Uromodulin (Tamm–Horsfall protein): guardian of urinary and systemic homeostasis

Abstract

Biology has taught us that a protein as abundantly made and conserved among species as Tamm-Horsfall protein (THP or uromodulin) cannot just be a waste product serving no particular purpose. However, for many researchers, THP is merely a nuisance during urine proteome profiling or exosome purification and for clinicians an enigmatic entity without clear disease implications. Thanks to recent human genetic and correlative studies and animal modeling, we now have a renewed appreciation of this highly prevalent protein in not only guarding urinary homeostasis, but also serving as a critical mediator in systemic interorgan signaling. Beyond a mere barrier that lines the tubules, or a surrogate for nephron mass, mounting evidence suggests that THP is a multifunctional protein critical for modulating renal ion channel activity, salt/water balance, renal and systemic inflammatory response, intertubular communication, mineral crystallization and bacterial adhesion. Indeed, mutations in THP cause a group of inherited kidney diseases, and altered THP expression is associated with increased risks of urinary tract infection, kidney stone, hypertension, hyperuricemia and acute and chronic kidney diseases. Despite the recent surge of information surrounding THP's physiological functions and disease involvement, our knowledge remains incomplete regarding how THP is normally regulated by external and intrinsic factors, how precisely THP deficiency leads to urinary and systemic pathophysiology and in what clinical settings THP can be used as a theranostic biomarker and a target for modulation to improve patient outcomes.

Extratubular polymerized uromodulin induces leukocyte recruitment and inflammationin vivo

“…To demonstrate that murine polymerized UMOD (murine pUMOD) is also able to induce inflammation in the mouse cremaster muscle, we additionally injected a recombinant form of the mouse protein i.s. This truncated form of murine UMOD (aa25-588) contains all important domains of UMOD (30) and also forms polymers (Supplemental Figure 1B). Similar to our findings with human pUMOD, murine pUMOD reduced leukocyte rolling flux fraction and increased the number of adherent cells (Supplemental Figure 2A and B) compared to the injection of mouse albumin (mALB).…”

“…Under homeostatic conditions, these two UMOD forms localize to two different body compartments after being released from tubular epithelial cells (2,14,30). The polymeric form is the predominant form found in the tubular lumen and urine, where it regulates water and electrolyte balance and protects the kidney from bacterial infections and kidney stone formation (2).…”

“…Additionally, tubular epithelial cells release, although to a lesser extent, UMOD to the basolateral site into the renal parenchyma. Basolaterally released UMOD does not polymerize, but instead is transported into the bloodstream where it circulates primarily in its monomeric form and exerts its systemic homeostatic functions (14,30). Therefore, under physiological conditions, the polymeric form is exclusively found in the urinary tract and is not For this reason, we tested whether pUMOD functions as a DAMP-like molecule triggering inflammation if reaching renal tissue outside of the urinary tract.…”

Urinary exosomal proteins as (pan‐)cancer biomarkers: insights from the proteome

“…For example although proteomics‐assisted discovery of blood biomarkers was initially hampered as a result of variations in highly abundant proteins, the advent of MS‐based proteomics has now potentiated diagnostics based on blood proteomics . Compared to blood, urine is a less complex and relatively clean biofluid, with the only relatively abundant protein being uromodulin . In normal physiological conditions, urine contains few cells: either epithelial cells from the lining of the urogenital tract, or blood‐derived, such as immune cells.…”

Perfil proteômico da lesão renal aguda induzida por isquemia e reperfusão

“…Além de atuar também no transporte de sódio e divalentes, modulando a atividade do cotransportador de sódio-potássio-cloreto NKCC2 e a abundância do canal de potássio ROMK2, (Craddock 1976;Renigunta et al 2011). A dosagem de UMOD se correlaciona bem com a função renal e pode ser usada como biomarcadora de doenças renais (Micanovic et al 2019). No transplante, a excreção de UMOD é reduzida em casos de início tardio da função do enxerto e com rejeição aguda, e aumentada com a recuperação da saúde renal (Kaden et al 1994).…”