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Tight Junction Claudins-associated vascular heterogeneity determines organotypic metastasis

ABSTRACT: To identify the underlying mechanisms associated with lung and kidney fibrosis inducing lung metastasis, we evaluated global transcriptomic changes in healthy lung, fibrotic lung fibrosis, and lung from mice with kidney fibrosis. Results provide information on the vascular remodeling of the lungs with organ fibrosis. Lung fibrosis is induced with intratracheal bleomycin administration. Kidney fibrosis is induced by unilateral ureter obstruction (UUO).

ORGANISM(S): Mus musculus

PROVIDER: GSE199178 | GEO | 2024/04/19

REPOSITORIES: GEO

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Genome-wide analysis of gene expression in normal and fibrotic mouse kidneys and normal and fibrotic mouse lungs

Project description:In this study, adult virgin female BALB/C mice were kidney and lungs were harvested for RNA extraction (healthy kidney and lung). Adult virgin female BALB/C mice were subjected to unilateral ureter obstruction (UUO) to induce kidney fibrosis and the fibrotic kidney was harvested for RNA extraction. Adult virgin female BALB/C mice were subjected to intratracheal administration of bleomycine to induce lung fibrosis and the fibrotic lungs was harvested for RNA extraction.

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Project description:Cellular senescence is associated with the progression of chronic kidney disease (CKD), and accelerated tubular cell senescence promotes the pathogenesis of renal fibrosis. We established three animal models related to Chronic Kidney Disease, including aristolochic acid nephropathy (AAN), bilateral ischemia/reperfusion injury (BIRI) and unilateral ureter obstruction (UUO). By RNA sequencing analysis in AAN, BIRI and UUO mice, we observed significant changes of senescence and fibrosis related genes.

2024-02-03 | GSE254440 | GEO

PFKFB3-mediated glycolysis boosts fibroblast activation and subsequent kidney fibrosis

Project description:<p>Renal fibrosis, a hallmark of chronic kidney diseases, is driven by the activation of renal fibroblasts. Recent studies have highlighted the role of glycolysis in this process. Nevertheless, one critical glycolytic activator, 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3), remains unexplored in renal fibrosis. Upon reanalyzing the single-cell sequencing data from Dr. Humphreys' lab, we noticed an upregulation of glycolysis, gluconeogenesis, and TGFβ signaling pathway in myofibroblasts from fibrotic kidneys after unilateral ureter obstruction (UUO) or kidney ischemia/reperfusion. Furthermore, our experiments showed significant induction of PFKFB3 in mouse kidneys following UUO or kidney ischemia/reperfusion. To delve deeper into the role of PFKFB3, we generated mice with Pfkfb3 deficiency specifically in myofibroblasts (Pfkfb3f/fPostnMCM). Following UUO or kidney ischemia/reperfusion, a substantial decrease of fibrosis in injured kidneys of Pfkfb3f/fPostnMCM mice was identified compared to their wild-type littermates. Additionally, in cultured renal fibroblast NRK-49F cells, PFKFB3 was elevated upon exposure to TGFβ1, accompanied by the increase of α-SMA and fibronectin. Notably, this upregulation was significantly diminished with PFKFB3 knockdown, correlated with a glycolysis suppression. Mechanistically, the glycolytic metabolite lactate promoted the fibrotic activation of NRK-49F. In conclusion, our study demonstrates the critical role of PFKFB3 in driving fibroblast activation and subsequent renal fibrosis.</p>

2024-03-12 | MTBLS8281 | MetaboLights

Mouse kidney tissue: UUO-METTL3fl/fl, cre T vs. UUO-METTL3fl/fl, wt

Project description:The mRNA transcriptome and m6A methylation microarray profiling of mouse kidney tissues. Kidney tissues from the sham-operated group and unilateral ureteral ligation/obstruction (UUO) kidney tissues were compared. The latter were mainly fibrotic kidney tissues. The goal was to identify the effect of the renal fibrosis on gene expression and corresponding m6A modifications during kidney fibrosis.

2023-08-09 | GSE226506 | GEO

Mouse kidney tissue: Control vs. UUO

2023-08-09 | GSE226505 | GEO

Exploring new pathways involved during experimental renal fibrogenesis in the Unilateral Ureteral Obstruction

Project description:Chronic kidney disease (CKD) is a burden for Public Health and concerns millions of individuals worldwide. Independently of the cause, CKD is secondary to the replacement of functional renal tissue by extra-cellular matrix proteins (i.e fibrosis) that progressively impairs kidney function. The pathophysiological pathways that control the development of renal fibrosis are common to most of the nephropathies involving native kidneys or kidney grafts. Unfortunately, very few treatments are available to stop renal fibrosis and most of the therapeutic strategies are often barely able to slow down the progression of fibrogenesis in native kidneys. Therefore, it is mandatory to discover new therapeutic pathways to stop renal fibrosis. Our objective is to study new pathways involved in renal fibrosis. We thus decided to use the model of Unilateral Ureteral renal Obstruction in mice, a fast and reproducible experimental model of renal fibrosis. We studied renal fibrosis using experimental model of ureteral unilateral obstruction in mice, which was performed by complete ligation of the left ureter. The control lateral right kidney served as internal control.

2013-02-10 | E-GEOD-38117 | biostudies-arrayexpress

Spiny mice (Acomys cahirinus) activate unique transcriptional programs after severe kidney injuries and regenerate organ function without fibrosis

Project description:Purpose: The goal of this study was to characterize the kidney transcriptome of Mus musculus and Acomys cahirinus after unilateral ureteral obstruction (UUO) kidney injury. Methods: Kidney mRNA-seq profiles of 10 week old mouse and spiny mouse were generated at 2 day and 5 days after unilateral ureteral obstruction injury in triplicate, using Illumina NovaSeq 6000. The sequence reads that passed quality filters were analyzed at the transcript isoform level with Salmon, edgeR and a limma-voom pipeline in R. Results: For both Mus musculus and Acomys cahirinus kidneys, we mapped about 50 million sequence reads per sample to the mouse transcriptome and identified 20580 transcripts in kidneys of Mus musculus and 54075 transcripts in the kidneys of Acomys cahirinus. Using 1.5 fold change and FDR < 0.05, number of transcripts that are significantly different between Mus musculus samples: 3915 between normal and day 2 after UUO, 5365 between normal and day 5 after UUO. For Acomys cahirinus: 1765 between normal and day 2 after UUO, 2499 between normal and day 5 after UUO. Conclusions: Our study demonstrate there were many conserved responses to kidney injury between M. musculus and A. cahirinus despite the divergent outcomes for kidney fibrosis.

2021-09-13 | GSE168876 | GEO

Axl targeting in experimental unilateral ureteral obstruction

Project description:We investigated if Axl receptor tyrosine kinase was up-regulated in unilateral ureteral obstruction (UUO) and if blocking of Axl by a small molecule called BGB324 (also called Bemcentinib) reduces fibrosis development in the ligated kidney as compared to treatment with its vehicle alone.

2019-03-01 | GSE123674 | GEO

Profiling of miRNA expression in mouse SHAM kidneys

Project description:Profiling of miRNA expression in mouse SHAM kidneys 9–12 weeks old male C57BL/6 mice were purchased from Charles River. Mice underwent anesthesia by intraperitoneal injection of pentobarbital (50 mg/kg body weight) and were subjected to Unilateral Ureteral Obstruction (UUO). After standard laparotomy, the left proximal ureter was exposed and ligated with 4-0 silk at two points. The sham operation consisted of a similar identification of the left ureter without ligation. Treated (S numbers) and non-treated (C numbers) mice miRNA expressions were then compared.

2013-08-31 | E-GEOD-39831 | biostudies-arrayexpress

Sprr2f protects against renal injury by decreasing the level of reactive oxygen species in female mice

Project description:Renal injury leads to chronic kidney disease for which women are not only more likely to be diagnosed with than men but also have poorer outcomes as well. We have previously shown that expression of Sprr2f, a member of the Small Proline Rich Region (Sprr) gene family, is increased several hundred fold after renal injury using a unilateral ureter obstruction (UUO) mouse model. To better understand the role of Sprr2f in renal injury, we generated a Sprr2f knockout (Sprr2f-KO) mouse model using CRISPR-Cas9 technology. To identify genes that are differentially expressed in Sprrf2f-KO mice after UUO, we performed gene expression profiling by RNA-seq on kidney tissues harvested from Sprr2f-KO mice at time 0 (n=4) and after 5 days (n=3), a time known to show dramatic changes in gene expression. Compared to day 0, expression levels of 162 genes were significantly changes with 121 up-regulated and 41 down-regulated 5 days after obstruction. Enrichment analysis using PANTHER Classification System identified 12 and 2 pathways enriched in genes that are upregulated or downregulated after UUO respectively. Eleven out of the 12 pathways enriched in the genes upregulated after UUO are related to metabolism such as drug metabolic process, consistent with a profound role of kidney as a major clearance organ of the body responsible for the elimination of many xenobiotics and prescription drugs. Interestingly, the only pathway not related to metabolism enriched in genes upregulated by UUO is oxidation-reduction, suggesting a potential role of oxidative stress in renal damage after UUO in Sprr2-KO animals. This phenotype is not observed in Sprr2f-WT animals after UUO in our previous gene expression profiling study, suggesting that Sprr2f function is sufficient to protect kidney from oxidative damage after UUO in Sprr2f-WT animals.

2020-10-13 | GSE153010 | GEO

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