165 leaves : / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / Thesis (M.D. 1972) from the Dept. of Medicine, University of Adelaide

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Bei einer Vielzahl von kardiovaskulären Erkrankungen, wie der Arteriosklerose, kommt es zur Aktivierung des Renin-Angiotensin-Aldosteron-Systems und einer steigenden Konzentration von Angiotensin II im Plasma. Ein weiteres Kennzeichen, z.B. bei der Herzinsuffizienz, ist die reduzierte Belastungstoleranz, die mit einer verminderten Skelettmuskelfunktion einhergeht. In dieser Studie wurden Untersuchungen an Skelettmuskeln von ApoE-knockout-Mäusen durchgeführt, die als Tiermodell für kardiovaskuläre Erkrankungen dienen. Als etabliertes Modell ist es durch das Fehlen von ApoE und die damit erhöhte Konzentration an Lipoproteinen charakterisiert, was für die Pathophysiolo-gie von kardiovaskulären Krankheiten von Bedeutung ist. Ziel der Studie war es, den Einfluss von Angiotensin II auf die metabolischen Veränderungen an der Skelettmuskulatur und auf die Skelettmuskelfunktion sowie die damit einhergehenden molekularen Veränderungen zu untersuchen. Des Weiteren wurde der Einfluss von zusätzlichem Ausdauertraining analysiert. Hauptaugenmerk wurde dabei auf die Erfassung von Veränderungen des metabolischen Profils in definierten Fasertypen (SO, FOG, FG) mittels Zytophotometrie gelegt. Es wurde die fasertypspezifische glykolytische und oxidative Enzymaktivität mittels Zytophotometer und im Muskelhomogenat gemessen. Eine Muskelfaseranalyse wurde durchgeführt. Weiterhin erfolgte die Untersuchung von funktionellen Veränderungen im Skelettmuskel nach Angiotensin II-Infusion und nach zusätzlichem Ausdauertraining. Ferner wurde der Beitrag von IGF-1 quantitativ erfasst. In dieser Studie konnte zum ersten Mal gezeigt werden, dass sich Faserzusammensetzung und Metabolismus der Skelettmuskulatur unter Angiotensin II-Gabe verändern. Durch Ausdauertraining werden diese Alterationen abgemildert bzw. rückgängig gemacht, was auf einen positiven Effekt von Ausdauertraining auf die Muskelfunktion schließen lässt.

acase@tulane.edu / Increased activity of the intrarenal renin-angiotensin system (RAS), in which proximal tubular angiotensinogen (AGT) is a key factor, has been implicated in the progression of diabetic nephropathy. AGT expression is upregulated in renal proximal tubular cells (PTC) by high glucose due to elevated reactive oxygen species (ROS) generation. Angiotensin II (Ang II) also promotes ROS generation. Glucose reabsorption in PTC occurs mainly through sodium-glucose co-transporter 2 (SGLT2). This study was performed to demonstrate that SGLT2 mediates AGT augmentation in PTC under hyperglycemic conditions. Furthermore, the enhancing effect of Ang II was investigated. Established mouse PTC were treated with 5 (normal), 15, or 25 mM D-glucose or D-mannitol (osmotic control). Pyruvate was used to investigate the role of glycolysis on AGT regulation. Glycolytic activity was quantified using a Seahorse metabolic analyzer. Tempol, an antioxidant, was used to determine the role of ROS. SGLT2 expression was silenced using shRNA. PTC were treated with high glucose and 10-10-10-7 M Ang II or an Ang II receptor blocker. AGT protein levels were increased by 15 (4.4 ± 0.2-fold over control) and 25 mM (4.6 ± 0.2-fold) glucose. AGT mRNA was also augmented (31.1 ± 3.5-fold) by 25 mM glucose, but not mannitol. AGT expression was stimulated by pyruvate (10.7 ± 1.0-fold over control), and exposure to 10, 15, or 25 mM glucose increased glycolytic activity (3.10 ± 0.28-fold, 2.74 ± 0.20-fold, and 2.75 ± 0.34-fold, respectively), suggesting that enhanced glycolysis stimulates AGT expression. ROS accumulation increased (3.03 ± 0.29-fold) in 25 mM glucose over control. Tempol attenuated glucose-induced AGT augmentation by 77%, suggesting that ROS generation contributes to AGT upregulation. SGLT2 knockdown prevented AGT augmentation in 15 mM glucose, indicating that SGLT2 plays a key role mediating AGT upregulation by high glucose. Ang II receptor blockade did not alter AGT levels, and Ang II did not enhance AGT expression in normal or high glucose. Similarly, SGLT2 expression was unchanged by glucose or Ang II. These results indicate that SGLT2 contributes to AGT upregulation in PTC by high glucose, which helps to explain the mechanisms causing intrarenal RAS activation and consequent diabetic nephropathy. / 1 / Michael W. Cypress

Inappropriate modulation of the renin angiotensin system (RAS) can lead to derangements of blood pressure homeostasis in humans. Cyp1a1-mRen2.F transgenic rats were used to define the renal mechanisms underlying the development of angiotensin II-dependent hypertension. These transgenic rats were previously generated by introducing the mouse Ren2 gene into the rat genome under the control of a Cyp1a1 inducible promoter. The aim of the current investigation was to establish the contribution of renal function to the development of hypertension in the Cyp1a1- mRen2.F transgenic rat. Expression of the mRen2 transgene was induced by daily gavage of indole 3 carbinol (I3C) at the dose of 100mg/kg. Blood pressure was measured in conscious rats after 1, 3 or 7 days of treatment. The control group received the vegetable oil carrier for 7 days. In addition blood pressure, renal haemodynamics and excretory function were measured under thiobutabarbital anaesthesia. Transgene induction caused a progressive increase in blood pressure in a time dependent manner. Neither glomerular filtration rate nor renal blood flow was affected. This indicates proper function of renal autoregulation during the experimental time course. Tubular sodium reabsorption was significantly increased after the first day of transgene induction and this effect was sustained for the duration of treatment. A pharmacological approach was used to localize the increased reabsorption to a specific region of the nephron and was found to reflect increased activity of the thiazide-sensitive cotransporter (NCC). Chronic administration of thiazide significantly blunted the hypertensive response to transgene induction. Similarly AT1 receptor blockade attenuated the hypertensive phenotype and prevented the transgene-induced stimulation of NCC activity. In contrast, mineralocorticoid receptor blockade did not prevent the development of either hypertension or increased NCC activity. The current study suggests that the development of angiotensin II-dependent hypertension is mediated by increased tubular sodium reabsorption. Increased activity of NCC is a key hypertensive mechanism in this model and results directly from the actions of angiotensin II at the AT1 receptor; indirect aldosterone pathways do not play a major role.

by Chi-shing Sum. / Thesis (M.Phil.)--Chinese University of Hong Kong, 1995. / Includes bibliographical references (leaves 84-96). / ACKNOWLEDGEMENT --- p.i / ABSTRACT --- p.ii / LIST OF ABBREVIATIONS --- p.iv / TABLE OF CONTENTS --- p.v / Chapter CHAPTER 1 --- p.1 / Chapter 1.1 --- Biochemistry of Renin-Angiotensin System --- p.1 / Chapter 1.2 --- Physiological Roles of Angiotensin --- p.5 / Chapter 1.3 --- Biochemistry of Angiotensin Receptors --- p.6 / Chapter 1.4 --- Tissue Renin-Angiotensin System --- p.13 / Kidney --- p.13 / Blood vessels --- p.14 / Heart --- p.15 / Brain --- p.16 / Testes --- p.17 / Chapter 1.5 --- Structure and Function of Vas Deferens --- p.18 / Chapter 1.6 --- Aim of Study --- p.21 / Chapter CHAPTER 2 --- p.22 / Chapter 2.1 --- introduction --- p.22 / Chapter 2.2 --- Materials --- p.23 / Chapter 2.3 --- methods --- p.23 / Chapter 2.3.1 --- Preparation of isolated epididymal rat vas deferens --- p.23 / Chapter 2.3.2 --- Concentration-responses to angiotensins --- p.24 / Chapter 2.3.3 --- Effects of angiotensin II in the presence of protease inhibitors --- p.24 / Chapter 2.3.4 --- Effect of losartan and CGP 42112 --- p.24 / Chapter 2.3.5 --- Schild analysis --- p.25 / Chapter 2.3.6 --- Interaction of angiotensin II with exogenous noradrenaline --- p.25 / Chapter 2.3.7 --- Statistical analysis --- p.25 / Chapter 2.4 --- results --- p.25 / Chapter 2.4.1 --- Effect of angiotensin on epididymal rat vas deferens --- p.25 / Chapter 2.4.2 --- Concentration-responses to angiotensins in epididymal rat vas deferens --- p.27 / Chapter 2.4.3 --- Effect of angiotensin II in the presence of protease inhibitors --- p.27 / Chapter 2.4.4 --- Effect of losartan ami CGP 42112 --- p.27 / Chapter 2.4.5 --- Schild analysis --- p.36 / Chapter 2.4.6 --- Interaction of angiotensin II with exogenous noradrenaline --- p.36 / Chapter 2.5 --- Discussion --- p.36 / Chapter CHAPTER 3 --- p.39 / Chapter 3.1 --- Introduction --- p.39 / Chapter 3.2 --- Materials --- p.39 / Chapter 3.3 --- Methods --- p.40 / Chapter 3.3.1 --- Preparation of isolated prostatic rat vas deferens --- p.40 / Chapter 3.3.2 --- Concentration-responses to angiotensins --- p.40 / Chapter 3.3.3 --- Effects of angiotensin II in the presence of protease inhibitors --- p.41 / Chapter 3.3.4 --- Effect oflosartan and CGP 42112 --- p.41 / Chapter 3.3.5 --- Schild analysis --- p.41 / Chapter 3.3.6 --- Interaction of angiotensin II with exogenous noradrenaline --- p.42 / Chapter 3.3.7 --- Concentration-response to angiotensin II after reserpine treatment --- p.42 / Chapter 3.3.8 --- Concentration-response to angiotensin II after desensitization of P2-purinoceptors --- p.42 / Chapter 3.3.9 --- Statistical analysis --- p.42 / Chapter 3.4 --- Results --- p.43 / Chapter 3.4.1 --- Effect of angiotensin on prostatic rat vas deferens --- p.43 / Chapter 3.4.2 --- Concentration-responses to angiotensins in prostatic rat vas deferens --- p.43 / Chapter 3.4.3 --- Effect of angiotensin II in the presence of protease inhibitors --- p.43 / Chapter 3.4.4 --- Effect of losartan and CGP 42112 --- p.49 / Chapter 3.4.5 --- Schild analysis --- p.49 / Chapter 3.4.6 --- Interaction of angiotensin II with exogenous noradrenaline --- p.49 / Chapter 3.4.7 --- Concentration-response to angiotensin II afier reserpine treatment --- p.54 / Chapter 3.4.8 --- Concentration-response to angiotensin II after desensitization of P2-purinoceptors --- p.54 / Chapter 3.5 --- Discussion --- p.63 / Chapter CHAPTER 4 --- p.66 / Chapter 4.1 --- introduction --- p.66 / Chapter 4.2 --- Materials and Methods --- p.66 / Chapter 4.2.1 --- Preparation of polyclonal angiotensin II antiserum --- p.66 / Chapter 4.2.1.1 --- Preparation of peptide conjugate --- p.66 / Chapter 4.2.1.2 --- Protein determination --- p.67 / Chapter 4.2.1.3 --- Immunization of rabbit with peptide conjugate --- p.67 / Chapter 4.2.1.4 --- Collecting rabbit serum --- p.68 / Chapter 4.2.2 --- Characterization of BSA-Ang II and Thy-Ang II antisera --- p.68 / Chapter 4.2.2.1 --- Slot blotting --- p.68 / Chapter 4.2.2.2 --- Enzyme-linked immunosorbent assay (ELISA) --- p.69 / Chapter 4.3 --- RESULT --- p.69 / Chapter 4.3.1 --- Preparation of polyclonal angiotensin II antiserum --- p.69 / Chapter 4.3.2 --- Characterization of BSA-Ang II and Thy-Ang II antisera --- p.70 / Chapter 4.3.2.1 --- Slot blotting --- p.70 / Chapter 4.3.2.2 --- Enzyme-linked immunosorbent assay (ELISA) --- p.70 / Chapter 4.3 --- discussion --- p.76 / Chapter CHAPTER 5 --- p.78 / Chapter 5. 1 --- General Discussions --- p.78 / REFERENCES --- p.84 / APPENDIX --- p.97 / Published Abstract and Paper --- p.97

Thesis (M. Med. Sc.)--University of Hong Kong, 2006.

Une des complications qui survient chez 1/3 des patients dans les 6 mois suivant une angioplastie est la resténose, réponse myoproliférative du muscle lisse vasculaire. Cette formation néointimale (LIU et al., 1989), nécessite souvent une angioplastie ultérieure ou un pontage aortocoronarien chez l'homme. Dans un modèle animal, cette resténose a été partiellement supprimée par des doses élevées d'inhibiteurs et d'antagonistes reliées au système rénine angiotensine. Nous avons démontré récemment sur ce modèle qu'une infusion intralésionelle de Br[indice inférieur 5]Ang, un antagoniste peptidique non-sélectif de longue durée d'action de l'angiotensine II (Ang), peut prévenir une formation néointimale (LAPORTE et ESCHER, 1992). Ces résultats démontrent que l'Ang est un médiateur nécessaire mais n'identifie pas le type de récepteur par lequel cette réponse est médiée. Pour résoudre cette question, une expérience avec des antagonistes sélectifs fut effectuée. L'angioplastie des artères carotides de rats Sprague-Dawley fut suivie d'un traitement continu de 14 jours par infusion intra-artérielle de losartan (antagoniste sélectif au récepteur AT[indice inférieur 1] de l'angiotensine II), de PD123319 (antagoniste sélectif au récepteur AT[indice inférieur 2] de l'angiotensine II), d'une combinaison de losartan et de PD123319 ou d'une infusion de salin. La morphométrie des coupes histologiques des artères recueillies 14 jours après l'angioplastie a permis de calculer la lumière vasculaire et l'épaisseur néointimale moyenne. Ces calculs démontrent une réduction de la resténose dans le groupe traité avec le losartan lorsque comparé au groupe contrôle. Cette réduction de la resténose est égale à celle observée avec la combinaison de losartan et de PD123319. Le PD123319 seul n'a pas reéduit la resténose de façon significative. Il semble alors que le récepteur AT[indice inférieur 1] de l'angiotensine II soit responsable en partie de la resténose post-angioplastique chez le rat Sprague-Dawley. Le récepteur AT[indice inférieur 2] de l'angiotensine II ne semble pas être impliqué de façon significative dans ce processus.

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published_or_final_version / Biological Sciences / Doctoral / Doctor of Philosophy