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Coming dissertations at MedFak

  • The Role of Kidney Oxygen Homeostasis for the Development of Kidney Disease Author: Carla Carvalho Link: Publication date: 2019-08-16 10:06

    The relation between oxygen supply and demand determines tissue oxygen tension (PO2). When intrarenal tissue PO2 decreases, any compensatory increase in oxygen supply via increased renal blood flow is likely to increase glomerular filtration rate. The resulting increased tubular load of electrolytes destined for active transport increases oxygen consumption, thus affecting intrarenal tissue PO2. Consequently, the kidney is particularly sensitive to alterations in oxygen homeostasis and kidney hypoxia is acknowledged as a common pathway to end stage renal disease. Different factors that can affect intrarenal oxygen homeostasis, including alterations in blood pressure and sodium intake dietary or pathologies such as diabetes mellitus, anemia or atherosclerosis. This thesis focuses on understanding how these factors influence kidney oxygen homeostasis.

    Pronounced reduction in sodium intake caused tissue hypoxia in kidney cortex via activation of the renin-angiotensin-aldosterone leading to increased tubular sodium reabsorption. Angiotensin II and aldosterone affect kidney oxygen handling differently. Whereas angiotensin II mainly affects kidney oxygen delivery, aldosterone mainly affects oxygen consumption.

    The hypoxia-inducible factor (HIF) system is a cellular defense mechanism against prolonged hypoxia. Although diabetes causes intrarenal hypoxia, hyperglycemia per se also prevents HIF-activation. Therefore, the effects of type 1 diabetes were evaluated in genetically modified mice with chronic HIF-activation. Diabetic mice with globally increased HIF activity, due to heterozygote prolyl hydroxylase-2 deficiency, displayed reduced mitochondria leak respiration and preserved cortical PO2. Diabetic mice with kidney-specific HIF activation, due to homozygous deficiency of von Hippel-Lindau, developed reduced mitochondria leak respiration and reduced urinary albumin excretion.

    The normal age-related decline in kidney function has been proposed to be due to, at least in part, increased oxidative stress, which can induce mitochondrial leak respiration via activation of uncoupling proteins. Indeed, two-year old mice deficient of uncoupling protein-2 presented with improved mitochondria efficiency and reduced urinary protein excretion.

    Summarizing, the data presented in this thesis provide clear support for potent influence of the renin-angiotensin-aldosterone system, HIF activation and mitochondria function on intrarenal oxygen availability. Maintaining kidney oxygen homeostasis may be a unifying strategy to protect kidney function.

  • Human adenovirus – host cell interplay : The role of the cellular zinc finger proteins and mitochondrial DNA Author: Kwangchol Mun Link: Publication date: 2019-08-15 09:36

    Human adenovirus (HAdV) is an abundant DNA virus with significant clinical relevance since it cauces a variety of respiratory, ocular, and gastrointestinal diseases. It is also intensively used as a therapeutic tool to treat cancers and to boost immune responses. In order to achieve a better control over the HAdV epidemiology and improved utilization for clinical applications, it is crucial to understand the molecular interaction between the host cell and HAdV.

    The aim of the current thesis is to delineate the molecular interactions between HAdV type 5 (HAdV-C5) protein VII (pVII), two cellular zinc finger proteins (MKRN1, ZNF622)  and mitochondrial DNA (mtDNA). In paper I, we have identified MKRN1 as one of the novel pVII-interacting proteins. Surprisingly, endogenous MKRN1 protein is down-regulated in the HAdV-infected cells due to its proteasomal degradation. Further, the pVII(wt) promoted  MKRN1 self-ubiquitination, which may explain the overall instability of the MKRN1 protein in the infected cells. In addition, we show that the MKRN1 protein is also down-regulated in measles virus- and vesicular stomatitis virus-infected cells. In paper II, we report that the cellular ZNF622 protein interacts with the pVII protein. Intriguingly, ZNF622 expression was enhanced in HAdV-C5-infected cells, implying its anti-viral role. Surprisingly, lack of the ZNF622 protein significantly enhanced formation of the infectious HAdV-C5 virions. Finally, we propose a model how the ZNF622/NPM1/pVII protein complex regulates the pVII protein binding to viral DNA. In paper III, we report that HAdV-C5 infection enhanced mtDNA release into cytosol. The enhanced mtDNA release can be partially explained by accumulation of the pVII protein since its down-regulation diminished mtDNA release into cyotosol. We also report pVII-regulated gene expression profile and show that cellular cytokine IL-32 mRNA accumulates in response to the pVII protein expression.

    Collectively, in this thesis we provide molecular characterization how two cellular zinc finger proteins (MKRN1 and ZNF622) and mtDNA behave in the context of lytic HAdV-C5 infection. The ZNF622 may act as a bona fide anti-viral factor blocking infectious virion formation via targeting the essential viral core protein pVII. The MKRN1 protein is efficiently eliminated in the infected cells, highlighting the essence of HAdV-C5-controlled proteasome. Finally, dynamical change of mtDNA induced by HAdV-C5 infection, might initiate a novel signaling pathway beneficial for the cells or the viruses.