| 1. |
- García, Maria C, et al.
(författare)
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Mature-onset obesity in interleukin-1 receptor I knockout mice.
- 2006
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Ingår i: Diabetes. - : American Diabetes Association. - 0012-1797 .- 1939-327X. ; 55:5, s. 1205-13
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Tidskriftsartikel (refereegranskat)abstract
- Interleukin-1 (IL-1) is a major mediator of inflammation that exerts its biological activities through the IL-1 type I receptor (IL-1RI). The body weights of IL-1RI(-/-) mice of both sexes started to deviate from those of wild-type mice at 5-6 months of age and were 20% higher at 9 months of age. Visceral and subcutaneous fat mass, measured by dual-energy X-ray absorptiometry and magnetic resonance imaging, was markedly (1.5- to 2.5-fold) increased. Lean body mass and crown-rump length were also slightly (11 and 5%, respectively) increased, as was serum IGF-I. Obese IL-1RI(-/-) mice were insulin resistant, as evidenced by hyperinsulinemia, decreased glucose tolerance, and insulin sensitivity. To elucidate the mechanisms for the development of obesity, young pre-obese IL-1RI(-/-) mice were investigated. They showed decreased suppression of body weight and food intake in response to systemic leptin treatment. The decreased leptin responsiveness was even more pronounced in older obese animals. Moreover, spontaneous locomotor activity and fat utilization, as measured by respiratory quotient, were decreased in pre-obese IL-1RI(-/-) mice. In conclusion, lack of IL-1RI-mediated biological activity causes mature-onset obesity. This obese phenotype is preceded by decreased leptin sensitivity, fat utilization, and locomotor activity.
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| 2. |
- Strandberg, Louise, 1981, et al.
(författare)
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Mice chronically fed high-fat diet have increased mortality and disturbed immune response in sepsis.
- 2009
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Ingår i: PloS one. - : Public Library of Science (PLoS). - 1932-6203. ; 4:10
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Sepsis is a potentially deadly disease that often is caused by gram-positive bacteria, in particular Staphylococcus aureus (S. aureus). As there are few effective therapies for sepsis, increased basic knowledge about factors predisposing is needed. METHODOLOGY/PRINCIPAL FINDINGS: The purpose of this study was to study the effect of Western diet on mortality induced by intravenous S. aureus inoculation and the immune functions before and after bacterial inoculation. Here we show that C57Bl/6 mice on high-fat diet (HFD) for 8 weeks, like genetically obese Ob/Ob mice on low-fat diet (LFD), have increased mortality during S. aureus-induced sepsis compared with LFD-fed C57Bl/6 controls. Bacterial load in the kidneys 5-7 days after inoculation was increased 10-fold in HFD-fed compared with LFD-fed mice. At that time, HFD-fed mice had increased serum levels and fat mRNA expression of the immune suppressing cytokines interleukin-1 receptor antagonist (IL-1Ra) and IL-10 compared with LFD-fed mice. In addition, HFD-fed mice had increased serum levels of the pro-inflammatory IL-1beta. Also, HFD-fed mice with and without infection had increased levels of macrophages in fat. The proportion and function of phagocytosing granulocytes, and the production of reactive oxygen species (ROS) by peritoneal lavage cells were decreased in HFD-fed compared with LFD-fed mice. CONCLUSIONS: Our findings imply that chronic HFD disturb several innate immune functions in mice, and impairs the ability to clear S. aureus and survive sepsis.
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| 3. |
- Betsholtz, Christer, 1959, et al.
(författare)
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Role of platelet-derived growth factor in mesangium development and vasculopathies: lessons from platelet-derived growth factor and platelet-derived growth factor receptor mutations in mice.
- 2004
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Ingår i: Current opinion in nephrology and hypertension. - 1062-4821. ; 13:1, s. 45-52
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE OF REVIEW: The phenotypic consequences of null mutations in the platelet-derived growth factor-B and the platelet-derived growth factor beta-receptor genes in mice have demonstrated that these proteins play pivotal roles in the development of the vascular smooth muscle cell lineage, including pericytes and mesangial cells. RECENT FINDINGS: The lethality of these mutants has precluded analysis of the physiological and pathophysiological consequences of platelet-derived growth factor-B and platelet-derived growth factor beta-receptor deficiency in adults. This review summarizes and discusses recent data from certain tissue-specific and subtle mutations in the platelet-derived growth factor-B and platelet-derived growth factor beta-receptor genes that are compatible with postnatal viability in spite of severe developmental deficits in pericyte and mesangial cell recruitment. In the postnatal period, the animals studied developed a characteristic set of pathological changes to small blood vessels of the retina and the kidney glomerulus, which sheds light on the importance of pericytes and mesangial cells for vascular integrity and function after birth. SUMMARY: These microvascular abnormalities and their consequences bear a resemblance to diabetic microangiopathy and nephropathy. The platelet-derived growth factor-B and platelet-derived growth factor beta-receptor mutant mouse models, therefore, might serve as valuable tools in the dissection of some of the pathogenic events in diabetic microangiopathy.
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| 4. |
- Bjarnegård, Mattias, 1970, et al.
(författare)
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Endothelium-specific ablation of PDGFB leads to pericyte loss and glomerular, cardiac and placental abnormalities
- 2004
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Ingår i: DEVELOPMENT. - : The Company of Biologists. - 0950-1991 .- 1477-9129. ; 131:8, s. 1847-1857
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Tidskriftsartikel (refereegranskat)abstract
- Platelet-derived growth factor-B (PDGFB) is necessary for normal cardiovascular development, but the relative importance of different cellular sources of PDGFB has not been established. Using Cre-lox techniques, we show here that genetic ablation of Pdgfb in endothelial cells leads to impaired recruitment of pericytes to blood vessels. The endothelium-restricted Pdgfb knockout mutants also developed organ defects including cardiac, placental and renal abnormalities. These defects were similar to those observed in Pdgfb null mice. However, in marked contrast to the embryonic lethality of Pdgfb null mutants, the endothelium-specific mutants survived into adulthood with persistent pathological changes, including brain microhemorrhages, focal astrogliosis, and kidney glomerulus abnormalities. This spectrum of pathological changes is reminiscent of diabetic microangiopathy, suggesting that the endothelium-restricted Pdgfb knockouts may serve as models for some of the pathogenic events of vascular complications to diabetes. Key words: PDGFB, Endothelium, Cre, loxP, Pericytes, Microaneurysm
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| 5. |
- Enge, Maria, 1970, et al.
(författare)
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Endothelium-specific platelet-derived growth factor-B ablation mimics diabetic retinopathy.
- 2002
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Ingår i: The EMBO journal. - : Wiley. - 0261-4189 .- 1460-2075. ; 21:16, s. 4307-16
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Tidskriftsartikel (refereegranskat)abstract
- Loss of pericytes from the capillary wall is a hallmark of diabetic retinopathy, however, the pathogenic significance of this phenomenon is unclear. In previous mouse gene knockout models leading to pericyte deficiency, prenatal lethality has so far precluded analysis of postnatal consequences in the retina. We now report that endothelium-restricted ablation of platelet-derived growth factor-B generates viable mice with extensive inter- and intra-individual variation in the density of pericytes throughout the CNS. We found a strong inverse correlation between pericyte density and the formation of a range of retinal microvascular abnormalities strongly reminiscent of those seen in diabetic humans. Proliferative retinopathy invariably developed when pericyte density was <50% of normal. Our data suggest that a reduction of the pericyte density is sufficient to cause retinopathy in mice, implying that pericyte loss may also be a causal pathogenic event in human diabetic retinopathy.
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| 6. |
- Enge, Maria, 1970
(författare)
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Conditional targeting of the PDGF-B gene
- 2002
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Platelet derived growth factors (PDGF) are known as mitogens for fibroblasts, smooth muscle cells (SMC) and glia cells in culture. Previous in vivo analyses have shown that PDGF-B is necessary for normal embryonic development and life after birth, but the relative importance of the various cellular sources of PDGF-B during development has not been clarified. In order to evaluate the role of PDGF-B from different cell types in embryonic as well as postnatal development, we have used the Cre/loxP system to enable tissue specific ablation of the PDGF-B gene. In this work we have studied the ablation of PDGF-B in blood vascular endothelium and in neurons. The endothelium-specific PDGF-B knockout leads to phenotypes similar to those seen in the total knockout, including loss of mesangial cells in the kidney glomeruli and loss of pericytes in the brain, leading to dilated capillaries. The severity of the phenotypes varies, depending on a variable chimeric situation caused by incomplete recombination of the PDGF-B gene. Most of the endothelium-specific mutants survive and reach adulthood, enabling studies of the retina, which develops postnatally. In these mice we found a situation similar to diabetic retinopathy, with pericyte loss leading to microangiopathy. However the chimeric situation led to an intraindividual variation of the pericyte amount, that correlated to the type of retinopathy. When the pericyte amount was below 52% of the normal situation, the retina showed signs of proliferative retinopathy, which was never seen above this threshold. We could also correlate the pericyte loss to regression of vessels. These findings indicate that endothelium derived PDGF-B is the critical source for the recruitment of pericytes to blood vessels and mesangial cells to the kidney glomeruli. Our data also suggest a causal link between pericyte loss and microangiopathy as well as proliferative retinopathy.The ablation of PDGF-B in neurons on the other hand did not lead to any obvious phenotypes. The animals develop into adulthood without apparent neuro-anatomical or behavioural defects. To evaluate a possible role of PDGF-B, following CNS trauma, we exposed these mice to electrical brain injury. This led to a normal healing process, showing reactive gliosis and neovascularization of the injured area.These results indicate that PDGF-B does not contribute to normal CNS development or reactive gliosis and hence the function of neural-derived PDGF-B is still unknown.
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| 7. |
- Lindblom, Per, 1974, et al.
(författare)
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Endothelial PDGF-B retention is required for proper investment of pericytes in the microvessel wall.
- 2003
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Ingår i: Genes & development. - : Cold Spring Harbor Laboratory. - 0890-9369 .- 1549-5477. ; 17:15, s. 1835-40
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Tidskriftsartikel (refereegranskat)abstract
- Several platelet-derived growth factor (PDGF) and vascular endothelial growth factor (VEGF) family members display C-terminal protein motifs that confer retention of the secreted factors within the pericellular space. To address the role of PDGF-B retention in vivo, we deleted the retention motif by gene targeting in mice. This resulted in defective investment of pericytes in the microvessel wall and delayed formation of the renal glomerulus mesangium. Long-term effects of lack of PDGF-B retention included severe retinal deterioration, glomerulosclerosis, and proteinuria. We conclude that retention of PDGF-B in microvessels is essential for proper recruitment and organization of pericytes and for renal and retinal function in adult mice.
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