| 1. |
- 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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| 2. |
- Bondjers, Cecilia, 1974, et al.
(författare)
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Microarray analysis of blood microvessels from PDGF-B and PDGF-Rbeta mutant mice identifies novel markers for brain pericytes.
- 2006
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Ingår i: The FASEB journal : official publication of the Federation of American Societies for Experimental Biology. - : Wiley. - 1530-6860. ; 20:10, s. 1703-5
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Tidskriftsartikel (refereegranskat)abstract
- Normal blood microvessels are lined by pericytes, which contribute to microvessel development and stability through mechanisms that are poorly understood. Pericyte deficiency has been implicated in the pathogenesis of microvascular abnormalities associated with diabetes and tumors. However, the unambiguous identification of pericytes is still a problem because of cellular heterogeneity and few available molecular markers. Here we describe an approach to identify pericyte markers based on transcription profiling of pericyte-deficient brain microvessels isolated from platelet-derived growth factor (PDGF-B)-/- and PDGF beta receptor (PDGFRbeta)-/- mouse mutants. The approach was validated by the identification of known pericyte markers among the most down-regulated genes in PDGF-B-/- and PDGFRbeta-/- microvessels. Of candidates for novel pericyte markers, we selected ATP-sensitive potassium-channel Kir6.1 (also known as Kcnj8) and sulfonylurea receptor 2, (SUR2, also known as Abcc9), both part of the same channel complex, as well as delta homologue 1 (DLK1) for in situ hybridization, which demonstrated their specific expression in brain pericytes of mouse embryos. We also show that Kir6.1 is highly expressed in pericytes in brain but undetectable in pericytes in skin and heart. The three new brain pericyte markers are signaling molecules implicated in ion transport and intercellular signaling, potentially opening new windows on pericyte function in brain microvessels.
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| 3. |
- He, L, et al.
(författare)
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Glomerulus-specific mRNA transcripts and proteins identified through kidney expressed sequence tag database analysis
- 2007
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Ingår i: Kidney International. - 1523-1755 .- 0085-2538. ; 71:9, s. 889-900
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Tidskriftsartikel (refereegranskat)abstract
- The kidney glomerulus plays a crucial role in blood filtration but the molecular composition and physiology of the glomerulus is not well understood. We previously constructed and large-scale sequenced four mouse glomerular expressed sequence tag (EST) libraries from newborn and adult mouse glomeruli. Here, we compared glomerular EST profiles with whole kidney EST profiles, thereby identifying 497 transcripts corresponding to UniGene clusters that were glomerulus-enriched, that is expressed more abundantly in glomeruli than in whole kidney. These include several known protein-coding glomerulus-specific transcripts critical for glomerulus development and function, but also a large number of gene transcripts, which have not previously been shown to be expressed in the glomerulus, or implicated in glomerular functions. We used in situ hybridization to demonstrate glomerulus-specific RNA expression for six novel glomerular genes and the public Human Protein Atlas to verify glomerular protein expression for another two. The higher mRNA abundance for the eight genes in glomeruli compared with whole kidney was also verified by Taqman quantitative polymerase chain reaction. We surmise that the further characterization of these genes and proteins will increase our understanding of glomerular development and physiology.
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| 4. |
- He, Liqun, et al.
(författare)
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The glomerular transcriptome and a predicted protein-protein interaction network
- 2008
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Ingår i: Journal of the American Society of Nephrology. - 1046-6673 .- 1533-3450. ; 19:2, s. 260-268
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Tidskriftsartikel (refereegranskat)abstract
- To increase our understanding of the molecular composition of the kidney glomerulus, we performed a meta-analysis of available glomerular transcriptional profiles made from mouse and man using five different methodologies. We generated a combined catalogue of glomerulus-enriched genes that emerged from these different sources and then used this to construct a predicted protein-protein interaction network in the glomerulus (GlomNet). The combined glomerulus-enriched gene catalogue provides the most comprehensive picture of the molecular composition of the glomerulus currently available, and GlomNet contributes an integrative systems biology approach to the understanding of glomerular signaling networks that operate during development, function, and disease.
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| 5. |
- Ishikawa, Takahiro, et al.
(författare)
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A novel podocyte protein, R3h domain containing-like, inhibits TGF-β-induced p38 MAPK and regulates the structure of podocytes and glomerular basement membrane
- 2021
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Ingår i: Journal of Molecular Medicine. - : Springer Science and Business Media LLC. - 0946-2716 .- 1432-1440. ; 99:6, s. 859-876
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Tidskriftsartikel (refereegranskat)abstract
- Not only in kidney glomerular physiological function but also glomerular pathology especially in diabetic condition, glomerular podocytes play pivotal roles. Therefore, it is important to increase our knowledge about the genes and proteins expressed in podocytes. Recently, we have identified a novel podocyte-expressed gene, R3h domain containing-like (R3hdml) and analyzed its function in vivo as well as in vitro. Transforming growth factor-β (TGF-β) signaling regulated the expression of R3hdml. And R3hdml inhibited p38 mitogen-activated protein kinase phosphorylation, which was induced by TGF-β, leading to the amelioration of podocyte apoptosis. Furthermore, a lack of R3hdml in mice significantly worsened glomerular function in streptozotocin (STZ)-induced diabetes, while overexpression of R3hdml ameliorated albuminuria in STZ-induced diabetes. Our results surmise that the functional analyses of R3hdml may lead to the development of novel therapeutic strategies for diabetic nephropathy in the future.
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| 6. |
- Patrakka, Jaakko, et al.
(författare)
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Expression and subcellular distribution of novel glomerulus-associated proteins dendrin, ehd3, sh2d4a, plekhh2, and 2310066E14Rik
- 2007
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Ingår i: Journal of the American Society of Nephrology. - : Ovid Technologies (Wolters Kluwer Health). - 1046-6673 .- 1533-3450. ; 18:3, s. 689-697
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Tidskriftsartikel (refereegranskat)abstract
- The glomerular capillary tuft is a highly specialized microcapillary that is dedicated to function as a sophisticated molecular sieve. The glomerulus filter has a unique molecular composition, and several essential glomerular proteins are expressed in the kidney exclusively by glomerular podocytes. A catalog of > 300 glomerulus-upregulated transcripts that were identified using expressed sequence tag profiling and microarray analysis was published recently. This study characterized the expression profile of five glomerulus-upregulated transcripts/proteins (ehd3, dendrin, sh2d4a, plekhh2, and 2310066E14Rik) in detail. The expression pattern of these novel glomerular transcripts in various mouse tissues was studied using reverse transcriptase-PCR, Northern blotting, and in situ hybridization. For studying the distribution of corresponding proteins, polyclonal antibodies were raised against the gene products, and Western blotting, immunofluorescence, and immunoelectron microscopic analyses were performed. Remarkably, it was discovered that all five transcripts/proteins were expressed in the kidney exclusively by glomerular cells. Ehd3 was expressed only by glomerular endothelial cells. Importantly, ehd3 is the first gene ever shown to be expressed exclusively by glomerular endothelial cells and not by other endothelial cells in the kidney. Dendrin, sh2d4a, plekhh2, and 2310066E14Rik, however, were transcribed solely by podocytes. With the use of polyclonal antibodies, dendrin, sh2d4a, and plekhh2 proteins were localized to the slit diaphragm and the foot process, whereas 2310066E14Rik protein was localized to the podocyte major processes and cell body. This study provides fresh insights into glomerular biology and uncovers new possibilities to explore the role of these novel proteins in the glomerular physiology and pathology.
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| 7. |
- Sakamoto, Kenichi, et al.
(författare)
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R3hdml regulates satellite cell proliferation and differentiation
- 2019
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Ingår i: EMBO Reports. - : John Wiley & Sons. - 1469-221X .- 1469-3178. ; 20:11
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Tidskriftsartikel (refereegranskat)abstract
- In this study, we identified a previously uncharacterized skeletal satellite cell-secreted protein, R3h domain containing-like (R3hdml). Expression of R3hdml increases during skeletal muscle development and differentiation in mice. Body weight and skeletal muscle mass of R3hdml knockout (KO) mice are lower compared to control mice. Expression levels of cell cycle-related markers, phosphorylation of Akt, and expression of insulin-like growth factor within the skeletal muscle are reduced in R3hdml KO mice compared to control mice. Expression of R3hdml increases during muscle regeneration in response to cardiotoxin (CTX)-induced muscle injury. Recovery of handgrip strength after CTX injection was significantly impaired in R3hdml KO mice, which is rescued by R3hdml. Our results indicate that R3hdml is required for skeletal muscle development, regeneration, and, in particular, satellite cell proliferation and differentiation.
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| 8. |
- Scheidl, Stefan Johannes, 1972, et al.
(författare)
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mRNA expression profiling of laser microbeam microdissected cells from slender embryonic structures.
- 2002
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Ingår i: The American journal of pathology. - 0002-9440. ; 160:3, s. 801-13
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Tidskriftsartikel (refereegranskat)abstract
- Microarray hybridization has rapidly evolved as an important tool for genomic studies and studies of gene regulation at the transcriptome level. Expression profiles from homogenous samples such as yeast and mammalian cell cultures are currently extending our understanding of biology, whereas analyses of multicellular organisms are more difficult because of tissue complexity. The combination of laser microdissection, RNA amplification, and microarray hybridization has the potential to provide expression profiles from selected populations of cells in vivo. In this article, we present and evaluate an experimental procedure for global gene expression analysis of slender embryonic structures using laser microbeam microdissection and laser pressure catapulting. As a proof of principle, expression profiles from 1000 cells in the mouse embryonic (E9.5) dorsal aorta were generated and compared with profiles for captured mesenchymal cells located one cell diameter further away from the aortic lumen. A number of genes were overexpressed in the aorta, including 11 previously known markers for blood vessels. Among the blood vessel markers were endoglin, tie-2, PDGFB, and integrin-beta1, that are important regulators of blood vessel formation. This demonstrates that microarray analysis of laser microbeam micro-dissected cells is sufficiently sensitive for identifying genes with regulative functions.
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| 9. |
- Shoda, Jumpei, et al.
(författare)
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Semaphorin 3G exacerbates joint inflammation through the accumulation and proliferation of macrophages in the synovium
- 2022
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Ingår i: Arthritis Research & Therapy. - : BioMed Central (BMC). - 1478-6354 .- 1478-6362. ; 24:1
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Tidskriftsartikel (refereegranskat)abstract
- Objectives Methotrexate (MTX) is an anchor drug for the treatment of rheumatoid arthritis (RA). However, the precise mechanisms by which MTX stalls RA progression and alleviates the ensuing disease effects remain unknown. The aim of the present study was to identify novel therapeutic target molecules, the expression patterns of which are affected by MTX in patients with RA. Methods CD4(+) T cells from 28 treatment-naive patients with RA before and 3 months after the initiation of MTX treatment were subjected to DNA microarray analyses. The expression levels of semaphorin 3G, a differentially expressed gene, and its receptor, neuropilin-2, were evaluated in the RA synovium and collagen-induced arthritis synovium. Collagen-induced arthritis and collagen antibody-induced arthritis were induced in semaphorin3G-deficient mice and control mice, and the clinical score, histological score, and serum cytokines were assessed. The migration and proliferation of semaphorin 3G-stimulated bone marrow-derived macrophages were analyzed in vitro. The effect of local semaphorin 3G administration on the clinical score and number of infiltrating macrophages during collagen antibody-induced arthritis was evaluated. Results Semaphorin 3G expression in CD4(+) T cells was downregulated by MTX treatment in RA patients. It was determined that semaphorin 3G is expressed in RA but not in the osteoarthritis synovium; its receptor neuropilin-2 is primarily expressed on activated macrophages. Semaphorin3G deficiency ameliorated collagen-induced arthritis and collagen antibody-induced arthritis. Semaphorin 3G stimulation enhanced the migration and proliferation of bone marrow-derived macrophages. Local administration of semaphorin 3G deteriorated collagen antibody-induced arthritis and increased the number of infiltrating macrophages. Conclusions Upregulation of semaphorin 3G in the RA synovium is a novel mechanism that exacerbates joint inflammation, leading to further deterioration, through macrophage accumulation.
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| 10. |
- Sun, Ying, et al.
(författare)
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Glomerular Transcriptome Changes Associated with Lipopolysaccharide-Induced Proteinuria
- 2009
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Ingår i: American Journal of Nephrology. - : S. Karger AG. - 0250-8095 .- 1421-9670. ; 29:6, s. 558-570
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Tidskriftsartikel (refereegranskat)abstract
- Background: Global gene expression patterns have recently been characterized in normal glomeruli, but gene expression changes that accompany glomerular disease remain poorly characterized. Method: Here, we mapped global glomerular gene expression profile changes occurring in conjunction with lipopolysaccharide (LPS)-induced proteinuria in mice. Results: We observed dramatic transcriptional reprogramming in glomeruli in response to LPS, representing some 20% of all genes and about 45% of the genes that are normally highly expressed in glomeruli. Bioinformatic analysis revealed significant changes in transcripts encoding proteins involved in the regulation of adherence junctions, actin cytoskeleton and survival in podocytes. In the LPS-treated mice, we observed dysregulation of genes expressed in glomerular endothelial and mesangial cells and in podocytes, there was also a significant decrease in podocyte number. Moreover, collagen alpha 1, alpha 2 (IV) and laminin 10 (laminin alpha 5 beta 1 gamma 1), which are expressed in immature glomeruli, were upregulated in the glomeruli of LPS-treated mice, suggesting remodeling of the glomerular basement membrane and activation of mesangial cells. By superimposing the LPS-induced changes onto GlomNet, a protein-protein interaction network was predicted for podocyte proteins affected by LPS. Conclusions: The detected changes in glomerular gene expression and their involvement in protein interaction networks provide putative markers for early and transient glomerular injury and proteinuria. Copyright (c) 2009 S. Karger AG, Basel
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