for approximately 30% of the weight of human THP and consist mainly of N-linked glycans of di-, tri-, and tetra-antennary type6, 34, 35, 36; however, 1 N-glycosylation site carries high mannose sequences.37 The tetra-antennary chains are elongated in a sizable percentage by repeating N-acetyllactosamine sequences and show marked heterogeneity because of differences in the extent of sialylation, fucosylation, and sulfation (Fig 2). 38, 39 Of the 8 potential N-glycosylation

Localization and biosynthesis of THP

When RNAs isolated from approximately 150 different cell tissues were hybridized using a large probe for human THP RNA, only RNA from human adult kidney gave a positive signal, indicating that this glycoprotein is exclusively produced by kidney cells.13 Immunofluorescence and immunochemical analyses by light and electron microscopy indicated that THP resides in kidney cells of TAL and early distal convoluted tubules.56, 57, 58, 59, 60, 61 When the cellular location of rat THP messenger RNA

Tendency to gelation/aggregation

One of the most peculiar features of THP in solution is its tendency to gelation/aggregation when sodium chloride concentration is close to 100 mmol/L or calcium chloride is 1 mmol/L.76, 77 Both conditions usually occur in normal urine, and a method based on this property has been set up to purify THP. When urine of healthy individuals is filtered through a diatomaceous earth filter, THP is entrapped selectively in the filter. Because gelation is reversed at a low ionic concentration, THP is

Clinical relevance of urinary THP

Urinary THP is believed to be involved in the pathogenesis of various disorders of distal nephrons and the urinary tract, such as cast nephropathy, urolithiasis, and tubulointerstitial nephritis (TIN). Moreover, reduced urinary THP excretion is considered a reliable index of distal tubular cell damage. Finally, a very recent study showed that familial juvenile hyperuricemic nephropathy (FJHN) and autosomal dominant medullary cystic kidney disease 2 (MCKD2) arise from mutations of the THP gene.

THP in biotechnology

Observations that the THP gene is transcribed exclusively by TAL cells and THP is largely excreted in urine recently have been used for the transgenic production of human therapeutic proteins.199, 200 This approach is based on recently developed technologies that allow one to generate transgenic mice by using a mouse gene promoter to direct the expression of proteins selectively released in urine.201 In comparison to the expression of human therapeutic proteins in milk of transgenic livestock,

Conclusion

Although the bulk of evidence shows the involvement of THP in pathological states of the kidney and urinary tract, there are no clear indications about its physiological role, although the structural, genetic, and cytological characterization largely has been clarified in the last 20 years. In the late 1980s, great enthusiasm accompanied the observation that urinary THP/uromodulin could have an immunoregulatory function in that it inhibits in vitro lymphocyte blastogenesis and interacts with

Acknowledgements

The authors thank Professor Fiorenzo Stirpe for critical review of the manuscript and anonymous reviewers for their accurate reading and useful suggestions.

References (206)

  • F. Dall’Olio et al.

    Structural analysis of the preponderant high-mannose oligosaccharides of human Tamm-Horsfall glycoprotein

    Carbohydr Res

    (1988)
  • F. Serafini-Cessi et al.

    Biosynthesis and oligosaccharide processing of human Tamm-Horsfall glycoprotein permanently expressed in HeLa cells

    Biochem Biophys Res Commun

    (1993)
  • R.L. Easton et al.

    Pregnancy-associated changes in the glycosylation of Tamm-Horsfall glycoprotein; Expression of sialyl Lewisx sequences on core 2 type O-glycans derived from uromodulin

    J Biol Chem

    (2000)
  • M. Olczak et al.

    Oligosaccharides released by hydrazinolysis from Tamm-Horsfall protein of various human donors contain similar high-mannose glycans

    Clin Chim Acta

    (1999)
  • J.A. Gokhale et al.

    Characterization of Tamm-Horsfall protein in a rat nephrolithiasis model

    J Urol

    (2001)
  • D.A. Brown et al.

    Sorting of GPI-anchored protein to glycolipid-enriched membrane subdomains during transport to the apical cell surface

    Cell

    (1992)
  • J.K. Horton et al.

    A new and rapid immunochemiluminometric assay for the measurement of Tamm-Horsfall glycoprotein

    Clin Chim Acta

    (1988)
  • K. Kobayashi et al.

    Conditions for solubilization of Tamm-Horsfall protein/uromodulin in human urine and establishment of a sensitive and accurate enzyme-linked immunosorbent assay (ELISA) method

    Arch Biochem Biophys

    (2001)
  • W.Z. Ying et al.

    Dietary salt regulates expression of Tamm-Horsfall glycoprotein in rats

    Kidney Int

    (1998)
  • F.K. Stevenson et al.

    The effect of ions on the viscometric and ultracentrifugal behaviour of Tamm-Horsfall glycoprotein

    Biochim Biophys Acta

    (1971)
  • R.C. Wiggins

    Uromucoid (Tamm-Horsfall glycoprotein) forms different polymeric arrangements on a filter surface under different physicochemical conditions

    Clin Chim Acta

    (1987)
  • F. Serafini-Cessi et al.

    Rapid isolation of Tamm-Horsfall glycoprotein (uromodulin) from human urine

    J Immunol Methods

    (1989)
  • D. Cavallone et al.

    Salt-precipitation method does not isolate to homogeneity Tamm-Horsfall glycoprotein from urine of proteinuric patients and pregnant women

    Clin Biochem

    (2002)
  • D.C.J. Rhodes et al.

    Tamm-Horsfall glycoprotein binds IgG with high affinity

    Kidney Int

    (1993)
  • D.C. Rhodes et al.

    Errors in reported association between Tamm-Horsfall protein and IgG

    Kidney Int

    (1999)
  • R.D. Cummings et al.

    Characterization of the structural determinants required for the high affinity interaction of asparagine-linked oligosaccharides with immobilized Phaseolus vulgaris leukoagglutinating and erythroagglutinating lectins

    J Biol Chem

    (1982)
  • A.P. Sherblom et al.

    The lectin-like interaction between recombinant tumor necrosis factor and uromodulin

    J Biol Chem

    (1988)
  • P. Moonen et al.

    Bioassay for interleukin-1 inhibitors

    J Immunol Methods

    (1987)
  • F. Dall’Olio et al.

    Immunosuppressive activity of Tamm-Horsfall glycoprotein oligosaccharidesEffect of removal of outer sugars and conjugation with a protein carrier

    Cell Immunol

    (1991)
  • M. Tandai-Hiruma et al.

    Detection of novel carbohydrate binding activity of interleukin-1

    J Biol Chem

    (1999)
  • J.K. Horton et al.

    Activation of the inflammatory response of neutrophils by Tamm-Horsfall glycoprotein

    Kidney Int

    (1990)
  • D.B.L. Thomas et al.

    Tamm Horsfall protein binds to a single class of carbohydrate specific receptors on human neutrophils

    Kidney Int

    (1993)
  • G. Toma et al.

    Uromodulin (Tamm-Horsfall protein) is a leukocyte adhesion molecule

    Biochem Biophys Res Commun

    (1994)
  • C.L. Yu et al.

    Tamm-Horsfall glycoprotein (THG) purified from normal human pregnancy urine increases phagocytosis, complement receptor expressions and arachidonic acid metabolism of polymorphonuclear neutrophils

    Immunopharmacology

    (1992)
  • C.L. Yu et al.

    Tamm-Horsfall urinary glycoprotein enhances monokine release and augments lymphocyte proliferation

    Immunopharmacology

    (1993)
  • I. Tamm et al.

    Characterization and separation of an inhibitor of viral hemagglutination present in urine

    Proc Soc Exp Biol Med

    (1950)
  • I. Tamm et al.

    A mucoprotein derived from human urine which reacts with influenza, mumps, and Newcastle disease viruses

    J Exp Med

    (1952)
  • A. Gottschalk

    Carbohydrate residue of a urine mucoprotein inhibiting influenza virus haemagglutination

    Nature

    (1952)
  • L. Odin

    Carbohydrate residue of a urine mucoprotein inhibiting influenza virus haemagglutination

    Nature

    (1952)
  • M.E. Bayer

    An electron microscope examination of urinary mucoprotein and its interaction with influenza virus

    J Cell Biol

    (1964)
  • A.P. Fletcher et al.

    Tamm-Horsfall urinary glycoprotein. The chemical composition

    Biochem J

    (1970)
  • A.P. Fletcher et al.

    Tamm-Horsfall urinary glycoprotein. The subunit structure

    Biochem J

    (1970)
  • A.M. Grant et al.

    The development of a radioimmunoassay for the measurement of urinary Tamm-Horsfall glycoprotein in the presence of sodium dodecyl sulphate

    Clin Sci

    (1973)
  • D.R. Dunstan et al.

    A protein immunologically similar to Tamm-Horsfall glycoprotein, produced by cultured baby hamster kidney cells

    Proc Soc Lond (B Biol Sci)

    (1974)
  • A.V. Muchmore et al.

    UromodulinA unique 85-kilodalton immunosuppressive glycoprotein isolated from urine of pregnant women

    Science

    (1985)
  • F. Serafini-Cessi et al.

    Specific interaction of human Tamm-Horsfall glycoprotein with leucoagglutinin, a lectin from Phaseolus vulgaris (red kidney bean)

    Biochem J

    (1979)
  • C. Franceschi et al.

    Monosaccharides and Tamm-Horsfall glycopeptide inhibit allogenic antigen-induced lymphocyte blastogenesis in one-way mixed lymphocyte reaction

  • D. Pennica et al.

    Identification of human uromodulin as the Tamm-Horsfall urinary glycoprotein

    Science

    (1987)
  • C. Hession et al.

    Uromodulin (Tamm-Horsfall glycoprotein)A renal ligand for lymphokines

    Science

    (1987)
  • M.A. Ferguson et al.

    Cell-surface anchoring of proteins via glycosyl-phosphatidylinositol structures

    Annu Rev Biochem

    (1988)
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    Supported in part by grants from Ministero Università Ricerca Scientifica Technologica (MURST-Rome) and the University of Bologna (ex 60% and funds for selected research topics).

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