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

Tamm–Horsfall protein was discovered in 1950 by Igor Tamm and Frank Horsfall,1 using a salt precipitation procedure to isolate a potent inhibitor of viral hemagglutination from urine. Muchmore and Decker,2 in 1985, isolated a glycoprotein (calling it uromodulin) with in vitro immunosuppressive properties from urine of pregnant women. In 1987, Pennica et al3 confirmed by cDNA analysis that uromodulin and Tamm–Horsfall protein were identical proteins. Since the initial discovery and without any clear understanding of the function of uromodulin, it was only in 2002 when Hart et al4 identified causative uromodulin mutations in a subset of families having familial juvenile hyperuricemic nephropathy and medullary cystic kidney disease type 2 that interest in uromodulin biology and function was revived. Interest in uromodulin was further revitalized by genome-wide association studies (GWASs) in 2009/2010 showing an association between common single-nucleotide polymorphisms in the upstream region of the UMOD gene with renal function and hypertension.5–8 In 2013, 2 independent groups undertaking post-GWAS functional dissection of the UMOD loci provided molecular insights into a new pathway for hypertension and sodium homeostasis involving uromodulin and opening an exciting line of investigation that could enhance our understanding of renal tubule physiology, sodium homeostasis, blood pressure (BP) regulation, and potentially lead to novel therapies for hypertension.9,10 Uromodulin is a protein exclusively expressed by epithelial cells of the thick ascending limb of Henle’s loop (TAL; Figure 1). The 640 amino-acid precursor is cotranslationally translocated into the endoplasmic reticulum (ER), extensively glycosylated, glypiated, and glycosylphosphatidylinositol anchored to the apical tubular cell membrane. From here it is released by a specific, but as yet unidentified, serine protease(s). The released protein is excreted in the urine at a rate of 20 to 100 mg/d and represents the most abundant urinary protein in …