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Characterization of Spontaneous Hypertension in Chlorocebus Aethiops Sabaeus, the African Green Monkey

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Characterization of Spontaneous Hypertension in Chlorocebus Aethiops Sabaeus, the African Green Monkey University of Kentucky UKnowledge Theses and Dissertations--Biology Biology 2018 CHARACTERIZATION OF SPONTANEOUS HYPERTENSION IN CHLOROCEBUS AETHIOPS SABAEUS, THE AFRICAN GREEN MONKEY Megan K. Rhoads University of Kentucky, [email protected] Author ORCID Identifier: https://orcid.org/0000-0001-7494-9815 Digital Object Identifier: https://doi.org/10.13023/etd.2018.374 Right click to open a feedback form in a new tab to let us know how this document benefits ou.y Recommended Citation Rhoads, Megan K., "CHARACTERIZATION OF SPONTANEOUS HYPERTENSION IN CHLOROCEBUS AETHIOPS SABAEUS, THE AFRICAN GREEN MONKEY" (2018). Theses and Dissertations--Biology. 55. https://uknowledge.uky.edu/biology_etds/55 This Doctoral Dissertation is brought to you for free and open access by the Biology at UKnowledge. It has been accepted for inclusion in Theses and Dissertations--Biology by an authorized administrator of UKnowledge. For more information, please contact [email protected]. STUDENT AGREEMENT: I represent that my thesis or dissertation and abstract are my original work. Proper attribution has been given to all outside sources. I understand that I am solely responsible for obtaining any needed copyright permissions. I have obtained needed written permission statement(s) from the owner(s) of each third-party copyrighted matter to be included in my work, allowing electronic distribution (if such use is not permitted by the fair use doctrine) which will be submitted to UKnowledge as Additional File. I hereby grant to The University of Kentucky and its agents the irrevocable, non-exclusive, and royalty-free license to archive and make accessible my work in whole or in part in all forms of media, now or hereafter known. I agree that the document mentioned above may be made available immediately for worldwide access unless an embargo applies. I retain all other ownership rights to the copyright of my work. I also retain the right to use in future works (such as articles or books) all or part of my work. I understand that I am free to register the copyright to my work. REVIEW, APPROVAL AND ACCEPTANCE The document mentioned above has been reviewed and accepted by the student’s advisor, on behalf of the advisory committee, and by the Director of Graduate Studies (DGS), on behalf of the program; we verify that this is the final, approved version of the student’s thesis including all changes required by the advisory committee. The undersigned agree to abide by the statements above. Megan K. Rhoads, Student Dr. Jeffrey L. Osborn, Major Professor Dr. David F. Westneat, Director of Graduate Studies CHARACTERIZATION OF SPONTANEOUS HYPERTENSION IN CHLOROCEBUS AETHIOPS SABAEUS, THE AFRICAN GREEN MONKEY DISSERTATION A dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the College of Arts and Sciences at the University of Kentucky By Megan Kathleen Rhoads Lexington, Kentucky Director: Dr. Jeffrey L Osborn, Professor of Biology Lexington, Kentucky 2018 Copyright © Megan Kathleen Rhoads 2018 ABSTRACT OF DISSERTATION CHARACTERIZATION OF SPONTANEOUS HYPERTENSION IN CHLOROCEBUS AETHIOPS SABAEUS, THE AFRICAN GREEN MONKEY Hypertension is a complex multifactorial pathology that is a major risk factor for the development of cardiovascular disease, stroke, and end stage renal disease. In the United States, hypertension affects over 1 in 3 adults and comprises an annual cost of over $58 billion in the healthcare industry. While remarkable strides in the diagnosis and treatment of hypertension have been made since the pathology was first treated in the 1960s, a remarkable 13% of patients with elevated blood pressures are classified as resistant hypertensive, where blood pressure remains uncontrolled while on three or more classes of anti-hypertensive drugs. This treatment gap suggests that researchers need to develop and utilize translational models that recapitulate the pathologies seen in patient populations. Non-human primates (NHP) are highly similar to humans in terms of physiology, circadian rhythmicity, behavior, and gene sequence and structure. Development of NHP models that spontaneously develop pathologies, like spontaneous hypertension, provide novel and vital tools to studying disease. Overall, this dissertation is a comparative analysis of the mechanisms that drive the development of spontaneous hypertension in Chlorocebus aethiops sabaeus, an Old World non-human primate, and known mediators of essential hypertension in human populations. Chapter 2 presents how hypertensive (HT) African Green Monkeys (AGMs) are older, with elevated heart rates, increased renal vascular wall/lumen ratios, and altered glomerular morphologies compared to normotensive (NT) controls. Chapter 3 describes metabolic studies performed in a large cohort of animals that identified elevated proteinuria and ion excretion in HT AGMs compared to NT animals. Chapter 4 focuses on the contribution of sympathetic nervous system to the development of hypertension in this animal model and describes the significant left ventricular hypertrophy and elevation of adrenergic receptor mRNA in HT AGMs. Chapter 5 examines how age affects hypertension and renal function in the NT and HT AGMs. Together these data provide a foundational basis for the development of spontaneous hypertension in the AGM and provide a novel translational model for the study of cardiovascular disease. KEYWORDS: Hypertension, Blood Pressure, African Green Monkey Megan Kathleen Rhoads August 31, 2018 Date CHARACTERIZATION OF SPONTANEOUS HYPERTENSION IN CHLOROCEBUS AETHIOPS SABAEUS, THE AFRICAN GREEN MONKEY By Megan Kathleen Rhoads Jeffrey L. Osborn Director of Dissertation David F. Westneat Director of Graduate Studies August 31, 2018 Date “You can never be overdressed or overeducated.” Oscar Wilde ACKNOWLEDGEMENTS The following dissertation, while an individual work, greatly benefited from the support, insight, and direction of several people. First, my Dissertation Committee Chair, Dr. Jeffrey Osborn, who taught me nearly everything I know about how to be a scientist, researcher, and educator. Thank you and I hope to be able to pay that huge debt forward someday. I also want to thank my entire Dissertation Committee: Dr. Vincent Cassone, Dr. Bruce O’Hara, Dr. Analia Loria and external examiner, Dr. James MacLeod. Each provided valuable guidance and insight that substantially improved this dissertation, my growth as a scientist, and my future career. In addition to the valuable technical advice provided above, this dissertation would not exist without the steadfast support of my family and friends. My husband, Ben, has been my shelter, foundation, and champion throughout my entire graduate career. Thank you for everything, my love. My family, every last one of you, has encouraged me every step of the way and believed in me even when I didn’t believe in myself. My lab mates: Jason, Brandon, and Chelsea; thank you for all the things you taught me, both about science and life. It’s been such fun and I’m grateful to call you all my friends and peers. My SORA circus family, you are the most supportive community of strong women and you each inspire me every day. You’ve made me a better person and I thank you all for that. iii TABLE OF CONTENTS ACKNOWLEDGEMENTS ............................................................................................... iii LIST OF TABLES ............................................................................................................ vii LIST OF FIGURES ......................................................................................................... viii CHAPTER ONE ................................................................................................................. 1 HYPERTENSION AND THE AFRICAN GREEN MONKEY ........................................ 1 1.1 Introduction ............................................................................................................... 2 1.2 Blood pressure control mechanisms ......................................................................... 4 1.2.1 Cardiovascular function and pathologies ............................................................... 4 1.2.2 Renal function and pathologies .............................................................................. 7 1.2.3 Acute control of blood pressure: Baroreceptors .................................................. 10 1.2.4 Acute control of blood pressure: Chemoreceptors ............................................... 12 1.2.5 Chronic control of blood pressure: Pressure natriuresis ...................................... 14 1.3 Hormonal regulation of blood pressure .................................................................. 16 1.3.1 Renin-angiotensin-aldosterone system ................................................................ 16 1.3.2 Sex hormones ....................................................................................................... 19 1.3.3 Other hormones .................................................................................................... 21 1.4 Neural regulation of blood pressure ........................................................................ 22 1.4.1 Sympathetic nervous system ................................................................................ 22 1.4.2 Renal sympathetic nerve activity ......................................................................... 24 1.5 Chlorocebus aethiops sabaeus, the African Green Monkey .................................
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