Dysregulated mesenchymal PDGFR-β drives kidney fibrosis
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE138819 | GEO | 2019/12/06
REPOSITORIES: GEO
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Project description:Dysregulated mesenchymal PDGFR-β drives kidney fibrosis
| PRJNA577448 | ENA
Project description:The scaffold protein synectin plays a critical role in the trafficking and regulation of membrane receptor pathways. As the platelet derived growth factor receptor (PDGFR) pathway is essential for hepatic stellate cell (HSC) activation and liver fibrosis, we sought to determine the role of synectin on the PDGFR pathway in HSC. To study the role of synectin in the development of liver fibrosis, mice with selective deletion of synectin from HSC were generated and found to be protected from fibrosis. RNAseq revealed that knockdown of synectin in HSC demonstrated reductions in the fibrosis pathway of genes including PDGFR-β, but not PDGFR-α. Chromatin Immunoprecipitation assay of the PDGFR-β promoter upon synectin knockdown revealed a pattern of histone marks associated with decreased transcription, dependent on p300. In contradistinction, synectin was found to regulate PDGFR-α through an alternative mechanism: protection from autophagic degradation. Site directed mutagenesis revealed that ubiquitination of specific PDGFR-α lysine residues is responsible for its autophagic degradation. Furthermore, functional studies showed decreased PDGF dependent proliferation and migration after synectin knockdown. Finally, human cirrhotic livers demonstrated increased synectin expression. This work provides insight into differential transcriptional and post-translational mechanisms of synectin regulation of PDGFRs, which are critical to fibrogenesis.
2017-12-31 | GSE93629 | GEO
Project description:Background & Aims: Rapid induction of beta-PDGF receptor (beta-PDGFR) is a core feature of hepatic stellate cell activation, the hallmark of liver fibrogenesis. However, biological consequences of the induction are not well characterized. We aimed to determine the involvement of beta-PDGFR-mediated molecular pathway activation on hepatic stellate cells in liver injury, fibrogenesis, and carcinogenesis in vivo. Methods: Loss and constitutive activation of beta-PDGFR were assessed in mouse models with either a stellate cell-specific beta-PDGFR knockout or the expression of an autoactivating mutation respectively. Liver injury and fibrosis were induced in two mechanistically distinct models: carbontetrachloride (CCl4) treatment and ligation of the common bile duct. Hepatocarcinogenesis with underlying liver injury/fibrosis was assessed by a single dose of diethylnitrosamine (DEN) followed by repeated injections of CCl4. Genome-wide expression profiling was performed isolated stellate cells from these models to determine deregulated pathways. Results: Depletion of beta-PDGFR in hepatic stellate cells led to decreased histological liver injury, serum transaminases, collagen alpha 1(I) and alpha smooth muscle actin expression, and collagen deposition. Stellate cell proliferation was significantly reduced after acute hepatic injury in vivo. In contrast, autoactivation of beta-PDGFR in stellate cells accelerated liver fibrosis, most prominently after 6 weeks of CCl4 induced injury. There was no difference in development of DEN-induced pre-neoplastic loci according to the status of beta-PDGFR. Conclusions: Depletion of beta-PDGFR in hepatic stellate cells attenuated the development of liver injury, fibrosis, and stellate cell proliferation in multiple animal models, whereas the constitutive activation of beta-PDGFR enhanced fibrosis. However, manipulation of beta-PDGFR alone did not reduce development of dysplastic nodules. These findings indicate that titration of receptor beta-PDGFR expression on stellate cells parallels fibrosis and injury, but may not impact the development of hepatic neoplasia alone. Hepatic stellate cells were isolated from liver of beta-PDGFR-wild-type or knockout mice, and treated with beta-PDGF ligand or vehicle control.
2015-02-19 | E-GEOD-52253 | biostudies-arrayexpress
Project description:In chronic kidney disease (CKD) and with ageing, individuals lose regenerative capacity after renal injury and are predisposed to progressive fibrosis and cardiovascular disease. With ageing and CKD increased numbers of activated leukocytes are present in the circulation and within the kidney where they correlate with progressive fibrosis. The potential role of activated leukocytes in mediating progressive renal and systemic fibrosis remains incompletely understood. Here, we show that tumour necrosis factor alpha (TNFa) released with injury and aging promotes renal and cardiac fibrosis. We identify a Ubiquitin D expressing population of TNFa induced inflammatory proximal tubular epithelia (iPT) responsible for Indian Hedgehog release in aged and fibrotic kidneys. Indian Hedgehog production by iPT cells activates canonical Hedgehog signalling in Gli1+ stromal cells leading to activation, proliferation and fibrosis deposition. Our data links the immune activation seen in aging and chronic kidney disease to cardio-renal fibrosis. This provides multiple targets for antifibrotic therapies which we validate in murine models of aging and kidney disease.
2023-01-30 | GSE178109 | GEO
Project description:Kidney fibrosis, characterized by excessive extracellular matrix (ECM) deposition, is a progressive disease that, despite affecting 10% of the population, lacks specific treatments and suitable biomarkers. Aimed at unraveling disease mechanisms and identifying potential therapeutic targets, this study presents a comprehensive, time-resolved multi-omics analysis of kidney fibrosis using an in vitro model system based on human kidney PDGFRβ+ mesenchymal cells. Using computational network modeling we integrated transcriptomics, proteomics, phosphoproteomics, and secretomics with imaging of the extracellular matrix (ECM). We quantified over 14,000 biomolecules across seven time points following TGF-β stimulation, revealing distinct temporal patterns in the expression and activity of known and potential novel renal fibrosis markers and modulators. The resulting time-resolved multi-omic network models allowed us to propose mechanisms related to fibrosis progression through early transcriptional reprogramming. Using siRNA knockdowns and phenotypic assays, we validated predictions and elucidated regulatory mechanisms underlying kidney fibrosis. Notably, we demonstrate that several early-activated transcription factors, including FLI1 and E2F1, act as negative regulators of collagen deposition and propose underlying molecular mechanisms. This work advances our understanding of the pathogenesis of kidney fibrosis and provides a valuable resource for the organ fibrosis research community.
2024-11-07 | E-MTAB-14521 | biostudies-arrayexpress
Project description:Tubular injury and peripheral fibroblast activation are the hallmarks of chronic kidney disease (CKD) and renal fibrosis, suggesting intimate communication between the two diseases. However, the underlying mechanisms remain to be determined. Exosomes play a role in shuttling proteins and other materials to recipient cells. In our study, we found that tubular cell-derived exosomes were aroused by β-catenin in kidney fibrogenesis. Osteopontin (OPN), especially its N-terminal fragments (N-OPN), was encapsulated in β-catenin-controlled tubular cell-derived exosome cargo, and subsequently passed to fibroblasts. Through binding with CD44, exosomal OPN promoted fibroblast proliferation and activation. Gene deletion of β-catenin in tubular cells (Ksp-β-catenin−/−) or gene ablation of CD44 (CD44−/−) greatly ameliorated renal fibrosis. Notably, N-OPN was secreted by exosome into the urine of patients with CKD, and negatively correlated with kidney function. The urinary exosomes from patients with CKD greatly accelerated renal fibrosis, which was blocked by CD44 deletion. These results suggest that exosome-mediated activation of the OPN/CD44 axis plays a key role in renal fibrosis, which is controlled by β-catenin.
2022-05-20 | PXD030696 | Pride
Project description:Background & Aims: Rapid induction of beta-PDGF receptor (beta-PDGFR) is a core feature of hepatic stellate cell activation, the hallmark of liver fibrogenesis. However, biological consequences of the induction are not well characterized. We aimed to determine the involvement of beta-PDGFR-mediated molecular pathway activation on hepatic stellate cells in liver injury, fibrogenesis, and carcinogenesis in vivo. Methods: Loss and constitutive activation of beta-PDGFR were assessed in mouse models with either a stellate cell-specific beta-PDGFR knockout or the expression of an autoactivating mutation respectively. Liver injury and fibrosis were induced in two mechanistically distinct models: carbontetrachloride (CCl4) treatment and ligation of the common bile duct. Hepatocarcinogenesis with underlying liver injury/fibrosis was assessed by a single dose of diethylnitrosamine (DEN) followed by repeated injections of CCl4. Genome-wide expression profiling was performed isolated stellate cells from these models to determine deregulated pathways. Results: Depletion of beta-PDGFR in hepatic stellate cells led to decreased histological liver injury, serum transaminases, collagen alpha 1(I) and alpha smooth muscle actin expression, and collagen deposition. Stellate cell proliferation was significantly reduced after acute hepatic injury in vivo. In contrast, autoactivation of beta-PDGFR in stellate cells accelerated liver fibrosis, most prominently after 6 weeks of CCl4 induced injury. There was no difference in development of DEN-induced pre-neoplastic loci according to the status of beta-PDGFR. Conclusions: Depletion of beta-PDGFR in hepatic stellate cells attenuated the development of liver injury, fibrosis, and stellate cell proliferation in multiple animal models, whereas the constitutive activation of beta-PDGFR enhanced fibrosis. However, manipulation of beta-PDGFR alone did not reduce development of dysplastic nodules. These findings indicate that titration of receptor beta-PDGFR expression on stellate cells parallels fibrosis and injury, but may not impact the development of hepatic neoplasia alone.
2015-02-19 | GSE52253 | GEO
Project description:Despite significant progress in therapy, there remains a lack of substantial evidence regarding the molecular factors that lead to renal fibrosis. Neuraminidase 4 (NEU4) is an enzyme that removes sialic acids from glycoconjugates, while the function of NEU4 in chronic progressive fibrosis has not been clearly explored. Here, we find that NEU4 expression is markedly upregulated in mouse fibrotic kidneys induced by folic acid or unilateral ureter obstruction, and this elevation was observed in patients with renal fibrosis. NEU4 knockdown specifically in the kidney attenuates the epithelial-to-mesenchymal transition and the production of pro-fibrotic cytokines in male mice. Conversely, NEU4 overexpression exacerbates the progression of renal fibrosis. Mechanistically, NEU4254-388aa interacts with Yes-associated protein YAP at WW2 domain (231-263aa), promotes its translocation to the nucleus, activates its target genes, and consequently contributes to renal fibrosis. 3,5,6,7,8,3ʹ,4ʹ-Heptamethoxyflavone, a natural compound, is identified as a novel inhibitor of NEU4 and effectively protects mice from renal fibrosis in a NEU4-dependent manner. Collectively, our findings suggest that NEU4 may represent a promising therapeutic target for kidney fibrosis.
2025-05-06 | PXD051726 | Pride
Project description:Tubular injury and peripheral fibroblast activation are the hallmarks of chronic kidney disease (CKD) and renal fibrosis, suggesting intimate communication between the two diseases. However, the underlying mechanisms remain to be determined. Exosomes play a role in shuttling proteins and other materials to recipient cells. In our study, we found that tubular cell-derived exosomes were aroused by β-catenin in kidney fibrogenesis. Osteopontin (OPN), especially its N-terminal fragments (N-OPN), was encapsulated in β-catenin-controlled tubular cell-derived exosome cargo, and subsequently passed to fibroblasts. Through binding with CD44, exosomal OPN promoted fibroblast proliferation and activation. Gene deletion of β-catenin in tubular cells (Ksp-β-catenin−/−) or gene ablation of CD44 (CD44−/−) greatly ameliorated renal fibrosis. Notably, N-OPN was secreted by exosome into the urine of patients with CKD, and negatively correlated with kidney function. The urinary exosomes from patients with CKD greatly accelerated renal fibrosis, which was blocked by CD44 deletion. These results suggest that exosome-mediated activation of the OPN/CD44 axis plays a key role in renal fibrosis, which is controlled by β-catenin.
2022-12-20 | GSE193282 | GEO
Project description:Purpose:Single cell RNA sequencing to identify PDGFR-beta expressing cells in the normal adult lung Methods: Adult Pdgfrb-CreERT2, ROSA26R(Zs/+) mice were induced with tamoxifen (1mg/day for 5 days) and rested for 5 days. Lungs were then harvested and prepared to obtain single cell suspension. Live Zs+ and Zs- cells were isolated by FACS and hash-tagged. Cells were then pooled together in PBS with 0.04% bovine serum albumin and subjected to library preparation and DropSeq. scRNA-seq data was processed with Cell Ranger v 3.1.0. Reads were aligned to a modified version of the mouse transcriptome mm10, including the sequence for the gene ZsGreen1. The top cell barcodes selected by Cell Ranger were utilized for downstream analysis. Results: In lung mesenchymal cells, populations of fibroblasts and pericytes express Pdgfr-beta.
2021-09-23 | GSE184671 | GEO