The importance of uromodulin as regulator of salt reabsorption along the thick ascending limb

Uromodulin (UMOD), also named Tamm Horsfall protein, is the most abundant protein secreted in the urine under normal conditions. It was purified the first time in 1950 and since then considerable efforts have highlighted its importance in human pathophysiology. However, its precise biological functions still remain elusive. The clinical interest in UMOD derives from the evidence that UMOD genetic mutations result in tubulointerstitial nephropathies currently known as UMOD-associated kidney disease (UAKD), rare genetic disorders characterized by hyperuricaemia, gout and a progressive decline of renal function [1]. In addition, UMOD has been proposed to modulate water and electrolyte homeostasis by acting on the main transporters expressed along the thick ascending limb (TAL) and the early distal convoluted tubule. The precursor undergoes extensive post-translational modifications through the endoplasmic reticulum (ER) and the Golgi apparatus, and ultimately it is targeted to the apical membrane [2]. From the luminal site, it is cleaved by an unknown protease and then released into the tubular fluid.