Circulating uromodulin inhibits vascular calcification by interfering with pro-inflammatory cytokine signalling

Cardiovasc Res. 2021 Feb 22;117(3):930-941. doi: 10.1093/cvr/cvaa081.


Aims: Uromodulin is produced exclusively in the kidney and secreted into both urine and blood. Serum levels of uromodulin are correlated with kidney function and reduced in chronic kidney disease (CKD) patients, but physiological functions of serum uromodulin are still elusive. This study investigated the role of uromodulin in medial vascular calcification, a key factor associated with cardiovascular events and mortality in CKD patients.

Methods and results: Experiments were performed in primary human (HAoSMCs) and mouse (MOVAS) aortic smooth muscle cells, cholecalciferol overload and subtotal nephrectomy mouse models and serum from CKD patients. In three independent cohorts of CKD patients, serum uromodulin concentrations were inversely correlated with serum calcification propensity. Uromodulin supplementation reduced phosphate-induced osteo-/chondrogenic transdifferentiation and calcification of HAoSMCs. In human serum, pro-inflammatory cytokines tumour necrosis factor α (TNFα) and interleukin-1β (IL-1β) co-immunoprecipitated with uromodulin. Uromodulin inhibited TNFα and IL-1β-induced osteo-/chondrogenic signalling and activation of the transcription factor nuclear factor kappa-light-chain-enhancer of activated β cells (NF-kB) as well as phosphate-induced NF-kB-dependent transcriptional activity in HAoSMCs. In vivo, adeno-associated virus (AAV)-mediated overexpression of uromodulin ameliorated vascular calcification in mice with cholecalciferol overload. Conversely, cholecalciferol overload-induced vascular calcification was aggravated in uromodulin-deficient mice. In contrast, uromodulin overexpression failed to reduce vascular calcification during renal failure in mice. Carbamylated uromodulin was detected in serum of CKD patients and uromodulin carbamylation inhibited its anti-calcific properties in vitro.

Conclusions: Uromodulin counteracts vascular osteo-/chondrogenic transdifferentiation and calcification, at least in part, through interference with cytokine-dependent pro-calcific signalling. In CKD, reduction and carbamylation of uromodulin may contribute to vascular pathology.

Keywords: Osteo-/chondrogenic transdifferentiation; Phosphate; Uromodulin; Vascular calcification; Vascular smooth muscle cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Animals
  • Aorta / immunology
  • Aorta / metabolism
  • Cell Transdifferentiation* / drug effects
  • Cells, Cultured
  • Chondrogenesis
  • Cytokines / genetics
  • Cytokines / metabolism*
  • Disease Models, Animal
  • Female
  • Humans
  • Inflammation Mediators / metabolism*
  • Male
  • Mice, Inbred C57BL
  • Mice, Inbred DBA
  • Mice, Knockout
  • Middle Aged
  • Muscle, Smooth, Vascular / drug effects
  • Muscle, Smooth, Vascular / immunology
  • Muscle, Smooth, Vascular / metabolism*
  • Myocytes, Smooth Muscle / drug effects
  • Myocytes, Smooth Muscle / immunology
  • Myocytes, Smooth Muscle / metabolism*
  • Osteogenesis
  • Phenotype
  • Protein Carbamylation
  • Renal Insufficiency, Chronic / blood*
  • Renal Insufficiency, Chronic / immunology
  • Signal Transduction
  • Uromodulin / blood*
  • Uromodulin / genetics
  • Uromodulin / pharmacology
  • Vascular Calcification / blood
  • Vascular Calcification / immunology
  • Vascular Calcification / prevention & control*
  • Young Adult


  • Cytokines
  • Inflammation Mediators
  • UMOD protein, human
  • Umod protein, mouse
  • Uromodulin