Uromodulin Biology and Pathophysiology – An Update

Abstract

Uromodulin (UMOD) is a glycoprotein expressed on the luminal surface of the apical membrane of renal tubular epithelial cells forming the thick ascending limb of Henle. Here, UMOD forms filamentous structures probably ensuring water impermeability and the countercurrent gradient. The multidomain structure, cellular topology of UMOD and clinical consequences associated with UMOD dysfunction, however, suggest that it may be involved in other biological processes such as receptor-mediated endocytosis, mechanosensation of urinary flow, Wnt-signaling, cell cycle regulation and planar cell polarity. A specific, but as yet unidentified, protease(s) releases UMOD into the urine, where it probably contributes to colloid osmotic pressure, retards passage of positively charged electrolytes, prevents urinary tract infection and modulates formation of supersaturated salts and their crystals. UMOD expression, biosynthesis and excretion are regulated in a complex manner, and dysregulation is found in a wide range of pathological conditions. It is strongly reduced or absent in cases with mutations in UMOD, renin, HNF1B and other genetic disorders causing autosomal dominant hyperuricemic nephropathy. In contrast, elevated UMOD excretion may be associated with, and thus predictive of, chronic kidney disease. UMOD analysis is therefore of importance in all conditions with renal involvement and may be useful in the proper classification of renal diseases.

Uromodulin, an Emerging Novel Pathway for Blood Pressure Regulation and Hypertension

“…From cDNA sequence, the uromodulin precursor is composed of 640 amino-acid residues, and motifs include signal sequence (residues 1-24) directing its entry in the secretory pathway; 1 epidermal growth factor-like and 2 calcium-binding epidermal growth factor-like domains (residues 31-64, 65-107, and 108-149) which have roles in adhesion, coagulation, and receptor-ligand interaction; 1 central domain of unknown function (named D8C containing eight conserved cysteines); 1 zona pellucida domain (residues 334-585) essential for protein polymerization; a glycosylphosphatidylinositol attachment site (residue 614); and 8 potential N-glycosylation sites. 11,12 The molecular weight of uromodulin (105 kDa) is significantly contributed (30%) by N-glycosylation, and there are 48 cysteine residues involved in disulfide bond formation. 16 The uromodulin signal peptide is cleaved in the ER, the protein is glycosylated on 7 of its 8 potential N-glycosylation sites, disulphide bridges are formed, and glypiation on its C terminus occurs.…”

Uromodulin: old friend with new roles in health and disease

“…The UMOD gene is located at chromosome 16p12.3-16p13.11 and is shown to comprise 11-12 exons [4][5][6]. Uromodulin is produced exclusively by the epithelial cells of the thick ascending limb (TAL) of the loop of Henle.…”

“…To maintain the efficiency of the countercurrent concentrating mechanism, the electrolyte-transporting TAL has to be impermeable to water. There is evidence that uromodulin in the polymerized form contributes to the water impermeability of TAL [5]. In addition, uromodulin increases membrane expression of the renal outer medullary potassium channel (ROMK2) and activates the TAL N-K-2Cl co-transporter in vitro [12,13].…”

“…The existence of renal disease caused by UMOD mutations has been known for some time, but the phenotypic and genotypic [5] features have only recently been characterized in detail. Collectively termed UAKD, they were initially lumped into the "nephronophthisis-medullary cystic disease complex," but are now recognized as a distinctly separate group of diseases.…”

Tamm Horsfall Glycoprotein and Uromodulin

“…It is a highly glycosylated molecule with a high number of cysteine residues. These cysteine residues crosslink to form the final filamentous gel-like structure of uromodulin (4). Uromodulin is translocated to the apical surface of the thick ascending limb, where it is bound to the cell membrane by a glycophosphatidylinositol anchor.…”