Wednesday, December 2, 2009

Tamm-Horsfall Protein

The Tamm-Horsfall protein is a glycoprotein isolated from normal urine by Tamm and Horsfall in the early fifties. This protein is excreted by the thick ascending branch of the loop of Henle and the first part of the distal tubules. Normal daily excreted quantity ranges from 25 to 50 mg. The protein has a huge molecular weight of around 7 millions Daltons, with 25% to 40% of its weight being carbohydrates. This protein is the major fraction of the uromucoprotein.

The Tamm-Horsfall protein is a glycoprotein that in humans is encoded by the UMOD gene. This gene encodes uromodulin, the most abundant protein in normal urine. Its excretion in urine follows proteolytic cleavage of the ectodomain of its glycosyl phosphatidylinosital-anchored counterpart that is situated on the luminal cell surface of the loop of Henle. Uromodulin may act as a constitutive inhibitor of calcium crystallization in renal fluids. Excretion of uromodulin in urine may provide defense against urinary tract infections caused by uropathogenic bacteria. Defects in this gene are associated with the autosomal dominant renal disorders medullary cystic kidney disease-2 (MCKD2) and familial juvenile hyperuricemic nephropathy. These disorders are characterized by juvenile onset of hyperuricemia, gout, and progressive renal failure. While several transcript variants may exist for this gene, the full-length natures of only two have been described to date. These two represent the major variants of this gene and encode the same isoform.

The Tamm-Horsfall protein (THP) is a GPI-anchored glycoprotein. It is produced by the thick ascending limb of the loop of Henle of mammalian kidney. While the monomeric molecule has a MW of approximately 68 kD, it is physiologically present in a highly aggregated state in urine. When this protein is concentrated at low pH, it forms a gel. Tamm-Horsfall protein is the most abundant protein in mammalian urine. It is the matrix of urinary casts derived from the secretion of renal tubular cells.

This protein precipitates as a gel in a 0.58M NaCl solution, and redissolves in deionized water, or in an alkaline buffered solution. If albumine is added to a pure water solution of TH protein, the latter will precipitate and form a gel, taking the shape of the glassware used. Because of this property, casts are believed to dissolve readily in diluted or alkaline urine. Transposing an in-vitro experiment in a real physiological situation is sometimes hasardous. Other factors could stabilize the cast, so that a slight alkalisation (bacterial growth) of the urine does not necessarily mean cast dissolution.

Studies using THP deficient mice revealed that THP may have a role in regulatory physiology and actually participates in transporter function. A role in bacterial binding and sequestration is suggested by studies showing that E.coli expressing MS (mannose-sensitive) pili or fimbriae can be trapped by Tamm-Horsfall protein via its mannose-containing side chains. Tamm-Horsfall protein is part of the matrix in renal calculi but a role in kidney stone formation remains debatable. Antibodies to Tamm-Horsfall protein have been seen in various forms of nephritis (eg, Balkan nephropathy), however, it remains unclear whether there is any (patho-)physiologic relevance to these findings.