Effect of global Caspase-1 (Casp1) knockout (KO) on kidney gene expression in an orthologous mouse model of polycystic kidney disease (PKD)
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ORGANISM(S): Mus musculus
PROVIDER: GSE207957 | GEO | 2022/09/30
REPOSITORIES: GEO
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Project description:Polycystic Kidney Disease (PKD) is a genetic disease of the kidney characterized by the gradual replacement of normal kidney parenchyma by fluid-filled cysts and fibrotic tissue. Autosomal Dominant Polycystic Kidney Disease (ADPKD) is caused by mutations in the PKD1 or PKD2 gene. Here we present an RNASeq experiment designed to investigate the effect of a kidney specific and Tamoxifen inducible knockout of the Pkd1 gene in mice. The Pkd1cko mice were harvested at different time points 2-weeks, 3-weeks, 5-weeks, 10.5-weeks, 11-weeks and 15-weeks after gene inactivation.
2019-12-24 | E-MTAB-8086 | biostudies-arrayexpress
Project description:Background The major gene mutated in autosomal dominant polycystic kidney disease was first identified over 20 years ago, yet its function remains poorly understood. We have used a systems-based approach to examine the effects of acquired loss of Pkd1 in adult mouse kidney as it transitions from normal to cystic state. Methods We performed transcriptional profiling of a large set of male and female kidneys, along with metabolomics and lipidomics analyses of a subset of male kidneys. We also assessed the effects of a modest diet change on cyst progression in young cystic mice. Fatty acid oxidation and glycolytic rates were measured in five control and mutant pairs of epithelial cells. Results We find that females have a significantly 46 less severe kidney phenotype and correlate this protection with differences in lipid metabolism. We show that sex is a major determinant of the transcriptional profile of mouse kidneys and that some of this difference is due to genes involved in lipid metabolism. Pkd1 mutant mice have transcriptional profiles consistent with changes in lipid metabolism and distinct metabolite and complex lipid profiles in kidneys. We also show that cells lacking Pkd1 have an intrinsic fatty acid oxidation defect and that manipulation of lipid content of mouse chow modifies cystic disease. Interpretation Our results suggest PKD could be a disease of altered cellular metabolism.
2016-01-26 | GSE72554 | GEO
Project description:Effect of global Caspase-1 (Casp1) knockout (KO) on kidney gene expression in an orthologous mouse model of polycystic kidney disease (PKD)
| PRJNA857739 | ENA
Project description:Polycystic Kidney Disease (PKD) is a genetic disease of the kidney characterized by the gradual replacement of normal kidney parenchyma by fluid-filled cysts and fibrotic tissue. Autosomal Dominant Polycystic Kidney Disease (ADPKD) is caused by mutations in the PKD1 or PKD2 gene. Here we present an RNASeq experiment designed to investigate the effect of a kidney specific and Tamoxifen inducible knockout of the Pkd1 gene in mice. 7 mice were grouped into two groups, 4 Tamoxifen treated mice which develop an adult onset Polycystic Kidney Disease phenotype and 3 untreated mice which have WT phenotype.
2016-06-01 | E-MTAB-4086 | biostudies-arrayexpress
Project description:Background: Autosomal dominant polycystic kidney disease (ADPKD) affects more than 12 million people worldwide. Mutations in PKD1 and PKD2 cause cyst formation through unknown mechanisms. To unravel the pathogenic mechanisms in ADPKD, multiple studies have investigated transcriptional mis-regulation in cystic kidneys from patients and mouse models, and numerous dysregulated genes and pathways have been described. Yet, the concordance between studies has been rather limited. Furthermore, the cellular and genetic diversity in cystic kidneys has hampered the identification of mis-expressed genes in kidney epithelial cells with homozygous PKD mutations, which are critical to identify polycystin-dependent pathways. Methods: Autosomal dominant polycystic kidney disease (ADPKD) affects more than 12 million people worldwide. Mutations in PKD1 and PKD2 cause cyst formation through unknown mechanisms. To unravel the pathogenic mechanisms in ADPKD, multiple studies have investigated transcriptional mis-regulation in cystic kidneys from patients and mouse models, and numerous dysregulated genes and pathways have been described. Yet, the concordance between studies has been rather limited. Furthermore, the cellular and genetic diversity in cystic kidneys has hampered the identification of mis-expressed genes in kidney epithelial cells with homozygous PKD mutations, which are critical to identify polycystin-dependent pathways. Results: Autosomal dominant polycystic kidney disease (ADPKD) affects more than 12 million people worldwide. Mutations in PKD1 and PKD2 cause cyst formation through unknown mechanisms. To unravel the pathogenic mechanisms in ADPKD, multiple studies have investigated transcriptional mis-regulation in cystic kidneys from patients and mouse models, and numerous dysregulated genes and pathways have been described. Yet, the concordance between studies has been rather limited. Furthermore, the cellular and genetic diversity in cystic kidneys has hampered the identification of mis-expressed genes in kidney epithelial cells with homozygous PKD mutations, which are critical to identify polycystin-dependent pathways. Conclusions: Autosomal dominant polycystic kidney disease (ADPKD) affects more than 12 million people worldwide. Mutations in PKD1 and PKD2 cause cyst formation through unknown mechanisms. To unravel the pathogenic mechanisms in ADPKD, multiple studies have investigated transcriptional mis-regulation in cystic kidneys from patients and mouse models, and numerous dysregulated genes and pathways have been described. Yet, the concordance between studies has been rather limited. Furthermore, the cellular and genetic diversity in cystic kidneys has hampered the identification of mis-expressed genes in kidney epithelial cells with homozygous PKD mutations, which are critical to identify polycystin-dependent pathways.
2021-07-15 | GSE179947 | GEO
Project description:Autosomal Dominant Polycystic Kidney Disease (ADPKD; MIM ID's 173900, 601313, 613095) is estimated to affect almost 1/1000 and is the most common genetic cause of end stage renal disease (Torres et al., 2007). While advances have been made in slowing the progression of some other forms of chronic kidney disease, standard treatments have not reduced the need for renal replacement therapy in ADPKD (Spithoven et al., 2014). Unfortunately, several experimental interventions also have recently failed to show significant benefit in slowing the rate of functional decline (Serra et al., 2010; Walz et al., 2010; Schrier et al., 2014; Torres et al., 2014), and the only positive study reported very modest effects (Torres et al., 2012). These findings suggest new treatment strategies are required. A central dogma of molecular genetics is that discovery of the causative genes will lead to identification of key pathways and potential targets for intervention. In the case of ADPKD, the two genes mutated in the disorder, PKD1 and PKD2, were identified almost 20 years ago and yet their functions remain poorly understood. The PKD1 gene product, polycystin-1 (PC1), encodes a large membrane protein that requires the PKD2 gene product, polycystin-2 (PC2), for its trafficking to the primary cilium where the two are thought to form a receptor channel complex (Kim et al., 2014; Cai et al., 2014). What the complex senses and what it signals remains controversial. The primary cilium has emerged as a key player in the pathogenesis of PKD as mutations in dozens of different genes that encode either essential ciliary components or factors in ciliary signaling pathways result in PKD. A recent report suggests that the relationship between the polycystin complex and ciliary signaling is complicated, however.While ablation of primary cilia by mutation of core ciliary components results in cysts, these same perturbations done in the setting of Pkd1 or Pkd2 inactivation results in significant attenuation of cystic disease (Ma et al., 2013). These data suggest that the polycystin complex provides a suppressive signal for a novel, cilia-dependent growth-promoting pathway that is independent of MAPK/ERK, mTOR, or cAMP pathways, three effector pathways previously implicated as major drivers of cyst growth. The identities of the growth-promoting and growth-inhibiting pathways remain unknown. We have taken a systems-based approach to study Pkd1 gene function. Building on our previous work identifying markedly different outcomes in animals with induced Pkd1 inactivation before or after P12 and correlating this susceptibility with metabolic status (Piontek et al., 2007; Menezes et al., 2012), we now show that female sex is partially protective in adult-induced Pkd1 inactivation, that sex differences in metabolic status may account for this effect, and that cells lacking Pkd1 have abnormal fatty acid oxidation. Finally, manipulating diet in Pkd1 mouse models, we demonstrate a positive correlation between lipid content in mouse chow and cystic kidney disease severity. Our results therefore suggest that abnormal lipid metabolism is an intrinsic component of PKD and an important modifier of disease progression.
2017-09-11 | ST000878 | MetabolomicsWorkbench
Project description:Gender has strong impact on kidney performance. Female gender tends to be renal protective. PKD/Mhm is rat model for human polycystic kidney disease (PKD) caused by a mutation in gene Anks6. PKD progresses faster in male rats compared with females. We used microarrays to detect gender-dependent gene expression in kidney of 36d old PKD/Mhm rats. Keywords: gender, genotype
2009-09-30 | GSE13065 | GEO
Project description:Background: Autosomal dominant polycystic kidney disease (PKD) is characterized by extensive cyst formation and progressive fibrosis. However, the molecular mechanisms whereby the loss/loss-of-function of polycystin 1 or 2 (PC1/2) provokes fibrosis are largely unknown. The small GTPase RhoA has been implicated in cystogenesis, while we have shown that the RhoA/cytoskeleton/myocardin-related transcription factor (MRTF) pathway is a key inducer of epithelium-induced fibrogenesis. Therefore, we hypothesized that MRTF 1) is activated by PC1/2 loss, and 2) plays a critical role in fibrogenic repogramming of the epithelium and the subsequent induction of fibrosis. Methods: PC1/2 loss was achieved by gene silencing in tubular cells (in vitro) and in PKD1 (RC/RC) and PKD2 (ws25/-) mice (in vivo). RhoA activation was measured by pull-down assays and immunofluorescence. MRTF localization (nuclear/cytosolic ratio, intensity) was quantified in large cell populations and in renal tissue using automated image analysis. PC1/PC2 loss-promoted, MRTF-dependent gene expression was followed by qPCR, RNAseq and RNAscope. MRTF-dependent paracrine effects were assessed by a bioassay. Results: Loss of PC1 or PC2 activated RhoA in vitro and in vivo, resulting in cytoskeletal remodelling and robust nuclear MRTF translocation, accompanied by increased MRTF expression. Nuclear translocation occurred predominantly in dilated tubules, while overexpression in the cyst-lining epithelium. A large cohort of PC1/PC2 downregulation-induced genes was MRTF-dependent, including cytoskeletal, integrin-related, and matricellular/fibrogenic proteins. Epithelial MRTF was necessary for paracrine priming of fibroblast-myofibroblast transition. Conclusion: The Rho/MRTF pathway is a critical novel mediator of PC1/2 loss-induced acquisition of the profibrotic epithelial phenotype and the ensuing fibrosis.
2024-05-01 | GSE252716 | GEO
Project description:Gender has strong impact on kidney performance. Female gender tends to be renal protective. PKD/Mhm is rat model for human polycystic kidney disease (PKD) caused by a mutation in gene Anks6. PKD progresses faster in male rats compared with females. We used microarrays to detect gender-dependent gene expression in kidney of 36d old PKD/Mhm rats. Experiment Overall Design: Gender-dependent gene expression was examined both in heterozygous PKD/Mhm rats affected with PKD and in their wild type littermates. Three microarrays were hybridized for each combination of gender and genotype.
2009-10-11 | E-GEOD-13065 | biostudies-arrayexpress
Project description:Initial cysts that are formed upon Pkd1 loss in mice impose persistent stress on surrounding tissue and trigger a cystic snowball effect, in which local aberrant PKD-related signaling increases the likelihood of new cyst formation, ultimately leading to accelerated disease progression. Although many pathways have been associated with PKD progression, the knowledge of early changes near initial cysts is limited. To perform an unbiased analysis of transcriptomic alterations in the cyst microenvironment, microdomains were collected from kidney sections of iKsp-Pkd1del mice with scattered Pkd1-deletion using Laser Capture Microdissection. These microdomains were defined as F4/80-low cystic, representing early alterations in the cyst microenvironment, F4/80-high cystic, with more advanced alterations, or non-cystic. RNA sequencing and differential gene expression analysis revealed 953 and 8088 dysregulated genes in the F4/80-low and F4/80-high cyst microenvironment, respectively, when compared to non-cystic microdomains. In the early cyst microenvironment, several injury-repair, growth, and tissue remodeling-related pathways were activated, accompanied by mild metabolic changes. In the more advanced F4/80-high microdomains, these pathways were potentiated and the metabolism was highly dysregulated. Upstream regulator analysis revealed a series of paracrine factors with increased activity in the early cyst microenvironment, including TNFSF12 and OSM. In line with the upstream regulator analysis, TWEAK and Oncostatin-M promoted cell proliferation and inflammatory gene expression in renal epithelial cells and fibroblasts in vitro. Collectively, our data provide an overview of molecular alterations that specifically occur in the cyst microenvironment and identify paracrine factors that may mediate early and advanced alterations in the cyst microenvironment.
2023-12-27 | GSE231304 | GEO