Background: Serum levels of uromodulin (also known as Tamm-Horsfall protein) are reduced in patients with chronic kidney disease (CKD), but the physiological functions of serum uromodulin are still elusive. In CKD, medial vascular calcification is a common complication and associated with increased risk for cardiovascular events and mortality. The present study investigated the effects of uromodulin on medial vascular calcification. Methods: Experiments were performed in serum samples from patients with CKD, in primary human (HAoSMCs) and mouse (MOVAS) aortic smooth muscle cells and in a cholecalciferol-overload mouse vascular calcification model following AAV-mediated uromodulin overexpression. Results: As a result, in three independent cohorts of patients with CKD, serum uromodulin concentrations were inversely correlated with serum calcification propensity, a marker for increased risk for vascular calcification. Uromodulin supplementation in the cell culture medium suppressed phosphate-induced osteo-/chondrogenic transdifferentiation and calcification of HAoSMCs. Similarly, uromodulin supplementation suppressed uremic serum-induced osteo-/chondrogenic transdifferentiation of HAoSMCs. Furthermore, uromodulin blunted osteo-/chondrogenic signaling and activation of the pro-inflammatory transcription factor NF-kB induced by the cytokines TNFα and IL-1β. Uromodulin supplementation also blunted phosphate-induced NF-kB-dependent transcriptional activity in HAoSMCs. In human serum, TNFα and IL-1β co-immunoprecipitated with uromodulin, suggesting that uromodulin is able to bind circulating pro-inflammatory cytokines. In-vivo, AAV-mediated overexpression of uromodulin reduced vascular calcification and stiffness as well as aortic osteo-/chondrogenic signaling in mice with cholecalciferol overload. In accordance, phosphate-induced osteo-/chondrogenic transdifferentiation of murine MOVAS cells was suppressed following mouse uromodulin supplementation or overexpression. Conclusions: Uromodulin inhibits osteo-/chondrogenic transdifferentiation and calcification of vascular smooth muscle cells, at least partly, through inhibition of osteoinductive signaling induced by pro-inflammatory cytokines.
Europhysiology 2018 (London, UK) (2018) Proc Physiol Soc 41, PCB368
Poster Communications: Uromodulin inhibits medial vascular calcification by interfering with pro-inflammatory cytokines
I. Alesutan1,2, T. Luong1, N. Schelski1, J. Masyout1, S. Hille3, M. Schneider4, D. Zickler5, N. Verheyen6, M. Estepa1, A. Pasch7, W. Maerz8, A. Tomaschitz9, S. Pilz10, N. Frey3, F. Lang11, O. Mueller3, B. Pieske1,2,12, K. Eckardt5, J. Scherberich13, J. Voelkl1
1. Center for Cardiovascular Research Cardiology CVK, Charité - Universitätsmedizin Berlin, Berlin, Germany. 2. Berlin Institute of Health, Berlin, Germany. 3. Department of Internal Medicine III, University of Kiel, Kiel, Germany. 4. Department of Nephrology and Hypertension, Universität Erlangen-Nürnberg, Erlangen, Germany. 5. Department of Nephrology and Medical Intensive Care, Charité - Universitätsmedizin Berlin, Berlin, Germany. 6. Department of Cardiology, Medical University of Graz, Graz, Austria. 7. Calciscon, Nidau-Biel, Switzerland. 8. Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Graz, Austria. 9. Bad Gleichenberg Clinic, Bad Gleichenberg, Austria. 10. Department of Internal Medicine, Division of Endocrinology and Diabetology, Medical University of Graz, Graz, Austria. 11. Department of Physiology I, Eberhard-Karls University, Tübingen, Germany. 12. Department of Internal Medicine and Cardiology, DHZB, Berlin, Germany. 13. Department of Nephrology and Clinical Immunology, Klinikum München-Harlaching, Teaching Hospital of the Ludwig-Maximilians-Universität, Munich, Germany.
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Where applicable, experiments conform with Society ethical requirements.