Novel players in renal fibrosis uncovered by gene expression analyses of TGF-β1 treated renal tubular epithelial cells and diseased kidneys
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ABSTRACT:
PROVIDER: PRJNA854640 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR19909848_1.fastq.gz | Fastqsanger.gz | |||
| SRR19909848_2.fastq.gz | Fastqsanger.gz | |||
| SRR19909849_1.fastq.gz | Fastqsanger.gz | |||
| SRR19909849_2.fastq.gz | Fastqsanger.gz | |||
| SRR19909850_1.fastq.gz | Fastqsanger.gz |
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Project description:Tubular epithelial cells (TECs) play a major role in potentiating renal fibrosis. While TGF-β1 is a key inducer of the pro-fibrotic phenotype in TECs, inhibition of TGF-β1 also blocks its protective effects, making this an unsuccessful strategy for treating renal fibrosis. Molecules induced by TGF-β1 to regulate TEC phenotype would serve as more specific and effective targets. To uncover such molecules, we performed high throughput analyses on TGF-β1 treated renal tubular epithelial cells (HKC). RNA sequencing identified 3565 genes and proteomics identified 74 proteins differentially regulated by TGF-β1 in HKC. We then selected 47 genes that were most upregulated in our in vitro datasets and that do not have well-characterized roles in renal fibrosis based on our review of the literature. We searched 8 publicly available datasets containing transcriptomic data from diseased human kidneys for gene expression patterns of the selected genes and found that MARCKS and DOCK2 were amongst the most consistently upregulated in the human datasets. In HKC, MARCKS knockdown decreased TGF-β1 mediated upregulation of pro-fibrotic markers, while DOCK2 knockdown had the opposite effect. Our data suggests novel roles for these proteins in renal TECs as potential promoters the pro-fibrotic phenotype.
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Project description:Protein L-isoaspartyl/D-aspartyl Methyltransferase (PCMT1) plays a pivotal role in repairing a spontaneous post-translational modification (PTM) of L-isoaspartyl residues resulted from asparagine deamidation or aspartate isomerization. This PTM is particularly important for extracellular matrix (ECM) proteins because their low turnover rate and are susceptible to factors that could accelerate such modification. Therefore, it becomes imperative to comprehensively investigate the impact of PCMT1 on ECM homeostasis and its associated pathological alterations. In this study, we revealed that secreted PCMT1 repairs the isoaspartyl residues of the TGFBR2 protein on the cell membrane to suppress TGF-β1/Smad pathway. Through this novel PTM regulation, PCMT1 played essential roles in combating renal fibrosis, as lack of PCMT1 worsened tubular injury, collagen deposition, myofibroblast activation, and macrophage infiltration in total kidney and tubular contexts in a mouse model of chronic kidney disease. Moreover, PCMT1 level decreased in fibrotic kidney tissues and inversely related to kidney function in mice and in humans. Our study highlights the important function of PCMT1 in modifying proteins in the extracellular space and identified a novel role of PCMT1 in regulating TGF-β1 pathway in renal fibrosis. This study holds the potential of innovative therapeutic avenue for the mitigation of renal fibrosis.
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Project description:These data show that the genes that distinguish myofibroblasts from fibroblasts are myriad, and that some genes not traditionally associated with myofibroblast differentiation may serve as novel therapeutic targets for fibrosing disorders. Gene expression levels were assessed from total RNA on the Affymetrix U219 microarray. Here, we use transforming growth factor-β1 (TGF-β1) and prostaglandin E2 (PGE2), which has recently been shown to reverse myofibroblast differentiation, to investigate the transcriptomic changes that occur during TGF-β1-induced differentiation and PGE2-induced de-differentiation of myofibroblasts.
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Project description:In order to study the effect of mesenchymal stem cells on miRNAs in renal tubular epithelial cells during renal fibrosis, and to find new treatment methods for renal fibrosis, we used TGF-β1 to stimulate mouse tubular epithelial cells, co-cultured with mesenchymal stem cells for 48 hours, and collected renal tubular epithelial cells .The renal tubular epithelial cells that were only stimulated by TGF-β1 were used as a control group. High-throughput miRNA sequencing was used to detect the increased and decreased miRNAs after co-culture.
2020-04-07 | GSE148144 | GEO
Project description:The distal convoluted tubule (DCT) plays a key role in the fine-tuning of renal Mg2+ reabsorption. In recent years, hereditary magnesium (Mg2+) transport disorders have helped to identify important players in DCT Mg2+ homeostasis. Here, we report the Mg2+-sensitive transcriptional expression of the DCT transcriptome using gene expression microarray analysis. Mice expressing eGFP under a DCT-specific promoter were subjected to Mg2+-deficient or Mg2+-enriched diets. Subsequently, the Complex Object Parametric Analyzer and Sorter (COPAS) allowed isolation of eGFP-positive DCT cells. RNA extracts were subjected to pair-wise microarray analysis, high vs. low Mg2+. Of all genes in the genome, 46 were shown to be differentially expressed with a minimal fold-change of 2. Several known magnesiotropic genes, such as Trpm6 and Parvalbumin, were upregulated in the low Mg2+ fraction. Moreover, new genes were identified that are potentially involved in renal Mg2+ homeostasis. To confirm that the selected candidate genes are regulated by dietary Mg2+ availability, the expression levels of Slc41a3, Pcbd1, Tbc1d4 and Umod were determined by RT-PCR analysis. Indeed, all four genes were shown to be significantly upregulated in mice fed the Mg2+-deficient diet. In conclusion, by elucidating the Mg2+-sensitive DCT transcriptome, new candidate players in renal Mg2+ homeostasis were identified. RNA samples were isolated from PV-eGFP-positive tubules from mice fed on a low (L-samples) or high (H-samples) magnesium diet. Littermate H and L samples were labeled and put on mouse microarrays together. Two of the four sample sets were analyzed in dye-swap to compensate for dye-biases.
2013-12-13 | E-GEOD-40208 | biostudies-arrayexpress
Project description:To compare the transcriptional profile in renal tubules conditional deletion of Cpt1a, to floxed littermate controls.
2024-03-01 | GSE246150 | GEO
Project description:Fibrotic diseases have significant health impact and have been associated with differentiation of the resident fibroblasts into myofibroblasts. In particular, stiffened extracellular matrix and TGF-β1 in fibrotic lesions have been shown to promote pathogenic myofibroblast activation and progression of fibrosis in various tissues. To better understand the roles of mechanical and chemical cues on myofibroblast differentiation and how they may crosstalk, we cultured primary valvular interstitial cells (VICs) isolated from porcine aortic valves and studied how traditional TCPS culture, which presents a non-physiologically stiff environment, and TGF-β1 affect native VIC phenotypes. We carried out gene expression profiling using porcine genome microarrays from Affymetrix and found that traditional TCPS culture induces major changes in gene expression of native VICs, rendering these cells more activated and similar to cells treated with TGF-β1. We also monitored time-dependent effects induced by TGF-β1 by examining gene expression changes induced by TGF-β1 at 8 hours and 24 hours. Porcine aortic VICs were isolated and cultured with or without TGF-β1 treatment for RNA extraction and hybridization on Affymetrix microarrays. We included 3 biological replicates for each condition. P0 VICs were freshly isolated cells which had not been cultured. P2 VICs were cells that had been passaged 2 times and cultured on plastic plates in low serum media. Some of the P2 VICs were treated with TGF-β1 at 5ng/ml for 8 hours or 24 hours. All the control and TGF-β1-treated conditions were collected at the same time on day 3 of culture.
2013-09-02 | E-GEOD-48839 | biostudies-arrayexpress
Project description:The distal convoluted tubule (DCT) plays a key role in the fine-tuning of renal Mg2+ reabsorption. In recent years, hereditary magnesium (Mg2+) transport disorders have helped to identify important players in DCT Mg2+ homeostasis. Here, we report the Mg2+-sensitive transcriptional expression of the DCT transcriptome using gene expression microarray analysis. Mice expressing eGFP under a DCT-specific promoter were subjected to Mg2+-deficient or Mg2+-enriched diets. Subsequently, the Complex Object Parametric Analyzer and Sorter (COPAS) allowed isolation of eGFP-positive DCT cells. RNA extracts were subjected to pair-wise microarray analysis, high vs. low Mg2+. Of all genes in the genome, 46 were shown to be differentially expressed with a minimal fold-change of 2. Several known magnesiotropic genes, such as Trpm6 and Parvalbumin, were upregulated in the low Mg2+ fraction. Moreover, new genes were identified that are potentially involved in renal Mg2+ homeostasis. To confirm that the selected candidate genes are regulated by dietary Mg2+ availability, the expression levels of Slc41a3, Pcbd1, Tbc1d4 and Umod were determined by RT-PCR analysis. Indeed, all four genes were shown to be significantly upregulated in mice fed the Mg2+-deficient diet. In conclusion, by elucidating the Mg2+-sensitive DCT transcriptome, new candidate players in renal Mg2+ homeostasis were identified.
2013-12-13 | GSE40208 | GEO
Project description:Background: Increased Galectin 3-binding protein (Lgals3bp) serum levels have been used to assess hepatic fibrosis stages and the severity of hepatocellular carcinoma (HCC). Considering the crucial role of transforming growth factor-β1 (TGF-β1) in the emergence of these diseases, the present study tested the hypothesis that Lgals3bp regulates the TGF-β1 signaling pathway. Methods: The expression levels of Lgals3bp and TGF-β1 were analyzed in patients with non-alcoholic steatohepatitis (NASH) and HCC. Multiple omics techniques, such as RNA-sequencing, transposase-accessible chromatin-sequencing assay, and liquid chromatography-tandem mass spectrometry proteomics, were used to identify the regulatory mechanisms for the Lgals3bp-TGF-β1 axis. Moreover, the effects of altered TGF-β1 signaling in chronic inflammatory conditions were investigated in conditional Lgals3bp-knockin and Lgals3bp-knockout mice. Results: In patients with NASH and HCC, the levels of Lgals3bp and TGF-β1 exhibited positive correlations. Stimulation of Lgals3bp by the inflammatory cytokine interferon α in HCC cells or ectopic overexpression of Lgals3bp in hepatocytes promoted the expression levels of TGFB1. Aggravated fibrosis was observed in the livers of hepatocyte-specific Lgals3bp knock-in mice, with increased TGF-β1 levels. Lgals3bp directly bound to and assembled integrin αV, an integral mediator required for releasing active TGF-β1 from extracellular latent complex with the rearranged F-actin cytoskeleton. The released TGF-β1 activated JunB transcription factor, which in turn promoted the TGF-β1 positive feedback loop. Lgals3bp deletion in the hepatocytes downregulated TGF-β1 signaling and CCl4 induced fibrosis. Finally, Lgals3bp depletion hindered hepatocarcinogenesis by limiting the availability of fibrogenic TGF-β1. Conclusion: Lgals3bp plays a crucial role in hepatic fibrosis and carcinogenesis by controlling the TGF-β1 signaling pathway, making it a promising therapeutic target in TGF-β1-related diseases.
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