Uromodulin and Translational Medicine

Abstract

Tamm-Horsfall protein (THP) was originally described in 1895 as “urinary mucoprotein” and biochemically characterized approximately 50 years ago. Kidney epithelial cells of all placental mammals synthesize THP, and it is the most abundant protein in normal urine.1,2 Pirica, a novel THP-like gene that is induced in response to predation, was recently identified in tadpoles, suggesting that THP family proteins are also present in invertebrate species.3 Uromodulin was originally reported as a unique immunosuppressive glycoprotein from the urine of pregnant women,4 and its amino acid composition is identical to THP.5 Standard nomenclature for THP is now uromodulin. Uromodulin provides a protein infrastructure for urinary casts used to diagnosis various kidney diseases in the clinic. Experimentalists have used both in vitro and in vivo models to define the biology of uromodulin in the urinary tract, and protein chemists have extensively characterized its biochemical properties and domains.6–10 Despite these efforts, the function of uromodulin remains an enigma. Published data suggest uromodulin is glycosyl phosphatidyl inositol-anchored along the apical domain of some kidney epithelia and secreted into urine and blood. It inhibits both bacterial colonization of the urinary track and stone formation, binds and activates leukocytes, and generates the water impermeability of the thick ascending limb of Henle by assembly into filaments through its zona pelucida domain. Tissue distribution of pirica, the amphibian uromodulin-like protein, also supports the hypothesis that uromodulin regulates the water permeability of tissue.3 Mutations in UMOD , the gene that encodes uromodulin, cause rare, autosomal dominant, primary tubulointerstitialkidney diseases, particularly familial juvenile hyperuricemicnephropathy (FJHN; OMIM 191845) and a form of medullary cystic kidney disease (MCKD2; …