Ioana Alesutan1,2,3,4, Trang T D Luong1,2, Nadeshda Schelski2, Jaber Masyout2, Susanne Hille5,6, Markus P Schneider7,8, Delyth Graham9, Daniel Zickler10, Nicolas Verheyen11, Misael Estepa2, Andreas Pasch1,12,13,14, Winfried Maerz15,16,17, Andreas Tomaschitz18, Stefan Pilz19, Norbert Frey5,6, Florian Lang20, Christian Delles9, Oliver J Müller5,6, Burkert Pieske2,3,4,21, Kai-Uwe Eckardt7,8,10, Juergen Scherberich22, Jakob Voelkl1,2,4,10. 1. Institute for Physiology and Pathophysiology, Johannes Kepler University Linz, Altenberger Strasse 69, 4040 Linz, Austria. 2. Department of Internal Medicine and Cardiology, Campus Virchow-Klinikum, Charité - Universitätsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany. 3. Berlin Institute of Health (BIH), Anna-Louisa-Karsch 2, 10178 Berlin, Germany. 4. DZHK (German Centre for Cardiovascular Research), partner site Berlin, Hessische Strasse 3-4, 10115 Berlin, Germany. 5. Department of Internal Medicine III, University of Kiel, Arnold-Heller-Str. 3, 24105 Kiel, Germany. 6. DZHK (German Centre for Cardiovascular Research), partner site Hamburg/Kiel/Lübeck, Martinistr. 52, 20246 Hamburg, Germany. 7. Department of Nephrology and Hypertension, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Ulmenweg 18, 91054 Erlangen, Germany. 8. German Chronic Kidney Disease (GCKD) Study. 9. Institute of Cardiovascular and Medical Sciences, BHF Glasgow Cardiovascular Research Centre, University of Glasgow, 126 University Place, Glasgow G12 8TA, UK. 10. Department of Nephrology and Medical Intensive Care, Charité - Universitätsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany. 11. Department of Cardiology, Medical University of Graz, Auenbruggerplatz 15, 8036 Graz, Austria. 12. Calciscon AG, Aarbergstrasse 5, 2560 Nidau-Biel, Switzerland. 13. Nierenpraxis Bern, Bubenbergplatz 5, 3011 Bern, Switzerland. 14. Department of Nephrology, Lindenhofspital, Bremgartenstrasse 117, 3001 Bern, Switzerland. 15. Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Auenbruggerplatz 15, 8036 Graz, Austria. 16. Medical Clinic V (Nephrology, Hypertensiology, Rheumatology, Endocrinology, Diabetology), Medical Faculty Mannheim, University of Heidelberg, Ludolf Krehl Street 7-11, 68167 Mannheim, Germany. 17. Synlab Academy, SYNLAB Holding Deutschland GmbH, P5,7, 68161 Mannheim, Germany. 18. Health Center Trofaiach, Gössgrabenstrasse 2a, 8739 Trofaiach, Austria. 19. Department of Internal Medicine, Division of Endocrinology and Diabetology, Medical University of Graz, Auenbruggerplatz 15, 8036 Graz, Austria. 20. Department of Physiology, Eberhard-Karls University, Wilhelmstr. 56, 72076 Tübingen, Germany. 21. Department of Internal Medicine and Cardiology, German Heart Center Berlin (DHZB), Augustenburger Platz 1, 13353 Berlin, Germany. 22. Department of Nephrology and Clinical Immunology, Klinikum München-Harlaching, Teaching Hospital of the Ludwig-Maximilians-Universität, Sanatoriumsplatz 2, 81545 München, Germany.
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. Published on behalf of the European Society of Cardiology. All rights reserved.
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. Published on behalf of the European Society of Cardiology. All rights reserved.
Authors: Ahmed F Elhabashi; Leena Sulaibeekh; Nahed Seddiq; Salman Alali; Amjad K Abdulmajeed; Nuria S Perez Journal: Risk Manag Healthc Policy Date: 2020-08-03
Authors: Radmila Micanovic; Kaice A LaFavers; Kavish R Patidar; Marwan S Ghabril; Emma H Doud; Amber L Mosley; Angela R Sabo; Shehnaz Khan; Tarek M El-Achkar Journal: Am J Physiol Renal Physiol Date: 2022-01-31
Authors: Ioana Alesutan; Laura A Henze; Beate Boehme; Trang T D Luong; Daniel Zickler; Burkert Pieske; Kai-Uwe Eckardt; Andreas Pasch; Jakob Voelkl Journal: Biomolecules Date: 2022-08-21