University of Groningen
Klotho in vascular biology
Mencke, Rik
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Publication date: 2018
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Mencke, R. (2018). Klotho in vascular biology. Rijksuniversiteit Groningen.
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Klotho in Vascular Biology
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© Rik Mencke, 2018
All rights are reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, without permission of the author. Cover Design and Art Work: Spinning the thread of life, Ineke Jansen
Book Design: Rik Mencke
Print: GVO drukkers en vormgevers B.V. ISBN (printed): 978-94-034-1025-8
ISBN (digital): 978-94-034-1024-1 This PhD project was financially supported by: University Medical Center Groningen
Groningen University Institute for Drug Exploration
Junior Scientific Masterclass, Faculty of Medicine, University of Groningen Dutch Kidney Foundation
Jan Kornelis de Cock Foundation
The printing of this thesis was kindly supported by: University Medical Center Groningen
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Klotho in Vascular Biology
Proefschrift
ter verkrijging van de graad van doctor aan de Rijksuniversiteit Groningen
op gezag van de
rector magnificus prof. dr. E. Sterken en volgens besluit van het College voor Promoties.
De openbare verdediging zal plaatsvinden op maandag 19 november 2018 om 11.00 uur
door
Rik Mencke
geboren op 1 augustus 1990 te Emmen
4 Promotor Prof. dr. J.L. Hillebrands Copromotor Dr. M.G. Vervloet Beoordelingscommissie Prof. dr. G. Molema Prof. dr. S.P. Berger Prof. dr. L. Schurgers
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Paranimfen
L.F.A. van Dullemen W.T. van Haaften
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Table of Contents
Chapter 1 General introduction page 9
Chapter 2 The role of the anti-ageing protein Klotho in vascular page 21 physiology and pathophysiology
Part I Vascular and renal Klotho expression page 81
Chapter 3 Tissue expression and source of circulating αKlotho page 83
Chapter 4 Membrane-bound Klotho is not expressed endogenously in page 133 healthy or uremic human vascular tissue
Chapter 5 Assessment of vascular Klotho expression and functionality page 165
Chapter 6 Human alternative Klotho mRNA is a nonsense-mediated page 191 mRNA decay target inefficiently spliced in renal disease
Part II Klotho and arterial remodeling page 231
Chapter 7 Imaging of incipient vascular calcification in Klotho deficiency page 233
Chapter 8 Klotho deficiency induces arteriolar hyalinosis in a trade-off page 259 with vascular calcification
Chapter 9 Klotho deficiency promotes and induces the development of page 285 intimal hyperplasia
Chapter 10 Characterization of vascular function in Klotho deficiency page 309
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Part III Towards clinical applications of Klotho page 355
Chapter 12 Effects of Klotho on fibrosis and cancer: a renal focus on page 357 mechanisms and therapeutic strategies
Chapter 13 Clinical aspects of Klotho in vascular disease page 401
Chapter 14 Association of Klotho allele variants with graft survival page 437 after kidney transplantation
Chapter 15 General discussion and future perspectives page 451
Appendices page 465
Nederlandse samenvatting page 467
Acknowledgments page 475
Author affiliations page 483
Publications page 489
