Determinants of renal microvascular reactivity in rat models of diabetes mellitus and obesity. Marjon Troost-Roos

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1 Determinants of renal microvascular reactivity in rat models of diabetes mellitus and obesity Marjon Troost-Roos

2 The studies presented in this thesis were performed at the Laboratory for Physiology of the VU University Medical Center, van der Boechorststraat 7, 1081 BT Amsterdam, The Netherlands. Printing of this dissertation was financially supported by the Dutch kidney foundation J.E. Jurriaanse stichting Dutch Diabetes foundation Novo Nordisk LifeScan Harlan Determinants of renal microvascular reactivity in rat models of diabetes mellitus and obesity. / Marjon Roos Dissertation, Vrije Universiteit Amsterdam ISBN: Copyright 2006 by Marjon Troost-Roos, Hilversum, The Netherlands All rights reserved. No part of this book may be reproduced or transmitted in any form or by any means without the prior written permission of the holder of the copyright. This dissertation was printed by Febodruk, Enschede, The Netherlands

3 VRIJE UNIVERSITEIT Determinants of renal microvascular reactivity in rat models of diabetes mellitus and obesity ACADEMISCH PROEFSCHRIFT ter verkrijging van de graad Doctor aan de Vrije Universiteit Amsterdam, op gezag van de rector magnificus, in het openbaar te verdedigen ten overstaan van de promotiecommissie van de faculteit der Geneeskunde op dinsdag 17 oktober 2006 om uur in het auditorium van de universiteit, De Boelelaan 1105 door Maria Hendrika Troost-Roos geboren te Oosterbeek

4 promotoren: copromotor: prof.dr. G.J. Tangelder prof.dr. P.M. ter Wee dr. W.F. van Rodijnen

5 "In het huidige tijdperk is verandering de enige constante." - H.M. Koningin Beatrix voor Roelof

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7 Table of Contents Chapter 1 General introduction 11 Part I Chapter 2 Chapter 3 Chapter 4 Part II Chapter 5 Part III Chapter 6 Diabetes mellitus Diabetes mellitus impairs the renal microvascular myogenic response more easily in rats from breeders selected for large litter size Increased production of thromboxane A 2 via the COX-2 pathway contributes to normal renal microvascular responsiveness to angiotensin II in experimental diabetes Restoration of attenuated preglomerular microvascular reactivity to angiotensin II in experimental type 1 diabetes mellitus by aselective COX-inhibition Obesity Preglomerular vasodilatation, postglomerular vasoconstriction and augmented reactivity to angiotensin II in obese euglycemic proteinuric Zucker rats Rho-kinase Renal microvascular constriction to membrane depolarization and other stimuli: pivotal role for rho kinase Chapter 7 General discussion 115 Chapter 8 Summary & samenvatting 137 List of publications 147 Dankwoord 149 Curriculum Vitae 155

8 List of abbreviations AA Afferent arteriole ACE Angiotensin converting enzyme AGEs Advanced glycation end products AngII Angiotensin II AUC Area under the curve BaCl 2 Barium chloride EA Efferent arteriole C Control rats Ca 2+ Calcium CaM Calmodulin camp Cyclic adenosine monophosphate CCD Charge coupled device cgmp Cyclic guanosine monophosphate COX Cyclo-oxygenase DAG Diacylglycerol DM Diabetic rats DMEM Dulbecco s Modified Eagle s Medium Base GFR Glomerular filtration rate Hba1c Percentage glycated hemoglobins IC 50 Concentration eliciting halve of the effect ILA Distal interlobular artery i.m. Intramuscularly i.p. Intraperitoneally IP 3 Inositol 1,4,5-triphosphate i.v. Intravenously IP 3 R IP 3 receptor KCl Potassium chloride LPA Lysophosphatidic acid MLC Myosin light chain MLCK MLC kinase Myosin-P Phosphorylation of myosin NO Nitric oxide PGE 2 /I 2 Prostaglandin E 2 /I 2 PI3K Phosphatidyl inositol 3-kinase PIP 2 Phosphatidylinositol 4,5-biphosphate PKC Protein kinase C PLA 2 Phospholipase A 2 PLC Phospholipase C Pt Patients Ref Reference RAS Renin angiotensin system ROS Reactive oxygen species RPF Renal plasma flow SR Sarcoplasmic reticulum

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