EP300 promotes renal tubular epithelial cell fibrosis by accelerating HIF2α in diabetic nephropathy
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ABSTRACT:
PROVIDER: PRJNA802187 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR17833957_1.fastq.gz | Fastqsanger.gz | |||
| SRR17833957_2.fastq.gz | Fastqsanger.gz | |||
| SRR17833958_1.fastq.gz | Fastqsanger.gz | |||
| SRR17833958_2.fastq.gz | Fastqsanger.gz |
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Project description:The target gene of EP300 action was detected in human renal tubular epithelial cells
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Project description:Diabetic nephropathy is considered one of the most common microvascular complications of diabetes and the pathophysiology involves multiple factors. Progressive diabetic nephropathy is believed to be related to the structure and function of the tubular epithelial cells in the kidney. However, the role of lysine acetylation in lesions of the renal tubular epithelial cells arising from hyperglycemia is poorly understood. Consequently, in this study, we cultured mouse renal tubular epithelial cells in vitro under high glucose conditions and analyzed the acetylation levels of proteins by liquid chromatography-high-resolution mass spectrometry. We identified 48 upregulated proteins and downregulated 86 proteins. In addition, we identified 113 sites with higher acetylation levels and 374 sites with lower acetylation levels. Subcellular localization analysis showed that the majority of the acetylated proteins were located in the mitochondria (43.17%), nucleus (28.57%) and cytoplasm (16.19%). Enrichment analysis indicated that these acetylated proteins are primarily associated with oxidative phosphorylation, the citrate cycle (TCA cycle), metabolic pathways and carbon metabolism. In addition, we used the MCODE plug-in and the cytoHubba plug-in in Cytoscape software to analyze the PPI network and displayed the first four most compact MOCDEs and the top 10 hub genes from the differentially expressed proteins between global and acetylated proteomes. Finally, we extracted 37 conserved motifs from 4915 acetylated peptides. Collectively, this comprehensive analysis of the proteome reveals novel insights into the role of lysine acetylation in tubular epithelial cells and may make a valuable contribution towards the identification of the pathological mechanisms of diabetic nephropathy.
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Project description:Using a combination of single-cell RNAseq methods and murine pulmonary hypertension models, we show HIF2α overexpressing pericytes’ transformation into SMC-like cells, confirming HIF2α as a major molecular regulator in hypoxia-induced pulmonary hypertension (PH) and vascular remodeling. We demonstrate that HIF2α overexpression in pericyte-dominant transgenic mice exacerbates PH and right ventricular hypertrophy (RVH), whereas disruption of HIF2α expression attenuates the development of PH.
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Project description:The study used a clinically relevant mouse model of chronic aristolochic acid nephropathy (AAN) to investigate the responses of proximal tubular cells during kidney fibrosis by single-nucleus RNA sequencing. The experiment involved 4 mice with AAN induced chronic renal fibrosis and 4 naive controls.
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Project description:Background: in clear cell renal cell carcinoma (ccRCC), 80% of cases have biallelic inactivation of VHL gene, leading to constitutive activation of both HIF1α and HIF2α. As HIF2α is the driver of the disease promoting tumour growth and metastasis, drugs targeting HIF2α have been developed. However, resistance is common, therefore new therapies are needed. Methods: we generated the 786-0 HIF2α knockout (KO) cell line and assessed the HIF2α antagonist PT2385 in several steps of tumour development. RNA sequencing was performed to identify genes differentially expressed between them and a drug screening was used to identify drugs with differential effects on HIF2α-expressing and KO cells. Results: HIF2α KO promoted cell migration, reduced proliferation and clonogenicity, as well as metastasis, whereas PT2385 treatment only inhibited tumour cell invasion. There was a large set of co-ordinately regulated genes, but HIF2α KO cells also had up-regulation of genes related to EMT and downregulation of genes involving cell migration and extracellular matrix. The HIF2α KO increased sensitivity to statins, while PT2385 had no effect. Conclusions: this study shows new pathways that could be targeted combined with PT2385 to enhance its therapeutic effects and delay resistance.
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Project description:The occurrence of a spontaneous nephropathy in laboratory mice, characterized by tubular degeneration and intranuclear inclusions, has puzzled pathologists for over four decades. While the condition takes a more severe course in immunodeficient animals suggesting an infectious cause, its etiology has remained elusive. Using an unbiased metagenomics approach, we have identified the causative agent as a novel virus, mouse kidney parvovirus (MKPV), belonging to a divergent and unclassified genus of the Parvoviridae. MKPV was found to be present in animal facilities in Australia and North America, is transmitted via the orofecal route and is controlled by the adaptive immune system. Detailed analysis of the clinical course and histopathologic features demonstrated a stepwise progression of pathology ranging from sporadic tubular inclusions to extensive tubular degeneration and interstitial fibrosis culminating in renal failure. In summary, we identify a novel, widely distributed pathogen in laboratory mice causing significant impact on the interpretation and outcome of biomedical research based on mouse models. Additionally, we establish MKPV-induced nephropathy as a new tool for elucidating the mechanisms of tubulointerstitial fibrosis that shares molecular features with chronic kidney disease in humans.
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Project description:Proteinuria is the most important predictor of outcome in glomerulonephritis and experimental data suggest that the tubular cell response to proteinuria is an important determinant of progressive fibrosis in the kidney. However, it is unclear whether proteinuria is a marker of disease severity or has a direct effect on tubular cells in the kidneys of patients with glomerulonephritis. Accordingly we studied an in vitro model of proteinuria, and identified 231 albumin-regulated genes differentially expressed by primary human kidney tubular epithelial cells exposed to albumin. We translated these findings to human disease by studying mRNA levels of these genes in the tubulo-interstitial compartment of kidney biopsies from patients with IgA nephropathy using microarrays. Biopsies from patients with IgAN (n=25) could be distinguished from those of control subjects (n=6) based solely upon the expression of these 231 albumin-regulated genes. The expression of an 11-transcript subset related to the degree of proteinuria, and this 11-mRNA subset was also sufficient to distinguish biopsies of subjects with IgAN from control biopsies. We tested if these findings could be extrapolated to other proteinuric diseases beyond IgAN and found that the all forms of primary glomerulonephritis (n=33) can be distinguished from controls (n=21) based solely on the expression levels of these 11 genes derived from our in vitro proteinuria model. Pathway analysis suggests common regulatory elements shared by these 11 transcripts. In conclusion, we have identified an albumin-regulated 11-gene signature shared between all forms of primary glomerulonephritis. Our findings support the hypothesis that albuminuria may directly promote injury in the tubulo-interstitial compartment of the kidney in patients with glomerulonephritis. We used microarrays to analyze the transcriptome of microdissected renal biopsies from patients with IgA nephropathy (IgAN) RNA from tubulointerstitial compartments was extracted and processed for hybridization on Affymetrix HG-U133A microarrays.
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