ReviewTamm-Horsfall glycoprotein: biology and clinical relevance
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.
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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).