| 1. |
- Elvin, Johannes, et al.
(författare)
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Melanocortin 1 Receptor Agonist Protects Podocytes Through Catalase and RhoA Activation.
- 2016
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Ingår i: American journal of physiology. Renal physiology. - : American Physiological Society. - 1522-1466 .- 1931-857X. ; 310:9
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Tidskriftsartikel (refereegranskat)abstract
- Drugs containing adrenocorticotropic hormone (ACTH) have been used as therapy for patients with nephrotic syndrome. We have previously shown that ACTH and a selective agonist for the melanocortin 1 receptor (MC1R) exert beneficial actions in experimental membranous nephropathy with reduced proteinuria, reduced oxidative stress, improved glomerular morphology and function. Our hypothesis is that MC1R activation in podocytes elicits beneficial effects by promoting stress fibers and maintaining podocyte viability. To test the hypothesis, we cultured podocytes and used highly specific agonists for the MC1R. The podocytes were subjected to the nephrotic-inducing agent puromycin aminonucleoside and downstream effects of MC1R activation on podocyte survival; antioxidant defense and cytoskeleton dynamics were studied. To increase the response and enhance the intracellular signals, podocytes were transduced to overexpress MC1R. We show that puromycin promotes MC1R expression in podocytes and that activation of the MC1R promotes an increase of catalase activity and reduces oxidative stress, which results in dephosphorylation of p190RhoGAP and formation of stress fibers through RhoA. In addition, MC1R agonists protects against apoptosis. Together, these mechanisms protect the podocyte against puromycin. Our findings strongly support the hypothesis that selective MC1R activating agonists protect podocytes and may therefore be useful to treat patients with nephrotic syndromes commonly considered as podocytopathies.
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| 2. |
- Lindskog Jonsson, Annika, et al.
(författare)
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Bacterial profile in human atherosclerotic plaques
- 2017
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Ingår i: Atherosclerosis. - : Elsevier BV. - 0021-9150 .- 1879-1484. ; 263, s. 177-183
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Tidskriftsartikel (refereegranskat)abstract
- Background and aims Several studies have confirmed the presence of bacterial DNA in atherosclerotic plaques, but its contribution to plaque stability and vulnerability is unclear. In this study, we investigated whether the bacterial plaque-profile differed between patients that were asymptomatic or symptomatic and whether there were local differences in the microbial composition within the plaque. Methods Plaques were removed by endarterectomy from asymptomatic and symptomatic patients and divided into three different regions known to show different histological vulnerability: A, upstream of the maximum stenosis; B, site for maximum stenosis; C, downstream of the maximum stenosis. Bacterial DNA composition in the plaques was determined by performing 454 pyrosequencing of the 16S rRNA genes, and total bacterial load was determined by qPCR. Results We confirmed the presence of bacterial DNA in the atherosclerotic plaque by qPCR analysis of the 16S rRNA gene but observed no difference (n.s.) in the amount between either asymptomatic and symptomatic patients or different plaque regions A, B and C. Unweighted UniFrac distance metric analysis revealed no distinct clustering of samples by patient group or plaque region. Operational taxonomic units (OTUs) from 5 different phyla were identified, with the majority of the OTUs belonging to Proteobacteria (48.3%) and Actinobacteria (40.2%). There was no difference between asymptomatic and symptomatic patients, or plaque regions, when analyzing the origin of DNA at phylum, family or OTU level (n.s.). Conclusions There were no major differences in bacterial DNA amount or microbial composition between plaques from asymptomatic and symptomatic patients or between different plaque regions, suggesting that other factors are more important in determining plaque vulnerability. © 2017 Elsevier B.V.
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| 3. |
- Lindskog Jonsson, Annika, et al.
(författare)
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Drug the Bug!
- 2015
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Ingår i: Cell. - : Elsevier BV. - 0092-8674. ; 163:7, s. 1565-6
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Tidskriftsartikel (refereegranskat)abstract
- Microbial metabolism of dietary components has been causally linked to cardiovascular disease and atherosclerosis. Now, Wang et al. demonstrate that inhibition of microbial TMA lyases, essential for production of pro-atherogenic trimethylamines, prevents atherosclerosis in vivo.
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| 4. |
- Lindskog Jonsson, Annika, et al.
(författare)
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Effects of Melanocortin 1 Receptor Agonists in Experimental Nephropathies
- 2014
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Ingår i: Plos One. - : Public Library of Science (PLoS). - 1932-6203. ; 9:1
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Tidskriftsartikel (refereegranskat)abstract
- Nephrotic syndrome, characterized by massive proteinuria, is caused by a large group of diseases including membranous nephropathy (MN) and focal segmental glomerulosclerosis (FSGS). Although the underlying mechanisms are beginning to unravel, therapy is unspecific and far from efficient. It has been suggested that adrenocorticotropic hormone (ACTH) has beneficial effects in patients with MN and possibly in other nephrotic diseases. We have previously reported that ACTH may act directly on podocytes through the melanocortin 1 receptor (MC1R). In the present study, we evaluate the effect of highly specific MC1R agonists in two different nephrotic disease models. Experimental MN: Passive Heymann nephritis (PHN) was induced in rats that were treated for four weeks with MS05, a selective MC1R agonist, or saline. The degree of albuminuria was significantly reduced over time and the effect was sustained one week after treatment withdrawal (p<0.05). Experimental FSGS: Based on a dose-response study, two doses of adriamycin were used for induction of nephropathy in Balb/c mice. Mice were treated with either a synthetic MC1R agonist (BMS-470539), with alpha-melanocyte stimulating hormone (alpha-MSH) or with saline. There was no beneficial effect of treatment. In summary, MC1R agonists reduce albuminuria and improve morphology in experimentally induced MN whereas they have no effect in experimental FSGS. The results illustrate the differences in these podocytopathies in terms of signaling mechanisms underlying proteinuria, and progression of disease.
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| 5. |
- Lindskog Jonsson, Annika, et al.
(författare)
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Impact of Gut Microbiota and Diet on the Development of Atherosclerosis in Apoe(-/-) Mice
- 2018
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Ingår i: Arteriosclerosis Thrombosis and Vascular Biology. - : Ovid Technologies (Wolters Kluwer Health). - 1079-5642 .- 1524-4636. ; 38:10, s. 2318-2326
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Tidskriftsartikel (refereegranskat)abstract
- Objective To investigate the effect of gut microbiota and diet on atherogenesis. Approach and Results Here, we investigated the interaction between the gut microbiota and diet on atherosclerosis by feeding germ-free or conventionally raised Apoe(-/-) mice chow or Western diet alone or supplemented with choline (which is metabolized by the gut microbiota and host enzymes to trimethylamine N-oxide) for 12 weeks. We observed smaller aortic lesions and lower plasma cholesterol levels in conventionally raised mice compared with germ-free mice on a chow diet; these differences were not observed in mice on a Western diet. Choline supplementation increased plasma trimethylamine N-oxide levels in conventionally raised mice but not in germ-free mice. However, this treatment did not affect the size of aortic lesions or plasma cholesterol levels. Gut microbiota composition was analyzed by sequencing of 16S rRNA genes. As expected, the global community structure and relative abundance of many taxa differed between mice fed chow or a Western diet. Choline supplementation had minor effects on the community structure although the relative abundance of some taxa belonging to Clostridiales was altered. Conclusions In conclusion, the impact of the gut microbiota on atherosclerosis is dietary dependent and is associated with plasma cholesterol levels. Furthermore, the microbiota was required for trimethylamine N-oxide production from dietary choline, but this process could not be linked to increased atherosclerosis in this model.
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| 6. |
- Lindskog Jonsson, Annika
(författare)
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The role of melanocortin 1 receptor in kidney disease
- 2012
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Nephrotic syndrome is a term describing a group of poorly understood glomerular diseases that are responsible for a steadily increasing number of patients requiring active uremic care. Characteristic symptoms of nephrotic syndrome are proteinuria, hypoalbuminemia, hyperlipidemia and peripheral edema, and treatment of these symptoms, rather than their cause, is currently the only option available to the clinician. While the mechanisms underlying these diseases remain elusive, a number of studies have lately revisited adrenocorticotropic hormone (ACTH) as a potential treatment option since it has been shown to reduce proteinuria and improve glomerular function. Thus, the aim of this thesis has been to elucidate the mechanisms behind this treatment strategy. The hypothesis is that ACTH mediates its effect by a kidney specific receptor. The gene expression of all ACTH receptors, melanocortin receptors (MCR) 1-5, was therefore investigated. MC1R gene expression was detected in kidney tissue, including cells specific for the glomerular filtration barrier (endothelial cells, podocytes and mesangial cells). MC1R protein was also detected and found to be co-localized with synaptopodin, a podocyte specific marker. In order to assess the relevance of MC1R in disease, selective agonists were used in experimental nephrotic models. MC1R agonists ameliorated the disease in a rat model resembling membranous nephropathy, and reduced proteinuria, improved morphology and reduced oxidative stress. MC1R agonists did not reduce proteinuria in a model resembling focal segmental glomerulosclerosis, suggesting different mechanistic pathways. Signaling pathways were investigated by stimulating podocytes with a selective MC1R agonist. Several known intracellular pathways were activated, including cAMP, phosphorylation of ERK1/2 and activation of catalase, an anti-oxidative enzyme. MC1R stimulation may also have a protective effect in nephrotoxin-induced rearrangement of the actin cytoskeleton. In conclusion, this thesis has provided new data on the mechanisms behind the beneficial effects of ACTH treatment in nephrotic patients. MC1R, expressed in podocytes, likely mediates these effects. The results presented herein will pave the way for new, more specific and possibly curative treatment options, without severe side effects, for nephrotic patients.
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