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Uromodulin (Tamm-Horsfall protein) is the most abundant protein excreted in the
urine under physiological conditions. It is exclusively produced in the kidney
and secreted into the urine via proteolytic cleavage. Its biological function is
still not fully understood. Uromodulin has been linked to water/electrolyte
balance and to kidney innate immunity. Also, studies in knockout mice
demonstrated that it has a protective role against urinary tract infections and
renal stone formation. Mutations in the gene encoding uromodulin lead to rare
autosomal dominant diseases, collectively referred to as uromodulin-associated
kidney diseases. They are characterized by progressive tubulointerstitial
damage, impaired urinary concentrating ability, hyperuricemia, renal cysts, and
progressive renal failure. Novel in vivo studies point at intracellular
accumulation of mutant uromodulin as a key primary event in the disease
pathogenesis. Recently, genome-wide association studies identified uromodulin as
a risk factor for chronic kidney disease (CKD) and hypertension, and suggested
that the level of uromodulin in the urine could represent a useful biomarker for
the development of CKD. In this review, we summarize these recent
investigations, ranging from invalidation studies in mouse to Mendelian
disorders and genome-wide associations, which led to a rediscovery of uromodulin
and boosted the scientific and clinical interest for this long discovered
molecule.
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