Thesis (doctoral)--Uppsala University, 1983. / Includes bibliographical references (p. 29-33).

The kidneys are amazingly versatile organs that perform a wide range of vital bodily functions. This thesis provides an analysis into a range of mathematical models of the tubuloglomerular feedback (TGF) mechanism. The TGF mechanism is an autoregulatory mechanism unique to the kidney that maintains approximately constant blood flow to the organ despite wide fluctuations in pressure. Oscillations in pressure, flow, and sodium chloride concentration have been attributed to the action of the TGF mechanism through a number of experimental studies. These oscillations appear spontaneously or in response to a natural or artificial pressure step or microperfusion. The reason for sustained oscillatory behaviour in nephrons is not immediately clear. Significant research has gone into experimentally determining the signal to the TGF mechanism, but the physiological significance is not mentioned in the literature. Considerable modelling of the oscillations attributed to the TGF mechanism has also been undertaken. However, this modelling uses models that are inherently oscillatory, such as a second-order differential equation or delay differential equations. While these models can be fitted to closely approximate the experimental results they do not address the physiological factors that contribute to sustained oscillations. This thesis aims to determine the contributing factors to the sustained oscillations. By understanding these factors a better hypothesis of the physiological role of the oscillations should be possible. Chapter 3 presents a mathematical model by Holstein-Rathlou and Marsh [28] that uses a partial differential equation (PDE) model for the tubule and a second-order differential equation for the TGF feedback. The remainder of this chapter shows that oscillations occur without an inherently oscillatory second-order differential equation due to the delays in the system. Tubular compliance was also shown to be necessary for sustained oscillations. Sustained oscillations were not exhibited in the TGF model with a noncompliant tubule. Although damped oscillations were exhibited for a wide range of parameter space. Adding compliance to the tubule increased the delay around the loop of Henle. This additional delay elicited sustained oscillations. The computationally expensive PDE model of 3 was simplified to an ordinary differential equation (ODE) model in Chapter 4 by assuming a spatial profile. This model exhibits much of the same qualitative behaviour as the PDE model including sustained oscillations for similar ranges of parameter space. Compliance was also found to be important in the generation of sustained oscillations in agreement with the PDE tubule model. This model is less computationally expensive than the PDE model and allows analysis that was unfeasible with the PDE model. Significant natural and artificial blood pressure fluctuation occur in experimental rat models. Chapter 5 examines the effect of inlet pressure forcing on a nonoscillatory and an oscillatory model. The inherently nonoscillatory noncompliant model becomes oscillatory with a physiologically realistic pressure forcing. The oscillatory compliant model remains oscillatory with the addition of a inlet pressure forcing. Pressure fluctuations were hypothesised to contribute to sustained oscillations and could be validated experimentally. Two extensions to the single nephron TGF models are presented in Chapter 6. A realistic juxtaglomerular delay is added to the single nephron models with both the ODE and PDE tubular models. Physiologically realistic juxtaglomerular delays induce sustained oscillations in the otherwise nonoscillatory noncompliant models. The remainder of this chapter presents a different model for a variable interstitial sodium chloride concentration profile. This model demonstrates experimentally observed function of the countercurrent mechanism by which a concentration gradient is set up and maintained in the interstitium. Two single nephron models with ODE tubular models are coupled in Chapter 7. The coupling is modelled through the effect on the resistance of their neighbouring nephron's afferent arteriole resistance. The coupled nephron model exhibits entrainment as observed experimentally. Inhibiting the oscillation in one nephron reduces the amplitude of the oscillation in its neighbour. This result compares well with experiments where the TGF mechanism in one nephron is blocked by the administration of furosemide.

Submitted by Suzana Dias (suzana.dias@famerp.br) on 2018-10-25T18:25:42Z No. of bitstreams: 1 ElizabethCestario_tese.pdf: 1605128 bytes, checksum: 627109b3f3b0eb4f3992e765cc2dbc5c (MD5) / Made available in DSpace on 2018-10-25T18:25:42Z (GMT). No. of bitstreams: 1 ElizabethCestario_tese.pdf: 1605128 bytes, checksum: 627109b3f3b0eb4f3992e765cc2dbc5c (MD5) Previous issue date: 2018-06-27 / Resistant hypertension (RHT) is a clinical entity, difficult to manage. To identify the contribution of the volume as well as the renin activity from the maintenance of blood pressure levels could individualize the treatment. Objectives: To demonstrate the efficacy of therapy of sequential nephron blocking (SNB) in relation to the double blockade of the renin-angiotensin-aldosterone system associated with beta-blockers (DBRAS) in patients with RHT with > 85%-adherence rate after 20 weeks of treatment. Casuistic and Methods: A prospective study was conducted, open, randomized, parallel comparison between two regimens for RHT: SNB versus RAASDB. SNB consists in a progressive increase of sodium depletion with thiazide, followed by a blockade of mineralocorticoid receptor, followed by progressive doses of loop diuretics and finally blocking sodium channels. RAASDB consists in reinforcing the effect of angiotensin receptor blocker (ARB) with an angiotensin converting enzyme inhibitors (ACEI), followed by betablockers to decrease the renin secretion. Seventy two patients were randomized (35 to SNB 13M/22F and 37 to RAASDB14M/23F) coming from the tertiary outpatient clinic (HB-FAMERP). We used the criteria of VII Guidelines for Hypertension and V Guidelines for ABPM and HBPM SBC-SBH. The BP was monitored with the SpaceLabs 90207 ABPM using appropriate software of the equipment and issuing reports. Results: Baseline clinical characteristics and laboratory parameters of the 72 patients with primary resistant hypertension randomized to SNB (n=35) or RAASDB (n=37) were similar across both study groups. At the end of the study, a significant reduction of the office pressure was observed (SBP and DBP) in both postintervention groups (SNB group: initial SBP: 174.5 ± 21.08; final SBP: 127.0 ± 14.74; Initial DBP: 105.3 ± 15.5, final DBP: 78.11 ± 9.28 (p <0.0001), RAASDB group: initial SBP: 178.4 ± 21.08, final SBP: 134.4 ± 23.25, initial DBP: 102.7 ± 11.07, final DBP: 77.33 ± 13.75 (p <0.0001). Central systolic pressure had a greater reduction in the SNB group (p <0.005). ABPM had a significant reduction of SBP and DBP in both groups (SNB group p <0.0001 for SBP and DBP pre x post-intervention, RAASDB group p <0.0001 for SBP and DBP pre x post-intervention). No discontinuation due drug-related adverse events in both study groups. Conclusion: SNB and RAASDB associated with the beta-blocker in RHT patients with full adherence to the treatment showed excellent therapeutic efficacy. However, the SNB group disclosed a greater absolute reduction of central blood pressure values. / Hipertensão arterial resistente (HAR) é uma entidade clínica de difícil manejo. Identificar a contribuição do volume e da atividade da renina na manutenção dos níveis pressóricos poderia individualizar o tratamento. Objetivos: Demonstrar a eficácia da terapêutica do bloqueio sequencial do néfron (BSN) em relação ao bloqueio duplo do sistema renina-angiotensina-aldosterona associado ao betabloqueador (BDSRA) em pacientes com HAR com taxa de adesão > 85%, após 20 semanas de tratamento. Casuística e Métodos: Foi realizado um estudo prospectivo, aberto, randomizado, paralelo de comparação entre dois regimes terapêuticos para HAR: BSN versus BDSRA. BSN consiste em um aumento progressivo da depleção de sódio com diurético tiazídico, seguido de bloqueio do receptor mineralocorticoide, seguido de doses progressivas de diuréticos de alça e finalmente bloqueio dos canais de sódio. BDSRA consiste em reforçar o efeito do bloqueador do receptor da angiotensina I (BRA) com um inibidor da enzima conversora da angiotensina (IECA), seguido de um betabloqueador para diminuir a secreção de renina. Foram randomizados setenta e dois pacientes HAR (35 para BSN 13M/22F e 37 para DBSRA 14M/23F) procedentes do ambulatório terciário (HB-FAMERP). Foram usados os critérios das VII Diretrizes de Hipertensão e V Diretrizes de MAPA e MRPA SBC-SBH. A PA foi monitorada com equipamento o SpaceLabs 90207 com para programação do equipamento e emissão de relatórios. Resultados: As características clínicas e os parâmetros laboratoriais dos 72 pacientes com HAR randomizados para BSN (n=35) ou DBSRA (n=37) foram semelhantes em ambos os grupos. No final do estudo, houve redução significante da pressão de consultório (PAS e PAD) em ambos os grupos pós-intervenção (Grupo BSN: PAS inicial: 174,5 ±21,08; PAS final: 127,0 ± 14,74; PAD inicial:105,3 ±15,5; PAD final: 78,11 ±9,28 (p<0,0001); Grupo DBSRA: PAS inicial: 178,4 ±21,08; PAS final: 134,4 ± 23,25; PAD inicial:102,7 ±11,07; PAD final: 77,33 ±13,75 (p<0,0001). A maior redução da pressão sistólica central foi observada no grupo BSN (p<0,005.) A MAPA apresentou redução significativa da PAS e PAD em ambos os grupos (Grupo BSN p<0,0001 para PAS e PAD pré x pós-intervenção. Grupo DBSRA p<0,0001 para PAS e PAD pré x pós-intervenção). Não houve abandono do tratamento devido a eventos adversos da medicação. Conclusão: BSN e DBSRA associados ao betabloqueador em hipertensos resistentes com adesão plena ao tratamento apresentaram excelente eficácia terapêutica. Entretanto, o grupo BSN mostrou maior redução absoluta dos valores da pressão arterial sistólica central.

Gao, Si. / Thesis (M.Phil.)--Chinese University of Hong Kong, 2010. / Includes bibliographical references (leaves 77-85). / Abstracts in English and Chinese. / Acknowledgement --- p.i / Abstract --- p.ii / Abstract (in Chinese) --- p.iv / List of Abbreviations --- p.v / List of Figures --- p.vii / Table of Contents --- p.ix / Chapter Chapter One: --- Introduction --- p.1 / Chapter 1.1. --- Cancer --- p.1 / Chapter 1.2. --- Chemotherapy --- p.2 / Chapter 1.3. --- Cisplatin --- p.3 / Chapter 1.4. --- Cisplatin-induced nephrotoxicity --- p.4 / Chapter 1.5. --- Mechanisms of cisplatin-induced nephrotoxicity --- p.5 / Chapter 1.5.1. --- Apoptosis in cisplatin-induced nephrotoxicity --- p.5 / Chapter 1.5.2. --- MAPK activation in cisplatin-induced nephrotoxicity --- p.7 / Chapter 1.5.3. --- Oxidative stress in cisplatin-induced nephrotoxicity --- p.8 / Chapter 1.6. --- Polyphenols --- p.10 / Chapter 1.7. --- Anthocyanins --- p.10 / Chapter 1.8. --- Rose --- p.11 / Chapter 1.9. --- Cyanidin --- p.12 / Chapter 1.10. --- Objectives of this project --- p.13 / Chapter Chapter Two: --- Materials and Methods --- p.15 / Chapter 2.1. --- Materials --- p.15 / Chapter 2.2. --- Cell culture --- p.15 / Chapter 2.3. --- Drug treatment --- p.16 / Chapter 2.4. --- MTT assay --- p.16 / Chapter 2.5. --- Lactate dehydrogenase (LDH) assay --- p.16 / Chapter 2.6. --- TUNEL assay and DAPI staining --- p.17 / Chapter 2.7. --- Flow cytometric analysis --- p.17 / Chapter 2.8. --- Determination of caspase-3 activity --- p.18 / Chapter 2.9. --- Measurement of ROS generation --- p.18 / Chapter 2.10. --- Evaluation of mitochondrial membrane potential --- p.19 / Chapter 2.11. --- Single Cell Gel Electrophoresis (Comet Assay) --- p.19 / Chapter 2.12. --- Western blot analysis --- p.20 / Chapter 2.13. --- Statistical analysis --- p.21 / Chapter Chapter Three: --- Results --- p.22 / Chapter 3.1. --- Cyanidin attenuates cisplatin-induced cytotoxicity in HK-2 cells --- p.22 / Chapter 3.1.1. --- Cytotoxicity induces by cisplatin in HK-2 cells --- p.22 / Chapter 3.1.2. --- Rose extract attenuates cisplatin-induced cytotoxicity and LDH leakage --- p.26 / Chapter 3.1.3. --- Cyanidin attenuates cisplatin-induced cytotoxicity and LDH leakage --- p.26 / Chapter 3.1.4. --- Cyanidin did not affect cisplatin-induced cytotoxicity in Hela cell --- p.30 / Chapter 3.2. --- Cyanidin rescues HK-2 cells from cisplatin-induced apoptosis --- p.31 / Chapter 3.2.1. --- Cisplatin induces cell apoptosis in HK-2 cells --- p.31 / Chapter 3.2.2. --- Rose extract rescues HK-2 cells from cisplatin-induced apoptosis --- p.31 / Chapter 3.2.3. --- Cyanidin rescues HK-2 cells from cisplatin-induced apoptosis --- p.32 / Chapter 3.3. --- Cyanidin suppresses cisplatin-induced activation of caspase and cleavage of PARP --- p.38 / Chapter 3.3.1. --- Cisplatin induces activation of caspase-3 --- p.38 / Chapter 3.3.2. --- Rose extract suppresses cisplatin-induced activation of caspase-3 --- p.38 / Chapter 3.3.3. --- Cyanidin suppresses cisplatin-induced activation of caspase-3 --- p.38 / Chapter 3.3.4. --- Rose extract suppresses cisplatin-induced caspase activation and PARP cleavage --- p.41 / Chapter 3.3.5. --- Cyanidin suppresses cisplatin-induced caspase activation and PARP cleavage --- p.43 / Chapter 3.4. --- Cyanidin rescues HK-2 cells from cisplatin-induced mitochondrial dysfuntion by regulating the expression of Bcl-2 family proteins --- p.43 / Chapter 3.4.1. --- Cyanidin prevents cisplatin-induced loss of mitochondrial membrane potential (A^m) --- p.43 / Chapter 3.4.2. --- Cyanidin regulates the expression of Bcl-2 family proteins to prevent cisplatin-induced mitochondrial dysfunction --- p.44 / Chapter 3.5. --- Cyanidin reduces cisplatin-induced apoptosis by suppressing the activation of p53 --- p.46 / Chapter 3.6. --- Cyanidin inhibits ROS-mediated DNA damage in HK-2 cells --- p.48 / Chapter 3.6.1. --- Cyanidin prevents cisplatin-induced DNA damage --- p.48 / Chapter 3.6.2. --- Cyanidin inhibits cisplatin-induced accumulation of ROS --- p.48 / Chapter 3.7. --- "Cyanidin suppresses cisplatin-induced apoptosis by activation of AKT, JNK and ERK" --- p.52 / Chapter 3.7.1. --- Cisplatin activates ERK and AKT pathways --- p.52 / Chapter 3.7.2. --- Cyanidin suppresses cisplatin-induced activation of MAPKs and AKT pathways --- p.52 / Chapter 3.7.3. --- AKT and ERK Inhibitors attenuates cisplatin-induced apoptosis in HK-2 cells --- p.53 / Chapter Chapter Four: --- Discussion --- p.60 / Chapter 4.1. --- Cell model and cisplatin treatment --- p.60 / Chapter 4.2. --- Cisplatin nephrotoxicity and its renoprevention --- p.61 / Chapter 4.3. --- Rose extract prevents cisplatin-induced apoptosis in HK-2 cells --- p.62 / Chapter 4.3.1. --- Rose extract prevents cisplatin-induced apoptosis in HK-2 cells --- p.63 / Chapter 4.3.2. --- Rose extract inhibits cisplatin-induced caspase activation and PARP cleavage --- p.64 / Chapter 4.4. --- Cyanidin prevents cisplatin-induced apoptosis in HK-2 cells --- p.66 / Chapter 4.4.1. --- Cyanidin will not affect cisplatin-induced cell death in HeLa cells --- p.66 / Chapter 4.4.2. --- Cyanidin prevents cisplatin-induced apoptosis by inhibiting caspase activation and PARP cleavage in HK-2 cells --- p.66 / Chapter 4.4.3. --- Cyanidin prevents the cisplatin-induced loss of mitochondrial membrane potential by regulating Bcl-2 proteins in HK-2 cells --- p.67 / Chapter 4.4.4. --- Cyanidin suppresses cisplatin-induced total and phosphorylated p53 activation --- p.68 / Chapter 4.4.5. --- Cyanidin prevents the cisplatin-induced overproduction of intracellular ROS and subsequent DNA damage in HK-2 cells --- p.69 / Chapter 4.4.6. --- Cyanidin suppresses the cisplatin-induced activation of MAPKs and AKT pathways in HK-2 cells --- p.71 / Chapter Chapter Five: --- Conclusion --- p.74 / References --- p.77