In this thesis we analyzed the pathogenetic sequence of renal cyst and aneurysm formation in PKD mouse models. Cyst formation in the mouse model, Pkd1nl/nl with reduced Pkd1 transcripts was studied... Show moreIn this thesis we analyzed the pathogenetic sequence of renal cyst and aneurysm formation in PKD mouse models. Cyst formation in the mouse model, Pkd1nl/nl with reduced Pkd1 transcripts was studied by analyzing tubular cell proliferation, apoptosis, extracellular matrix remodeling, and the expression the Na+K+2Cl- co-transporter. These mice presented with a rapidly progressive phenotype and, in time, cyst formation was nephron segment-dependent. Interestingly, the expression of Na+K+2Cl- co-transporters was also segment-dependent. TGF__ signaling, the most important cytokine involved in fibrosis, is activated at the progressive stages of the disease and coincides with mild fibrosis and increased expression of TGF__ target genes. These results suggest that the TGF__ signaling pathway is probably not implicated in initial steps of cyst formation, but indicate an important role during cyst progression and in fibrogenesis of progressive ADPKD. Aneurysm formation was found in the Pkd1nl/nl, indicating a direct association between Pkd1 and vessel wall integrity. But, selective disruption of Pkd1 in vascular smooth muscle cells (SM22-Pkd1del/de micel) did not induce any gross structural blood vessel abnormalities. However, SM22-Pkd1del/del mice significantly showed reduced decrease in heart rate upon Angiotensin II-induced hypertension. These findings further demonstrate in vivo, that adaptation to hypertension is altered in SM22-Pkd1del/del mice. Show less
In this thesis the role of murine FcgammaR in autoimmune diseases is analyzed with special focus on arthritis and lupus. Series of studies performed with a variety of arthritis models established... Show moreIn this thesis the role of murine FcgammaR in autoimmune diseases is analyzed with special focus on arthritis and lupus. Series of studies performed with a variety of arthritis models established in mice deficient for one or more FcgammaR provided direct evidence for a prominent role of FcgammaR in arthritis (Chapter 2). Chapters 3 to 5 provide new insights into the role of individual FcgammaR in arthritis pathology. The precise contribution of FcgammaRIIB to the development of autoimmunity has been a matter of debate. In Chapter 6, we provide direct evidence that FcgammaRIIB on its own plays a limited role in the development of spontaneous autoimmunity in C57Bl/6 mice. Our results suggest that the role of FcgammaRIIB in the development of spontaneous autoimmunity (Systemic Lupus Erythematosus) is more restricted as originally postulated on the basis of the phenotype of FcgammaRIIB129-/- mice, whereas its role in induced autoimmunity is prominent, supporting the hypothesis that FcgammaRIIB represents a late checkpoint in B cell tolerance. In Chapter 7 we describe the generation and characterization of a novel B cell-specific inducible Cre transgenic mouse line. The results presented in this thesis provide new insights in the role of FcgammaRs in protective immunity and immuno-pathology. Show less
In this thesis we focused on the causes and consequences of hepatic steatosis. Epidemiological studies in humans, as well as experimental studies in animal models, have shown an association between... Show moreIn this thesis we focused on the causes and consequences of hepatic steatosis. Epidemiological studies in humans, as well as experimental studies in animal models, have shown an association between visceral obesity and dyslipidemia, insulin resistance and type 2 diabetes mellitus. The mechanism underlying this association remains unclear. Recently, attention has focused on the role of excessive accumulation of triglycerides (TG) in the liver (hepatic steatosis) in this association. Hepatic steatosis was considered a benign condition until it was discovered that a nonalcoholic fatty liver is associated with many cardiovascular risk factors. Subsequently, many studies have shown a strong association between hepatic TG content and hepatic insulin resistance. The studies in this thesis show that hepatic steatosis is actively and passively involved in the metabolic disturbances in the glucose and lipid metabolism. The prevalence of hepatic steatosis in western countries is high and will certainly increase with the epidemics of obesity and diabetes. This will put an increasing number of subjects at risk for disturbances in the glucose and lipid metabolism and concomitantly for cardiovascular disease. Show less
The work described in this thesis was aimed at identifying the role of cell cycle and apoptosis genes in atherosclerosis. Atherosclerosis is the primary cause of cardiovascular disease, a disorder... Show moreThe work described in this thesis was aimed at identifying the role of cell cycle and apoptosis genes in atherosclerosis. Atherosclerosis is the primary cause of cardiovascular disease, a disorder occurring in the large and medium-sized arteries of the body. Although in the beginning 90s promising lipid lowering therapies predicted a strong reduction in cardiovascular deaths, in westernized societies it is still the underlying cause of about 40% of all deaths, indicating that treatment of atherosclerosis goes beyond lipid lowering solely. In addition to lipids, continuous cell growth (cell cycle) and cell death (i.e. apoptosis and necrosis) processes play a central role in the development of atherosclerosis. To investigate the role of several cell cycle and apoptosis genes (i.e. p53, Rb and Mdm2) in atherosclerosis we generated and characterized several mouse models based on site-specific recombinase (SSR) technology. The studies described in this thesis show that next to therapies aiming at lifestyle interventions, lipid therapies and regulation of inflammation, targeting cell cycle and apoptosis genes on lesional or cellular level might prove the most effective way to reduce the burden of atherosclerosis. Show less
