Diss. (sammanfattning) Stockholm : Karolinska institutet, 2002. / Härtill 6 uppsatser.

Thesis (Ph. D.)--University of Hong Kong, 2009. / Includes bibliographical references (leaves 141-162). Also available in print.

Techn. Universiẗat, Diss., 2005--München.

Regensburg, Univ., Diss., 2002.

Currently, it is reported that ~65% and 34% of the U.S. population is overweight and obese, respectively. Obesity is a major risk factor for cardiovascular disease. Overweight and obese individuals are also at an increased risk of developing hypertension. Whole-body insulin sensitivity is reduced in obesity, resulting in insulin resistance and increased risk of type 2 diabetes. One possible mechanism contributing to insulin resistance in obesity hypertension is renin-angiotensin system (RAS) overactivation. The RAS exhibits vasocontricting and sodium-retaining properties, yet in vivo and in vitro animal experiments suggest impairment of whole-body insulin sensitivity with increased angiotensin II (Ang II) exposure. Furthermore, evidence from clinical studies indicates Ang II receptor blockers (ARBs) may reduce the incidence of new-onset diabetes compared to other antihypertensive agents in at-risk hypertensive patients. However, it is unclear if whole-body insulin sensitivity is improved with Ang II receptor blockade in humans. Thus, we tested the hypothesis that 8-week Ang II receptor blockade with olmesartan would improve whole-body insulin sensitivity in overweight and obese individuals with elevated blood pressure (BP). Olmesartan was selected for the present study because it is devoid of partial PPARγ agonist activity. To test our hypothesis, intravenous glucose tolerance tests were performed to measure insulin sensitivity before and after control and ARB treatment in a randomized crossover manner. Because skeletal muscle tissue accounts for ~75-90% of insulin-stimulated glucose uptake, a secondary exploratory aim was to examine skeletal muscle inflammatory and collagen response in relation to insulin sensitivity during ARB treatment. No baseline differences were observed between treatments (P>0.05). Both systolic (-11.7 mmHg; P=0.008) and diastolic (-12.1 mmHg; P=0.000) BP were reduced with ARB treatment. Insulin sensitivity was not different between treatments (P>0.05). No correlates of insulin sensitivity were identified. In addition, skeletal muscle inflammatory and collagen gene expression did not change from pre- to post-ARB treatment (P>0.05). Our findings suggest that short-term RAS blockade in overweight and obese adults with elevated BP does not improve whole-body insulin sensitivity, despite a significant BP reduction. Further studies are needed to clarify the role of individual RAS blockers on insulin sensitivity during RAS inhibition in obesity hypertension. / Ph. D.

Fetal pancreatic tissues can be a promising source for pancreatic progenitor cells (PPCs). In this regard, we have successfully isolated and characterized a population of fetal PPCs from first trimester human fetal pancreas using a previously established basic protocol. Upon exposure to a cocktail of conventional growth factors, these PPCs are amenable to differentiate into insulin-secreting islet-like cell clusters (ICCs); however, these ICCs have yet to exert additional efforts to direct to glucose-responsive cells. To address this issue, we have proposed two novel morphogenic factors in the present study, namely PDZ-domain-containing 2 (PDZD2) and angiotensin II (Ang II), a physiologically active peptide of the renin-angiotensin system (RAS), that potentially promote the differentiation and maturation of PPCs/ICCs. / In light of these findings, we conclude that we have discovered two novel mechanisms, the PDZD2 and Ang II/AT2 receptor signaling pathways, in the regulation of the development of PPCs/ICCs, thus implying their novel roles during islet development in vivo. The present study provides a "proof-of-principle" that a local RAS is critically involved in governing islet cell development. This work may contribute to devising protocols for maturation of pancreatic progenitors for clinical islet transplantation. / Local RASs have been reported to regulate the differentiation of tissue progenitor cells. It has yet to be confirmed whether such systems exist and govern the PPC development. To address this issue, we herein provided evidence that expression of RAS components was highly regulated throughout PPC differentiation. Locally generated Ang II was found to maintain PPC growth and differentiation via mediation of the Ang II type 1 and type 2 (AT1 and AT 2) receptors. We found that the AT2, but not AT1, receptor was a key mediator of Ang II-induced upregulation of beta-cell transcription factors. Transplantation of AT2 receptor-depleted ICCs into immune-privileged diabetic mice failed to ameliorate hyperglycemia, implying that AT2 receptors are indispensable during ICC maturation in vivo. / PDZD2 and its secreted form (sPDZD2) have been found to express in our fetal PPCs. We first evaluated the potential role of sPDZD2 in stimulating PPC differentiation and established an optimal concentration for such stimulation. We found that 10-9 M sPDZD2 promoted PPC differentiation, as evidenced by the up-regulation of the pancreatic endocrine markers and C-peptide content in the ICCs. It enhanced their expression of the L-type voltage-gated calcium ion channel (Cav1.2) and conferred an ability to secrete insulin in response to membrane depolarization. Yet these ICCs remained glucose-unresponsive because of the minimal expression of GLUT-2. We thus attempted to study another potential morphogenic candidate, Ang II. / To further test whether a functional RAS is present and if so, whether it regulates islet development in vivo, we employed a mouse embryo model at different embryonic days and reported a stronger AT2 receptor expression during the 2nd developmental transition of pancreas development. AT2 receptor blockade from e8.0 resulted in abnormalities in fetal pancreatic development. Neonates from these mother mice displayed destructed pancreas/islet architecture, a hampered ability in glucose-stimulated insulin-secretion possibly attributed to a decreased ratio of beta-cell to alpha-cell, and an impaired glucose tolerance at 4-wk old. / Leung, Kwan Keung. / Adviser: Po Sing Leung. / Source: Dissertation Abstracts International, Volume: 72-04, Section: B, page: . / Thesis (Ph.D.)--Chinese University of Hong Kong, 2010. / Includes bibliographical references (leaves 254-284). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Electronic reproduction. Ann Arbor, MI : ProQuest Information and Learning Company, [200-] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstract also in Chinese.

Eine der häufigsten kardiovaskulären Erkrankungen ist die Atherosklerose. Bei der Entstehung einer Atherosklerose spielt eine Hyperlipoproteinämie eine entscheidende Rolle. Ein weiterer Faktor für die Entstehung kardiovaskulärer Erkrankungen ist ein hoher Blutdruck. In dieser Arbeit wurde eine mögliche Interaktion zwischen Lipoproteinen und den blutdruckregulierenden Endothelin- und Renin-Angiotensin-Systemen untersucht. Weiterführende Analysen erfolgten an Rezeptoren für die Aufnahme von nLDL und oxLDL. Abschließend wurden Signalwege untersucht, die durch nLDL und oxLDL aktiviert werden. Tierexperimentielle Untersuchungen in Aorten und Herzen fettreich gefütterter Wildtyp- Mäuse unterstützen die Zellkultur-Ergebnisse einer Induzierung des Endothelin-Systems durch erhöhte Lipoproteine. Zusammenfassend zeigt diese Arbeit neue Mechanismen der Interaktion von Lipoproteinen und blutdruckregulierenden Systemen in Endothelzellen. Die Rezeptoren scheinen dabei eine Schlüsselrolle zu spielen. Dies spricht für eine Potenzierung von Hyperlipoproteinämie und Hypertonie bei der Entstehung von Herz-Kreislauf-Erkrankungen.

Hypertonie ist die häufigste adipositas-assoziierte Erkrankung. Das vermehrt vorhandene Fettgewebe könnte von pathophysiologischer Bedeutung sein, da es eine Reihe von Substanzen sezerniert, die die Blutdruckregulation beeinflussen. Hinweise auf eine Rolle des adipocytären Renin-Angiotensin Systems für die Hypertonie ergeben sich aus der Assoziation von Adipositas und einer gesteigerten systemischen Aktivität des Renin-Angiotensin Systems, sowie aus dem Nachweis im Tiermodell, dass adipocytär gebildetes Angiotensinogen in die systemische Zirkulation gelangt. In der vorliegenden Untersuchung wurden 12 schlanke Normotonikerinnen, 8 adipöse Normotonikerinnen und 10 adipöse Hypertonikerinnen charakterisiert und die adipocytäre Genexpression des Renin-Angiotensin Systems untersucht. Adipocyten wurden mittels Nadelbiopsie und Kollagenaseverdau gewonnen, die Genexpression wurde durch real-time RT-PCR bestimmt. Der Vergleich der drei Gruppen zeigt, dass Adipositas mit einer Reduktion der Angiotensinogen-Expression einhergeht, die adipositas-assoziierte Hypertonie mit einer gesteigerten Expression von Renin, Angiotensin-Converting-Enzyme und Angiotensin II-Typ 1-Rezeptor. Dies führt zu der Hypothese, dass im Fettgewebe adipöser Hypertoniker vermehrt Angiotensin II gebildet wird und könnte den positiven Einfluß von ACE-Hemmern auf die Insulinresistenz und die Verringerung der Neuerkrankungsrate an Diabetes mellitus Typ 2 erklären. / Adipose tissue secretes vasoactive substances which may contribute to the development of obesity-related hypertension. We aimed to study the differential expression of renin-angiotensin system genes in subcutaneous abdominal adipocytes of 12 lean normotensive, 8 obese normotensive, and 10 obese hypertensive women in a cross-sectional study. 24h ambulatory blood pressure measurement, clinical chemistry, and anthropometry were used to characterize the volunteers. Adipocytes were obtained by abdominal subcutaneous needle biopsy and collagenase digestion. Gene expression was studied by quantitative real time RT-PCR. While expression of the angiotensinogen gene was significantly lower in adipocytes from both obese groups, the renin, angiotensin-converting enzyme and angiotensin II-type 1-receptor genes were significantly upregulated in obese hypertensives. In conclusion, renin-angiotensin system genes are differentially regulated in human obesity and hypertension. The data obtained suggest increased formation of angiotensin II in adipose tissue of obese hypertensive subjects. The role of the adipose-tissue renin-angiotensin system in the development of obesity-associated hypertension or metabolic disease clearly warrants further study.

Das Renin-Angiotensin-System ist nachweislich in die Entwicklung der schwangerschaftsspezifischen Erkrankung Präeklampsie involviert. Ziel der Arbeit ist die Charakterisierung der Effekte des zirkulierenden sowie uteroplazentaren Renin-Angiotensin-Systems im Rattenmodell. Wurden weibliche Ratten, transgen für humanes Angiotensinogen, mit männlichen Ratten, transgen für humanes Renin verpaart, so entwickelten sie während der Schwangerschaft Bluthochdruck und Proteinurie, während die umgekehrte Kreuzung diese Hauptsymptome der Präeklampsie nicht zeigte. Weiterhin wurde mit einer Kontrollgruppe sowie einer Angiotensin II behandelten Gruppe gearbeitet. Chronisch, systemische Angiotensin II Infusion (1000 ng/kg/min) erhöhte zirkulierendes Angiotensin II während in der umgekehrten, Präeklampsie-negativen Kreuzung uteroplazentares Angiotensin II erhöht war. In der Präeklampsie-positiven Gruppe war Angiotensin II zirkulär und uteroplazentar erhöht. Bluthochdruck und Albuminurie waren alleinig in den Tiermodellen mit erhöhtem zirkulierendem Angiotensin II nachweisbar. In der Kontrollgruppe kam es während der Schwangerschaft zu einer physiologischen Herzhypertrophie, während in der Präeklampsie-positiven Gruppe Anzeichen einer pathologischen Herzhypertrophie nachweisbar waren. Weiterhin unterstützte uteroplazentares Angiotensin II die tiefe Invasion von Trophoblasten in plazentafernen Spiralarterien, während zirkulierendes Angiotensin II die Trophoblasteninvasion im gesamten mesometrialen Dreieck diffus förderte. In Zellkulturexperimenten konnte gezeigt werden, dass Angiotensin II die Mobilität und die Invasion einer Trophoblastenzelllinie förderte. Ebenso erhöhte Angiotensin II die Migration von Trophoblasten in Plazentakulturen. Diese Ergebnisse verdeutlichen den unterschiedlichen Einfluss des zirkulierenden und uteroplazentaren Renin-Angiotensin-Systems auf die Schwangerschaft und tragen damit zum Verständnis pathologischer Prozesse bei, die zu Präeklampsie führen. / Dysregulation of the renin-angiotensin-system is important in preeclampsia, a pregnancy specific disorder, characterized by high blood pressure and albuminuria. Aim of this study is to characterize the effects of circulation and uteroplacental renin-angiotensin-system during pregnancy in a rat model. Female rats transgenic for the human angiotensinogen gene crossed with males transgenic for the human renin gene develop preeclampsia, whereas those of the opposite cross do not. We used this model to study the role of angiotensin II in trophoblast invasion, which is shallow in human preeclampsia but deeper in this model. We investigated the following groups: preeclampsia rats, opposite-cross rats, angiotensin II–infused rats and control rats. Angiotensin II infusion increased only circulating angiotensin II levels, opposite cross influenced only uteroplacental angiotensin II and preeclampsia rats showed increased circulating and uteroplacental angiotensin II. Blood pressure and albuminuria occurred in the models with high circulating angiotensin II but not in other models. Control rats showed physiological heart hypertrophy during pregnancy whereas pathological heart hypertrophy occurred in preeclampsia rats. High uteroplacental angiotensin II influenced deep trophoblast invasion in distant spiral arteries whilst the effect of circulating angiotensin II was more diffuse. We then studied human trophoblast cell line and villous explants derived from first-trimester pregnancy. Local angiotensin II dose-dependently increased migration, invasion and motility. The data suggest that angiotensin II stimulates trophoblast invasion in vivo in the rat and in vitro in human cells, a hitherto fore unrecognized function.

Jiang, Lili. / Thesis (Ph.D.)--Chinese University of Hong Kong, 2011. / Includes bibliographical references (leaves 215-235). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstract also in Chinese.