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Transcriptional effects of Pentraxin-2 in fibrotic disease of the kidney

ABSTRACT: Pentraxin-2 (PTX-2) is a constitutive, anti-inflammatory, innate immune plasma protein whose circulating level is decreased in chronic human fibrotic diseases. Recent studies indicate that systemic delivery of recombinant PTX-2 inhibits inflammatory diseases associated with fibrosis by blocking pro-fibrotic macrophage activation and promoting anti-inflammatory and regulatory macrophages. Here we show that recombinant human PTX-2 (rhPTX-2) retards the progression of chronic kidney disease in Col4a3 mutant mice that develop Alport syndrome, reducing blood markers of kidney failure, enhancing lifespan by 20%, and improving histological signs of disease. Exogenously-delivered rhPTX-2 is detected in macrophages but is also found in tubular epithelial cells where it counteracts macrophage activation and is cytoprotective for the epithelium. We performed transcriptional profiling of whole kidney homogenates and human proximal tubule epithelial cells (PTECs) to identify pathways differentially activated or suppressed in response to treatment with PTX-2. Computational analysis of genes regulated by rhPTX-2 identified the transcriptional regulator c-Jun and its binding partners, which form AP-1 complexes, as a central target for the function of rhPTX-2. Accordingly, PTX-2 attenuates c-Jun activation and reduces expression of AP-1 dependent inflammatory genes in both monocytes and epithelium. Our studies therefore identify rhPTX-2 as a potential therapy for chronic fibrotic disease of the kidney and an important inhibitor of pathological c-Jun signaling in this setting.

ORGANISM(S): Mus musculus Homo sapiens

PROVIDER: GSE85409 | GEO | 2016/08/11

SECONDARY ACCESSION(S): PRJNA338388

REPOSITORIES: GEO

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Transcriptional effects of Pentraxin-2 in fibrotic disease of the kidney

Project description:Pentraxin-2 (PTX-2) is a constitutive, anti-inflammatory, innate immune plasma protein whose circulating level is decreased in chronic human fibrotic diseases. Recent studies indicate that systemic delivery of recombinant PTX-2 inhibits inflammatory diseases associated with fibrosis by blocking pro-fibrotic macrophage activation and promoting anti-inflammatory and regulatory macrophages. Here we show that recombinant human PTX-2 (rhPTX-2) retards the progression of chronic kidney disease in Col4a3 mutant mice that develop Alport syndrome, reducing blood markers of kidney failure, enhancing lifespan by 20%, and improving histological signs of disease. Exogenously-delivered rhPTX-2 is detected in macrophages but is also found in tubular epithelial cells where it counteracts macrophage activation and is cytoprotective for the epithelium. We performed transcriptional profiling of whole kidney homogenates and human proximal tubule epithelial cells (PTECs) to identify pathways differentially activated or suppressed in response to treatment with PTX-2. Computational analysis of genes regulated by rhPTX-2 identified the transcriptional regulator c-Jun and its binding partners, which form AP-1 complexes, as a central target for the function of rhPTX-2. Accordingly, PTX-2 attenuates c-Jun activation and reduces expression of AP-1 dependent inflammatory genes in both monocytes and epithelium. Our studies therefore identify rhPTX-2 as a potential therapy for chronic fibrotic disease of the kidney and an important inhibitor of pathological c-Jun signaling in this setting. 1. Total RNA from whole kidney homogenates of wildtype (Col4a3+/+) and knockout (Col4a3-/-) mice treated with PTX-2 was isolated and hybidized to Illumina Mouse WG-6 v2 Expression BeadChips. 2. Total RNA from human proximal tubules treated with plasma and PTX-2 was isolated and hybidized to Illumina HumanHT-12 v4 Expression BeadChips.

2016-08-11 | E-GEOD-85409 | biostudies-arrayexpress

Genome-wide profiling of inflammatory cistrome reveals AP-1/c-Jun as a key regulator of TNFalpha-mediated triple-negative breast cancer progression [microarray]

Project description:Triple-negative breast cancer (TNBC) represents a highly aggressive form of breast cancer with limited treatment options. Proinflammatory cytokines such as TNFalpha can facilitate tumor progression and metastasis. However, our knowledge of the molecular mechanisms underlying TNBC progression mediated by inflammation is still limited. Here, we define the AP-1 transcription factor c-Jun cistrome, which is comprised of 13800 binding sites responsive to TNFalpha-induced signaling in TNBC cells. In addition, we show that c-Jun regulates nearly a third of the TNFalpha-elicited transcriptome. Expression of the c-Jun-regulated pro-invasion gene program is strongly associated with clinical outcomes in TNBCs. Mechanistically, we demonstrate that c-Jun drives TNFalpha-mediated TNBC tumorigenicity by transcriptional regulation of Ninj1. As exemplified by the c-Jun bound CXC chemokine genes clustered on chromosome 4, we demonstrate that NF-kB might be a pioneer factor and is required for the regulation of TNFalpha-inducible inflammatory genes, whereas c-Jun has little effect. Together, our results uncover AP-1 as an important determinant for inflammation-induced cancer progression, rather than inflammatory response. BT549 cells were cultured to 50% confluency and transfected with control or c-Jun siRNA for 72 hours, followed by treatment with or without TNFÎ± for 6 hours.

2016-01-20 | E-GEOD-71915 | biostudies-arrayexpress

Transcriptional effects of Pentraxin-2 in fibrotic disease of the kidney

Project description:Transcriptional effects of Pentraxin-2 in fibrotic disease of the kidney

| PRJNA338388 | ENA

Fibrosis associated changes detected in the proteome of surface epithelium overlying Crohn’s Disease Strictures

Project description:Background and aims: Intestinal fibrosis is a common complication of Crohn’s disease (CD). It is characterised by an excessive accumulation of fibroblasts differentiating into activated myofibroblasts secreting excessive extracellular matrix. The potential role of the intestinal epithelium in this fibrotic process remains poorly defined. Methods: A total of 113 CD and control subjects were studied. We performed a pilot proteomic study comparing the proteome of surface epithelium isolated by laser capture microdissection in normal and fibrotic zones of resected ileal CD strictures (n=5). Selected proteins were validated by immunohistochemistry (IHC) in colonic and ileal samples of stricturing CD patients (n=44), pure inflammatory CD (n=29) and control subjects (n=40). Functional assays with cell lines cultures and a fibroblast to myofibroblast differentiation model were used to assess the role of the highlighted epithelial proteins in CD fibrosis. Results: Proteomic study revealed an endoplasmic reticulum (ER) stress and unfolded protein response (UPR) markers increase in the epithelium overlying ileal fibrotic strictures, involving Anterior gradient protein 2 homolog (AGR2) and Binding immunoglobulin protein (BiP). This was confirmed by IHC. The ER stress induction in intestinal epithelial cells increased AGR2 as well as BiP expression and led to an extracellular secreted AGR2. A fibroblast to myofibroblast differentiation was obtained with the supernatant of intestinal epithelial cells pre-conditioned by ER stress and with recombinant AGR2. Conclusions: AGR2 and other ER stress markers are increased within the intestinal epithelium overlying fibrotic strictures and might contribute to profibrotic signals involved in CD fibrosis.

2022-04-04 | PXD022214 | Pride

Single-nuclear transcriptomics reveals a diversity of proximal tubule cell states in a dynamic response to acute kidney injury.

Project description:We performed a mild-to-moderate ischemia reperfusion injury (IRI) to model injury responses reflective of kidney injury in a variety of clinical settings. Single-nuclear RNA-sequencing (snRNA-seq) of genetically labeled injured PTCs at 7-days (“early”) and 28-days (“late”) time points post-IRI identified specific gene and pathway activity in the injury-repair transition. In particular, we identified Vcam1+/Ccl2+ proximal tubule cells at a late injury stage distinguished by marked activation of NF-kB-, TNF- and AP-1-signaling pathways. This population of PTCs showed features of a senescence-associated secretory phenotype but did not exhibit G2/M cell cycle arrest. These pro-inflammatory, pro-fibrotic proximal tubule cells are likely triggers for chronic disease progression.

2021-06-16 | GSE171417 | GEO

Genome-wide profiling of inflammatory cistrome reveals AP-1/c-Jun as a key regulator of TNFalpha-mediated triple-negative breast cancer progression [microarray]

2016-01-20 | GSE71915 | GEO

Genome-wide profiling of inflammatory cistrome reveals AP-1/c-Jun as a key regulator of TNFalpha-mediated triple-negative breast cancer progression [ChIP-seq]

Project description:Triple-negative breast cancer (TNBC) represents a highly aggressive form of breast cancer with limited treatment options. Proinflammatory cytokines such as TNF can facilitate tumor progression and metastasis. However, our knowledge of the molecular mechanisms underlying TNBC progression mediated by inflammation is still limited. Here, we define the AP-1 transcription factor c-Jun cistrome, which is comprised of 13800 binding sites responsive to TNFalpha-induced signaling in TNBC cells. In addition, we show that c-Jun regulates nearly a third of the TNFalpha-elicited transcriptome. Expression of the c-Jun-regulated pro-invasion gene program is strongly associated with clinical outcomes in TNBCs. Mechanistically; we demonstrate that c-Jun drives TNFalpha-mediated TNBC tumorigenicity by transcriptional regulation of Ninj1. As exemplified by the c-Jun bound CXC chemokine genes clustered on chromosome 4, we demonstrate that NF-kB might be a pioneer factor and is required for the regulation of TNFalpha-inducible inflammatory genes, whereas c-Jun has little effect. Together, our results uncover AP-1 as an important determinant for inflammation-induced cancer progression, rather than inflammatory response.

2016-01-20 | GSE71976 | GEO

AP-1 is a regulatory transcription factor of inflammaging in the murine kidney and liver

Project description:Aging is characterized by a chronic low-grade inflammation in multiple tissues, also termed as “inflammaging”, which represents a significant risk factor for many aging-related chronic diseases. However, the mechanisms and regulatory networks behind inflammaging across different tissues have not been fully elucidated. Here, by profiling transcriptomes and epigenomes of the kidney and liver from young and aged mice, we found that activation of inflammatory response was the conserved signature across tissues. Through integrative analysis, we revealed links between transcriptome change and chromatin dynamics, and identified AP-1 and ETS family transcription factors (TFs) were potential regulators of inflammaging. Further in-situ validation showed AP-1 was mainly activated in aged hepatic and renal cells, while enhanced ETS was almost caused by elevated infiltration of macrophages, indicating these TFs had different mechanisms in inflammaging. Functional data showed genetic knockdown of Fos, a major member of AP-1, significantly attenuated inflammatory response in aged kidneys and livers. Taken together, our analysis revealed conserved signatures and regulatory TFs of inflammaging in the kidney and liver, providing novel targets for the development of anti-aging interventions.

2022-12-30 | GSE221801 | GEO

miRNA expression profiling of hTERT-immortalized renal proximal tubule epithelial (RPTEC/TERT1) cell treated with mesenchymal stem cell-conditioned miedium (BMSC-CM) on polyacrylamide (PAA) gel platform

Project description:Chronic kidney disease (CKD) is a progressive condition characterized by sustained alterations in kidney structure and function. Long-term kidney fibrosis is marked by glomerulosclerosis, vascular sclerosis, and tubulointerstitial fibrosis. Therefore we investigated the therapeutic potential of BMSC-CM on RPTEC/TERT1 in a fibrotic environment. Using PAA gel platforms, we mimicked the stiffness typical of chronic kidney disease patients' kidneys.

2023-12-20 | GSE250271 | GEO

AP-1 family members act at DNA targets in conjunction with Sox9 to promote chondrocyte hypertrophy

Project description:A comprehensive analysis of Sox9 binding profiles in developing chondrocytes identified marked enrichment of an AP-1-like motif (Ohba et al. 2015). Here, we have explored the functional interplay between Sox9 and AP-1 in mammalian chondrocyte development. Among AP-1 family members, Jun and Fosl2 were highly expressed within prehypertrophic and early hypertrophic chondrocytes. Chromatin immunoprecipitation followed by DNA sequencing (ChIP-seq) showed a striking overlap in Jun- and Sox9-bound regions throughout the chondrocyte genome, a reflection of direct binding of each factor to target motifs in shared enhancers, and physical interactions of AP-1 with Sox9. In vitro expression analysis indicates that direct co-binding of Sox9 and AP-1 at target motifs enhanced target gene expression, while protein-protein interactions suppressed AP-1- and Sox9-driven transcription. Analysis of prehypertrophic chondrocyte removal of Sox9 demonstrated Sox9 was essential for hypertrophic chondrocyte development, while in vitro and ex vivo analyses showed AP-1 promotes chondrocyte hypertrophy. Sox9 and Jun co-bound and co-activated a Col10a1 enhancer in Sox9 and AP-1 motif-dependent manners consistent with their combined action promoting hypertrophic gene expression. Together, the data support a model where AP-1-family members promote Sox9-action in the transition of chondrocytes to a terminal hypertrophic program. Intersection of ChIP-seq data from Sox9 and AP-1 factor Jun, RNA-seq data from developing rib chondrocytes and Col10a1mCherry positive hypertrophic chondrocytes in neonatal mice to uncover regulation of Sox9 by AP-1 factors during chondrocyte hypertrophy.

2016-02-29 | E-GEOD-73372 | biostudies-arrayexpress

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