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

Alesutan I, Luong TT, Schelski N, Masyout J, Hille S, Schneider M, Graham D, Zickler D, Verheyen N, Estepa M, Pasch A, Maerz W, Tomaschitz A, Pilz S, Frey N, Lang F, Delles C, Müller OJ, Pieske B, Eckardt KU, Scherberich J, Voelkl J (2021)

Publication Type: Journal article

Publication year: 2021

Journal

Cardiovascular Research Oxford University Press

Book Volume: 117

Pages Range: 930-941

Journal Issue: 3

DOI: 10.1093/cvr/cvaa081

Abstract

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.

Authors with CRIS profile

Markus Schneider Medizinische Fakultät Kai-Uwe Eckardt Department of Medicine 4 – Nephrology and Hypertension

Involved external institutions

Johannes Kepler Universität (JKU) Linz AT Austria (AT) Christian-Albrechts-Universität zu Kiel DE Germany (DE) Ludwig-Maximilians-Universität (LMU) DE Germany (DE) Charité - Universitätsmedizin Berlin DE Germany (DE) University of Glasgow GB United Kingdom (GB) Medizinische Universität Graz AT Austria (AT) Eberhard Karls Universität Tübingen DE Germany (DE)

How to cite

APA:

Alesutan, I., Luong, T.T., Schelski, N., Masyout, J., Hille, S., Schneider, M.,... Voelkl, J. (2021). Circulating uromodulin inhibits vascular calcification by interfering with pro-inflammatory cytokine signalling. Cardiovascular Research, 117(3), 930-941. https://doi.org/10.1093/cvr/cvaa081

MLA:

Alesutan, Ioana, et al. "Circulating uromodulin inhibits vascular calcification by interfering with pro-inflammatory cytokine signalling." Cardiovascular Research 117.3 (2021): 930-941.

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