Angiopoietin-Tie2 signaling protects the kidney from ischemia-reperfusion injury in mice
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE185383 | GEO | 2023/01/23
REPOSITORIES: GEO
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Project description:Neuro-vascular communication is essential to synchronize central nervous system development. Yet, the specific cellular players, defined developmental processes and molecular mechanisms involved in this crosstalk remain poorly characterized. Here we identify the angiopoietin/Tie2 signaling axis as a crucial regulator of dendritic morphogenesis of Purkinje cells (PC) during cerebellum development. We show that in the developing cerebellum Tie2 expression is not restricted to blood vessels but it is also in PCs. Its ligands angiopoietin-1 (Ang1) and angiopoietin-2 (Ang2) are expressed in neural cells and endothelial cells (ECs), respectively. PC-specific deletion of Tie2 results in reduced dendritic arborization, which is recapitulated in neural-specific Ang1-knockout and Ang2 full-knockout mice. Mechanistically, RNA sequencing reveals that Tie2 deficient PCs present alterations in gene expression of multiple genes involved in cytoskeleton organization, dendritic formation, growth and branching. Functionally, those morphological changes are accompanied by alterations in PC network electrophysiology. Altogether, our data propose that the Ang/Tie2 signaling axis serve as mediator of intercellular communication between neural cells, ECs and PCs, required to regulate PC dendritic morphogenesis and function.
2021-12-31 | GSE178659 | GEO
Project description:Vascular endothelial protein tyrosine phosphatase (VE-PTP, PTPRB) is a receptor type phosphatase that is crucial for the regulation of endothelial junctions and blood vessel development. VE-PTP regulates vascular integrity by dephosphorylating substrates which are key players in endothelial junction stability, such as the angiopoietin receptor TIE2, the endothelial adherens junction protein VE-cadherin and the vascular endothelial growth factor receptor VEGFR2. Here, we have systematically searched for novel substrates of VE-PTP in endothelial cells by utilizing two approaches. First, we studied changes in the endothelial phosphoproteome upon exposing cells to a highly VE-PTP-specific phosphatase inhibitor followed by affinity isolation and mass-spectrometric analysis of phosphorylated proteins by phosphotyrosine-specific antibodies. Second, we used a substrate trapping mutant of VE-PTP to pull down phosphorylated substrates in combination with SILAC-based quantitative mass spectrometry measurements. We identified a set of substrate candidates of VE-PTP, of which a remarkably large fraction is related to cell junctions (48/165; 29.1%). Several of those were found in both screens and displayed very high connectivity in predicted functional interaction networks. The receptor protein tyrosine kinase EPHB4 was the most prominently phosphorylated protein upon VE-PTP inhibition among those VE-PTP targets that were identified by both proteomic approaches. Further analysis revealed that EPHB4 forms a ternary complex with VE-PTP and TIE2 in endothelial cells. VE-PTP controls the phosphorylation of each of these two tyrosine kinase receptors. Despite of their simultaneous presence in a ternary complex, stimulating each of the receptors with their own specific ligand did not cross-activate the respective partner receptor. Our systematic approach has led to the identification of novel substrates of VE-PTP, of which many are relevant for the control of cellular junctions further promoting the importance of VE-PTP as a key player of junctional signalling.
2019-08-20 | PXD011940 | Pride
Project description:Background: Recent single-cell RNA sequencing (scRNA-seq) analyses have offered much insight into cell-specific gene expression profiles in normal kidneys. However, in diseased kidneys, understanding of changes in specific cells, particularly glomerular cells, remains limited. Methods: To elucidate the glomerular cell–specific gene expression changes in diabetic kidney disease, we performed scRNA-seq analysis of isolated glomerular cells from streptozotocin-induced diabetic endothelial nitric oxide synthase (eNOS)–deficient (eNOS-/-) mice and control eNOS-/- mice. Results: We identified five distinct cell populations, including glomerular endothelial cells, mesangial cells, podocytes, immune cells, and tubular cells. Using scRNA-seq analysis, we confirmed the expression of glomerular cell–specific markers and also identified several new potential markers of glomerular cells. The number of immune cells was significantly higher in diabetic glomeruli compared with control glomeruli, and further cluster analysis showed that these immune cells were predominantly macrophages. Analysis of differential gene expression in endothelial and mesangial cells of diabetic and control mice showed dynamic changes in the pattern of expressed genes, many of which are known to be involved in diabetic kidney disease. Moreover, gene expression analysis showed variable responses of individual cells to diabetic injury. Conclusion: Our findings demonstrate the ability of scRNA-seq analysis in isolated glomerular cells from diabetic and control mice to reveal dynamic changes in gene expression in diabetic kidneys, with variable responses of individual cells. Such changes, which might not be apparent in bulk transcriptomic analysis of glomerular cells, may help identify important pathophysiologic factors contributing to the progression of diabetic kidney disease.
2019-03-08 | GSE127235 | GEO
Project description:We compared the gene expression analysis of 2 different glomerular isolation techniques (laser capture microdissection with 2 rounds of RNA amplification and unamplified glomerular RNA after iron perfusion with glomerular sieving) and obtained different results depending on the glomerular isolation technique that was used Experiment Overall Design: Paired kidneys from Lewis-Hsd rat kidneys were collected. The glomeruli of one kidney was obtained by LCM with 2 rounds of RNA amplification while the unamplified glomerular RNA of the contralateral kidney was obtained after perfusion with iron oxide and isolated by magnetic purification and a glomerular sieving technique. The RNA was analyzed using the Affymetrix Rat 230A microarrays.
2008-06-17 | E-GEOD-8998 | biostudies-arrayexpress
Project description:The long term objective is to create an encyclopedia of the expression levels of all genes in multiple components of the developing kidney. The central thesis is straightforward. The combination of fluorescent activated cell sorting (FACS) plus microarray analysis offers a powerful, efficient and effective method for the creation of a global gene expression atlas of the developing kidney. Microarrays with essentially complete genome coverage can be used to quantitate expression levels of every gene in FACS isolated components of the developing kidney. The ensuing rapid read-out provides an expression atlas that is more sensitive, more economical and more complete than would be possible by in situ hybridizations alone. Tie2-GFP transgenic mice were utilized to isolate the endothelial cell population from the glomerulus of adult kidneys. The glomerular endothelial cells were isolated from kidneys using a combination of collagenase treatment, differential seiving, trypsin treatment and FACS. The RNA was isolated from purified endothelial cells and the gene expression profiles were determined by microarrays.
2010-07-29 | E-GEOD-22561 | biostudies-arrayexpress
Project description:Diabetic nephropathy is a chronic complication of diabetes, presenting albuminuria at an early stage and leading to renal failure. Kidney is a complicated organ, which is responsible for body fluids control, acid-base balance, and removal of toxins. To better understand the progress of diabetic nephropathy, mice renal cortex of control mice, six-week db-/- (increased serum glucose without pathological changes in kidneys), and ten-week db-/- (with pathological changes in kidneys) were collected for single-cell sequencing analyses. A subgroup of glomerular endothelial cells with pro-angiogenetic features was identified in diabetic kidneys.
2023-10-27 | GSE206015 | GEO
Project description:Angiopoietin-Tie2 signaling protects the kidney from ischemia-reperfusion injury in mice
| PRJNA768855 | ENA
Project description:Males are 50% more likely to develop end stage kidney failure compared to women. In this study we wanted to find out the molecular mechanism responsible for this increased risk. We collected kidney samples from patients with and without kidney disease and performed a comprehensive gene expression analysis in healthy and diseased male and female kidneys. Interestingly, the set of gender biased genes in healthy kidneys were different from those in diseased kidneys indicating not only baseline gene expression differences but also that the male and female kidney respond differently to disease condition. Our studies indicate that men and women with kidney problems might need to be treated differently. Keywords: Gender difference We collected 42 kidney samples from healthy living transplant donors, nephrectomies and from diagnostic kidney biopsies. Preliminary studies did not show significant gene expression differences in control kidneys based on the collection method (i.e. living kidney biopsy vs. unaffected portion of tumor nephrectomy). We grouped the tissue samples based on the histological readings of the kidney biopsies. Samples with evidence of glomerular and tubulointerstitial fibrosis were assigned into the diseased group. Characteristics of the research participants indicate diverse ethnic and disease groups and mild (StageIII) CKD. The tissue was microdissected into glomerular and tubulointerstitial fractions and expression arrays were performed separately.
2010-04-13 | E-GEOD-12682 | biostudies-arrayexpress
Project description:Heparan sulfate (HS) is an important component of the kidney anionic filtration barrier, the glomerular basement membrane (GBM). HS chains attached to proteoglycan protein cores are modified by sulfotransferases in a highly ordered series of biosynthetic steps resulting in immense structural diversity due to negatively charged sulfate modifications. 3-O-sulfation is the least abundant modification generated by a family of seven isoforms but creates the most highly sulfated HS domains. We analyzed the kidney phenotypes in the Hs3st3a1, Hs3st3b1 and Hs3st6 -knockout (KO) mice, the isoforms enriched in kidney podocytes. Individual KO mice show no overt kidney phenotype, although Hs3st3b1 kidneys were smaller than wildtype (WT). Furthermore, Hs3st3a1-/-; Hs3st3b1-/- double knockout (DKO) kidneys were smaller but also had a reduction in glomerular size relative to wildtype (WT). Mass spectrometry analysis of kidney HS showed reduced 3-O-sulfation in Hs3st3a1-/- and Hs3st3b1-/-, but not in Hs3st6-/- kidneys. Glomerular HS showed reduced HS staining and reduced ligand-and-carbohydrate engagement (LACE) assay, a tool that detects changes in binding of growth factor receptor-ligand complexes to HS. Interestingly, DKO mice have increased levels of blood urea nitrogen, although no differences were detected in urinary levels of albumin, creatinine and nephrin. Finally, transmission electron microscopy showed irregular and thickened GBM and podocyte foot process effacement in the DKO compared to WT. Together, our data suggest that loss of 3-O-HS domains disrupts the kidney glomerular architecture without affecting the glomerular filtration barrier and overall kidney function.
2024-07-05 | GSE261059 | GEO
Project description:Glomerular and tubulointerstitial fractions were enriched from human kidneys samples. Ages of human kidney samples: 15, 29, 37, 61, 67 and 69 years of age. The glomerular and tubulointerstitial samples were processed to enrich for extracellular matrix components and the fractions analysed by mass spectrometry.
2022-02-22 | PXD022219 | Pride