Figure 2:

Uromodulin and disease. In CKD, uromodulin production is decreased because of decreased tubular cell mass. Additionally, sUMOD is carbamylated, and this leads to modified functions. As an example, its protective function against vascular calcification is lost. Gain-of-function UMOD mutations causing ADTKD typically interfere with uromodulin processing, leading to intracellular accumulation of abnormal uromodulin that causes proteotoxicity, as well as uromodulin deficiency in urine and the circulation [120]. The resultant phenotype of ADTKD is a combination of both decreased production of normal uromodulin and the production of abnormal uromodulin. Mutant uromodulin induces ER stress, unfolded protein response and accelerated apoptosis, leading to tubular cell death, nephron drop-out, fibrosis and progressive CKD. Simultaneously, wild-type uromodulin deficiency results in decreased activation of NKCC2 and annuls the water-impermeability of TAL; therefore, sodium reabsorption is reduced, and hypovolemia occurs. As a compensatory mechanism, it has been hypothesized [121] and in part experimentally demonstrated [122] that sodium reabsorption is increased in the proximal tubule, a process that is coupled with increased proximal urate reabsorption; thus, patients develop hypouricosuric hyperuricemia and gout early in life. Similarly, in hepsin-deficient mice, there is a combination of excess intracellular uromodulin causing cytotoxicity and insufficient extracellular uromodulin, potentially leading to features of uromodulin insufficiency.