Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

RAAS-Deficient Organoids Reveal that Delayed Angiogenesis Is The Pathomechanism Underlying Autosomal Recessive Renal Tubular Dysplasia

ABSTRACT: Autosomal Recessive Renal Tubular Dysgenesis (AR-RTD) is a fatal genetic disorder affecting proximal tubule (PT) development in patients harboring mutations in genes comprising the Renin–Angiotensin–Aldosterone System (RAAS). To uncover the pathomechanism of AR-RTD, we differentiated ACE and AGTR1 deficient pluripotent stem cells and reprogrammed AR-RTD patient cells into kidney organoids. Marker analyses confirmed that all mutant and control organoids generated PT in room air (21% O2) or under hypoxic conditions (2% O2). Mature (d24) AGTR1-/- and control organoids transplanted under the kidney capsule of immunodeficient mice engrafted and differentiated well, as did renal vesicle stage (d14) control organoids. By contrast, d14 AGTR1-/- organoids failed to engraft due to insufficient pro-angiogenic VEGF-A expression. When grown under hypoxic conditions VEGF-A expression was stimulated and organoids engrafted. Thus, PT dysgenesis in AR-RTD is a non-autonomous consequence of a developmental delay in VEGF-A induction linking ANGII pro angiogenic role to PT dysgenesis.

ORGANISM(S): Homo sapiens

PROVIDER: GSE229842 | GEO | 2023/10/18

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

The natural compound atraric acid suppresses androgen-regulated neo-angiogenesis of castration‑resistant prostate cancer through angiopoietin 2

Project description:Castration‑resistant prostate cancer (CRPC) is an aggressive lethal form of prostate cancer (PCa), which presents a major therapeutic challenge. Here, we show that the natural compound, atraric acid (AA), inhibits not only the androgen receptor (AR) but also targets those AR-mutants that confer therapy resistance to other clinically used AR-antagonists indicating a different mode of AR-antagonism. AA induces cellular senescence in CRPC and inhibits CRPC tumour growth in vivo xenograft model. The secretome of CRPC cells induces androgen-dependent angiogenesis, which is counteracted by AA regulated senescence-associated secretory phenotype (SASP) in two in vitro models using primary human endothelial cells. In line with this, in tumours, vessel number is decreased in the mouse group treated with AA suggesting the repression of intratumoural neo-angiogenesis by AA. Transcriptome sequencing and mass spec analysis of the secretome revealed upregulated angiogenic pathways by androgen, however, being VEGF-independent and pointing to the secretion of the pro-angiogenic factor angiopoietin 2 (ANGPT2) induced by androgens and repressed by AA as a key driver of neo-angiogenesis. In agreement with this, AA treatment of native patient-derived PCa tumour samples ex vivo inhibits ANGPT2 expression. Mechanistically, besides AA, immune-depletion of ANGPT2 or blocking ANGPT2-receptors inhibits androgen-induced angiogenesis. Taken together, we reveal a VEGF-independent ANGPT2 pathway targeted by AA to inhibit androgen-regulated neo-angiogenesis.

2022-06-23 | GSE172205 | GEO

Enhanced metanephric specification to functional proximal tubule enables toxicity screening and infectious disease modelling in kidney organoids

Project description:Improved specification of metanephric nephron progenitors in conditions that prolong differentiation while simultaneously preventing spontaneous nephron induction resulted in proximal tubule (PT)-enhanced kidney organoids. PT-enhanced organoids exhibited improved PT maturation, with elongated and aligned nephron segments as well as distinct loops of Henle. The striking proximo-distal orientation of nephrons was shown to result from localised WNT antagonism originating from the centre of the organoid.

2022-08-25 | GSE184928 | GEO

Genes associated with angiogenic response to Ang-1 or VEGF

Project description:Specific Aims To identify novel transcriptional events associated with angiogenesis in VEGF and Ang-1 stimulated rat aortic rings. Our studies take advantage of the capacity of rat aortic rings to generate new vessels in collagen gels. Rat aortic rings embedded in collagen gel immediately after excision from the animal produce a self-limited angiogenic response under serum-free conditions and in the absence of exogenous stimuli. This angiogenic response can be dose-dependently promoted by vascular endothelial growth factor (VEGF) and angiopoietin-1 (Ang-1), which are critical regulators of the angiogenic process during embryonal development and postnatal angiogenesis. Aortic rings lose their capacity to spontaneously generate new vessels if embedded in collagen gels 10-14 days after excision. VEGF has the capacity to turn back “on” these quiescent rings producing florid angiogenesis. Conversely, Ang-1 potentiates an existing angiogenic response, but is unable to turn the quiescent system “on”. Since VEGF-mediated induction of angiogenic sprouting occurs 1-2 days of treatment, we hypothesize that this process is regulated by a unique set of “angiogenesis inducer genes” that are activated by VEGF and not by Ang-1. Identification of the proteins encoded by these genes may advance our understanding of the molecular mechanisms that regulate the earliest stages of the angiogenic cascade. Keywords: Response to growth factors

2006-03-22 | GSE3355 | GEO

Histone modification profiles on Human Umbilical Vein Endothelial Cells (HUVECs) under Vasucular Endothelial Cell Growth Factor (VEGF) stimulation

Project description:Endothelial cells (ECs) are phenotypically heterogeneous mainly due to their dynamic epigenetic status. VEGF, the best-known angiogenic factor, activates calcium-NFAT signalling following acute angiogenic gene transcription. Here, we evaluated the global mapping of VEGF-mediated dynamic transcriptional events with a particular focus on major histone-code profiles using ChIP-seq. Remarkably, the regulatory regions of angiogenic transcription factors exclusively acquired embryonic stem-like bivalent histone marks after the VEGF stimulus. Moreover, the newly discovered NFAT-associated epigenome modifier, PTIP in the COMPASS complex, directed gene transcription via MLL3/4-enrichment which overwhelmed the polycomb-brakes. The non-canonical polycomb1 variant, PRC1.3, specifically bound to and allowed the transactivation of PRC2-enriched bivalent angiogenic genes until conventional PRC1 association and gene silencing. Knockdown of these epigenome modifiers abrogated postnatal aberrant neovessel formation via selective inhibition of acute angiogenic bivalent gene transcription. Collectively, the reported dynamic epigenome landscape in ECs may support the development of advanced therapeutic strategies against various vasculopathies.

2021-10-06 | GSE159075 | GEO

Genome-wide distribution of histone modification H3K36me3 in ECs during VEGF-signaling

Project description:Vascular endothelial growth factor (VEGF) signaling serves a central role in vascular development as well as maintaining vascular homeostasis. In endothelial cells (ECs), VEGF activates gene expression of angiogenic transcription factors (TFs) followed by downstream induction of angiogenic responsive genes. Recent findings support histone modification dynamics contribute to transcriptional control of genes important for EC functions. Lysine demethylase 2B (KDM2B) demethylates histone H3K4me3 and H3K36me2/3 and also mediates monoubiquitylation of histone H2A119K. KDM2B functions as a transcriptional repressor in somatic cell reprograming and tumor development. However, the role of KDM2B during VEGF-signaling remains to be elucidated. Here, we show in cultured human ECs that knockdown of KDM2B enhances VEGF-induced angiogenesis via increased abilities of migration and proliferation. In contrast, ectopic expression of KDM2B has inhibitory effects on angiogenesis. The function of KDM2B is possibly dependent on its catalytic Jumondi C domain. Genome-wide analysis further reveal that KDM2B selectively controls transcription of VEGF-induced angiogenic TFs where increased H3K4me3/H3K36me3 and decreased of H2A119Kub are associated. These findings suggest an essential role of KDM2B during VEGF-signaling in ECs. Because dysregulation of VEGF signaling in ECs is involved in various diseases including cancer, KDM2B may be a potential therapeutic target in VEGF-mediated vasculopathic diseases.

2022-04-01 | GSE196503 | GEO

RNA-seq analysis to examine the effect of KDM2B knockdown or overexpression on transcriptional responses in ECs during VEGF-signaling

2022-04-01 | GSE196505 | GEO

Loss of apelin blocks the emergence of sprouting angiogenesis in experimental tumors

Project description:Angiogenesis-inhibitor (AI) drugs targeting vascular endothelial growth factor (VEGF) signalling to the endothelial cell (EC) are used to treat various cancers types. However, primary or secondary resistance to therapy is common. Clinical and pre-clinical studies suggest that other alternative pro-angiogenic factors are up-regulated after VEGF-pathway inhibition. Therefore, identification alternative pro-angiogenic pathway(s) is critical for the development of more effective anti-angiogenic therapy. Here we study the role of apelin as a pro-angiogenic G-protein coupled receptor (GPCR) ligand in tumor growth and angiogenesis. We applied single-cell RNA-sequencing to Mouse Lewis lung carcinoma (LLC1) or B16F10 mouse melanoma cell lines (1 X 106) implanted subcutaneously into the flanks of 12 weeks old Apln-/y or littermate control mice in combination with sunitinib or control (vehicle) treatment. We found apelin loss reduced angiogenic sprouting and tip cell marker gene expression in comparison to the sunitinib-alone treated mice and prevented EC tip cell differentiation.

2023-04-06 | E-MTAB-11663 | biostudies-arrayexpress

Molecular biomarkers of neovascular age-related macular degeneration with incomplete response to anti-vascular endothelial growth factor treatment

Project description:The standard treatment for neovascular age-related macular degeneration (nAMD) consists of intravitreal anti-vascular endothelial growth factors (VEGF). However, for some patients, even maximal anti-VEGF treatment does notentirely suppress exudative activity. The goal of this study was to identify molecular biomarkers in nAMD with incomplete response to anti-VEGF treatment. Aqueous humor (AH) samples were collected from three groups of patients: 18 patients with nAMD responding incompletely to anti-VEGF, 19 patients affected by nAMD with normal treatment response, and 14 control patients without any retinopathy. Proteomic and multiplex analyses were performed on these samples. Proteomic analyses showed that nAMD patients with incomplete anti-VEGF response displayed an increased inflammatory response, complement activation, cytolysis, protein-lipid complex, and vasculature development pathways. Multiplex analyses revealed a significant increase of soluble vascular cell adhesion molecule-1 (sVCAM-1) [p=0.001], interleukin-6 (IL-6) [p=0.009], bioactive interleukin-12 (IL-12p40) [p=0.03], plasminogen activator inhibitor type 1 (PAI-1) [p=0.004], and hepatocyte growth factor (HGF)[p=0.004] levels in incomplete responders in comparison to normal treatment response. Interestingly, The same biomarkers showed a high intercorrelation with r2 values between 0.58 and 0.94. In addition, we confirmed by AlphaLISA the increase of sVCAM-1 [p<0.0001] and IL-6 [p=0.043] in incomplete responder group. Incomplete responders in nAMD are associated with activated angiogenic and inflammatory pathways. The residual exudative activity of nAMD despite maximal anti-VEGF treatment may be related to both angiogenic and inflammatory responses requiring specific adjuvant therapy.

2021-01-18 | PXD022471 | Pride

VEGF promotes RNAPII pausing release through ETS1 to stimulate angiogenesis

Project description:RNA polymerase II (RNAPII) pausing release is a recently recognized checkpoint for transcriptional regulation. The biological roles of RNAPII pausing release and the mechanisms that by which extracellular signals control it are incompletely understood. Here we identify a novel mechanism by which VEGF stimulates RNAPII pausing-release through acetylation of ETS1, a master endothelial cell transcriptional regulator. In endothelial cells (ECs), ETS1 uniquely bound transcribed gene promoters and stimulated their expression by broadly increasing RNA polymerase II (RNAPII) pause release. VEGF enhanced ETS1 chromatin occupancy. Furthermore, VEGF increased ETS1 acetylation, enhancing its binding by BRD4 and thereby stimulating RNAPII pause release. This ETS1-mediated transduction of VEGF signaling to increase RNAPII pausing release was essential for EC angiogenic responses in vitro and in vivo. Together, our results define a new angiogenic pathway in which VEGF enhances ETS1-Brd4 interaction to broadly promote RNAPII pause release and drive angiogenesis.

2016-12-31 | GSE93030 | GEO

Fibroblasts associated with tumors refractory to anti-VEGF treatment

Project description:PDGF-C mediates the angiogenic and tumorigenic properties of fibroblasts associated with tumors refractory to anti-VEGF treatment Tumor associated fibroblasts (TAF) from different tumors exhibit distinct angiogenic and tumorigenic properties. Unlike normal skin fibroblasts (NSF) or TAF (TAF-TIB6) from TIB6 tumors that are sensitive to anti-VEGF treatment, TAF (TAF-EL4) from resistant EL4 tumors can stimulate TIB6 tumor growth even when VEGF is inhibited. We show that platelet-derived growth factor (PDGF)-C is upregulated in TAFs from resistant tumors. PDGF-C neutralizing antibodies blocked the angiogenesis induced by such TAF in vivo and slowed the growth of EL4 and admixture (TAF-EL4 + TIB6) tumors and exhibited additive effects with anti-VEGF-A antibodies. Hence, our data reveal a novel mechanism for TAF mediated tumorigenesis and suggest that some tumors may overcome inhibition of VEGF-mediated angiogenesis through upregulation of PDGF-C

2009-01-05 | GSE13549 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data