Injured tubular epithelia-derived CCN1 promotes the mobilization of fibroblasts toward the injury sites in acute kidney injury
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ABSTRACT:
PROVIDER: PRJNA1042822 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR26879429.fastq.gz | Fastqsanger.gz | |||
| SRR26879430.fastq.gz | Fastqsanger.gz | |||
| SRR26879431.fastq.gz | Fastqsanger.gz | |||
| SRR26879432.fastq.gz | Fastqsanger.gz | |||
| SRR26879433.fastq.gz | Fastqsanger.gz |
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Project description:Humoral factors that prompt fibroblasts to migrate to an injury site at an appropriate time point are deemed indispensable for repair after kidney injury. We herein demonstrated the pivotal roles for of injured tubule-derived Cellular Communication Network Factor 1 (CCN1) in the mobilization of fibroblasts to the injury site after kidney injury. Based on analyses of ligand-receptor interactions in vitro and tubular epithelial-specific transcriptomics in vivo, we identified the up-regulation of CCN1 during the early phases of kidney injury. CCN1 promotes fibroblast chemotaxis through focal adhesion kinase-ERK signaling. In vivo analyses utilizing tubular-specific CCN1 knockout mice demonstrated the sparse accumulation of fibroblasts around injured sites after injury, resulting that tissue fibrosis was ameliorated in CCN1-KO mice. These results reveal an epithelial - fibroblast CCN1 signaling axis that mobilizes fibroblasts to injured tubule early after acute injury but that promotes interstitial fibrosis at late timepoints.
2025-03-03 | GSE248209 | GEO
Project description:Epidemiological studies showed that patients with heart failure frequently develop kidney dysfunction, called cardio-renal syndrome (CRS). Elevated central venous pressure rather than low cardiac output strongly correlates with worsening renal function, and is being increasingly recognized as the pathophysiology responsible for CRS. However, due to the lack of appropriate animal models, the molecular mechanisms underlying the congestion-mediated acceleration of kidney injury, called renal congestion, remain unclear. In the present study, using a novel mouse renal congestion model, we detected injured tubule-specific cell-cell interactions in congestive kidneys and showed that Cellular Communication Network Factor 1 (CCN1) played an important role in this process. Transcriptomics of kidneys with ischemia-reperfusion injury (IRI) and renal congestion revealed the up-regulation of paracrine chemokine-related pathways. The up-regulation of CCN1 was observed in the acute phase after kidney injury with renal congestion. Positive staining for phosphorylated focal adhesion kinase (pFAK), a downstream signaling molecule of CCN1, was noted in fibroblasts at injury sites in congestion-IRI kidneys. CCN1 activated the phosphorylation of FAK and ERK in vitro, which accelerated the migration of fibroblasts and macrophages. We then examined the effects of CCN1 deletion in tubular epithelia on congestion-mediated kidney injury in vivo. pFAK expression in injury sites was down-regulated in CCN1-KO mice, and the congestion-mediated worsening of tissue fibrosis was significantly ameliorated. In conclusion, we herein demonstrated the important role of injured tubule-derived CCN1 on pFAK-mediated fibroblast migration in congestive kidneys. The inhibition of CCN1 has potential as a therapeutic candidate for preventing the transition of renal congestion-mediated kidney injury to fibrosis.
2025-07-09 | GSE283859 | GEO
Project description:Injured tubule-derived CCN1 exacerbates renal congestion-mediated acute kidney injury and fibrosis
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Project description:Effects of the matricellular protein CCN1 on macrophage inflammatory gene expression was tested in a macrophage cell line I-13.35. CCN1 (CYR61) is a matricellular protein that is highly expressed at sites of inflammation and wound repair. In these contexts, CCN1 can modify the activities of specific cytokines, enabling TNF-alpha to be cytotoxic without blocking NFkB activity and enhancing the apoptotic activity of FasL and TRAIL. Here we show that CCN1 supports the adhesion of macrophages through integrin alphaMbeta2 and syndecan-4, activates NFkB-mediated transcription, and induces a pro-inflammatory genetic program characteristic of classically activated M1 macrophages that participates in Th1 responses. The effects of CCN1 include upregulation of cytokines (TNFa, IL-1a, IL-1b, IL-6, IL-12b), chemokines (MIP-1a, MCP-3, Gro1, Gro2, IP-10), regulators of oxidative stress and complement (iNOS, C3), and downregulation of specific receptors (TLR4, IL-10rb) and anti-inflammatory factors (TGF-b1). CCN1 regulates this genetic program through at least two distinct mechanisms: an immediate-early response resulting from direct activation of NFkB by CCN1, leading to the synthesis of cytokines including TNFa and IP-10; and a delayed response resulting from CCN1-induced TNFa, which acts as an autocrine/paracrine mediator to activate the expression of other cytokines including IL-1b and IL-6. These results identify CCN1 as a novel component of the extracellular matrix that activates pro-inflammatory genes in macrophages, implicating its role in regulating macrophage function during inflammation. Macrophage cell line I-13.35 (from Tlr4-defective C3H/HeJ) was treated with purified recombinant CCN1 protein for 6 hr. Total RNA was isolated, converted to cRNA probes, and hybridized to a oligonucleotide array representing 113 murine inflammation-related genes (from SA Biosciences at www.sabiosciences.com, Cat. Number OMM-011.) The array is a nylon membrane based DNA microarray on which 60-mer oligonucleotides probes were printed. Gene expression profile of resting cells incubated in serum-free medium (containing albumin, BSA) was used as a control for basal levels of gene expression.
2010-05-14 | E-GEOD-19731 | biostudies-arrayexpress
Project description:Effects of the matricellular protein CCN1 on macrophage inflammatory gene expression was tested in a macrophage cell line I-13.35. CCN1 (CYR61) is a matricellular protein that is highly expressed at sites of inflammation and wound repair. In these contexts, CCN1 can modify the activities of specific cytokines, enabling TNF-alpha to be cytotoxic without blocking NFkB activity and enhancing the apoptotic activity of FasL and TRAIL. Here we show that CCN1 supports the adhesion of macrophages through integrin alphaMbeta2 and syndecan-4, activates NFkB-mediated transcription, and induces a pro-inflammatory genetic program characteristic of classically activated M1 macrophages that participates in Th1 responses. The effects of CCN1 include upregulation of cytokines (TNFa, IL-1a, IL-1b, IL-6, IL-12b), chemokines (MIP-1a, MCP-3, Gro1, Gro2, IP-10), regulators of oxidative stress and complement (iNOS, C3), and downregulation of specific receptors (TLR4, IL-10rb) and anti-inflammatory factors (TGF-b1). CCN1 regulates this genetic program through at least two distinct mechanisms: an immediate-early response resulting from direct activation of NFkB by CCN1, leading to the synthesis of cytokines including TNFa and IP-10; and a delayed response resulting from CCN1-induced TNFa, which acts as an autocrine/paracrine mediator to activate the expression of other cytokines including IL-1b and IL-6. These results identify CCN1 as a novel component of the extracellular matrix that activates pro-inflammatory genes in macrophages, implicating its role in regulating macrophage function during inflammation.
2010-02-18 | GSE19731 | GEO
Project description:Resident Macrophages Reprogram Toward a Developmental State After Acute Kidney Injury
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Project description:Adult neural stem cells (NSCs) reside in specialized niches, which hold a balanced number of NSCs, their progeny, and other cells. How niche capacity is regulated to contain a specific number of NSCs remains unclear. Here, we show that ependyma-derived matricellular protein CCN1 (cellular communication network factor 1) negatively regulates niche capacity and NSC number in the adult ventricular-subventricular zone (V-SVZ). Adult ependyma-specific deletion of Ccn1 transiently enhanced NSC proliferation and reduced neuronal differentiation in mice, increasing the numbers of NSCs and NSC units. Although proliferation of NSCs and neurogenesis seen in Ccn1 knockout mice eventually returned to normal, the expanded NSC pool was maintained in the V-SVZ until old age. Inhibition of EGFR signaling prevented expansion of the NSC population observed in CCN1 deficient mice. Thus, ependyma-derived CCN1 restricts NSC expansion in the adult brain to maintain the proper niche capacity of the V-SVZ.
2020-02-19 | GSE137852 | GEO
Project description:The extent of liver injury determines hepatocyte fate toward senescence or cancer
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Project description:Tumor progression is often accompanied with increased extracellular matrix stiffness, but how this affects endothelial cells (ECs) is largely unknown. We used mass spectrometry to analyse the proteomic changes of primary human ECs cultured on physiological or tumor stiffness and found that CCN1/CYR61 is highly induced by tumor stiffness. Knock out of Ccn1 in the vasculature of Ccn1loxP/loxP mice by administrating a soluble form of Cre shows that fewer of the treated mice harbour circulating tumor cells and lung metastases, without affecting primary tumor growth, using the B16F10 syngeneic mouse melanoma model This demonstrates that CCN1 loss in the host impairs cancer metastasis and we dissected the molecular mechanism in vitro. Stiffness-induced CCN1 acts via (integrin αvβ3), FAK, beta-catenin signalling to increase N-Cadherin expression in ECs, which, in turn, leads to an elevated adhesion of cancer cells to ECs via N-Cadherin homophilic interactions.
2017-07-07 | PXD003316 | Pride
Project description:Melanoma is the leading cause of skin cancer-related death. As prognosis of melanoma patients remains problematic, identification of new therapeutic targets remains essential. Matricellular proteins are non-structural extracellular matrix proteins. They are secreted into the tumor microenvironment to coordinate behavior among different cell types, yet their contribution to melanoma is under-investigated. Examples of matricellular proteins include those comprising the CCN family. The CCN family member, CCN1, is highly pro-angiogenic. Herein, we show that, in human melanoma patients, although found in several tumor cell types, CCN1 is highly expressed by a subset of cancer-associated fibroblasts in melanoma patients and this expression correlates positively with expression of pro-angiogenic genes and progressive disease/resistance to anti-PD1 checkpoint inhibitors. Consistent with these observations, in a syngeneic C57BL6 mouse model of melanoma, loss of CCN1 expression from Col1A2-Cre-fibroblasts impaired metastasis of subcutaneously-injected B16F10 tumor cells to lung, concomitant with disrupted neovascularization and collagen organization. Disruption of the extracellular matrix in the loss of CCN1 was validated using a novel artificial intelligence-based image analysis platform that revealed significantly decreased phenotypic fibrosis and composite morphometric collagen scores. As drug resistance is linked to matrix deposition and neo-angiogenesis, these data suggest that CCN1, due to its multifaceted role, may represent a novel therapeutic target for drug-resistant melanoma. Our data further emphasize the essential role that cancer-associated, Col1A2-Cre-fibroblasts and extracellular matrix remodeling play in coordinating behavior among different cell types within the tumor microenvironment
2025-01-12 | GSE253482 | GEO