Electrolyte and Metabolite Composition of Cystic Fluid from a rat model of ARPKD
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ABSTRACT:
ORGANISM(S): Rattus norvegicus
PROVIDER: GSE261500 | GEO | 2024/03/30
REPOSITORIES: GEO
Similar Datasets
Project description:Autosomal recessive polycystic kidney disease (ARPKD) is caused by mutations in the PKHD1 gene in both humans and the orthologous PCK rat model. Although ARPKD results solely from PKHD1 mutations, the disease onset and severity are highly variable, indicating that other unknown genetic risk factor(s) modify ARPKD-associated phenotypes. To identify genetic modifiers of ARPKD severity, we created two genetically distinct Pkhd1 congenic rat strains on the Fawn-Hooded Hypertensive (FHH) and the Dahl S (SS) rat backgrounds (denoted FHH.Pkhd1 and SS.Pkhd1, respectively) that harbor the PCK-derived Pkhd1 allele. The FHH.Pkhd1 and SS.Pkhd1 strains had lower renal cyst formation at 30 days-of-age (5±2% and 8±2% cystic, respectively; P<0.001) compared to the PCK kidneys (26±4% cystic), which coincided with significantly reduced kidney weights in the FHH.Pkhd1 and SS.Pkhd1. Liver cyst formation and liver weight did not differ between PCK, FHH.Pkhd1, and SS.Pkhd1. These data indicated that the PCK genome harbors genetic modifier(s) of ARPKD severity that are not present in the FHH and SS genomes. Using high density SNP array genotyping and microarray expression analysis, we identified 50 potential modifiers of ARPKD severity in the PCK rat. Of these candidates, a damaging nonsynonymous variant in Nphp4 stood out as the most likely candidate based on variant segregation, protein modeling, network analysis, and gene ontology. Nphp4 is widely associated with the autosomal recessive cilliopathy and nephronopthisis, but had not been previously implicated in the molecular or cellular pathophysiology of ARPKD. Collectively, these data provide genetic evidence of disease modifier(s) in the PCK model of ARPKD and prioritized multiple candidates, including NPHP4, for further investigation in ARPKD pathogenesis. In this study, we used microarray to analyze transcript expression in the kidneys of 30 day old SD (n=4), PCK (n=4), FHH (n=4), FHH.Pkhd1 (n=4), SS (n=4), and SS.Pkhd1 (n=4). Samples were pooled and the pooled samples were run in triplicate. The 30 day timepoint was chosen because the differences in renal cyst formation between PCK, FHH.Pkhd1, and SS.Pkhd1 were greatest at this timepoint. To account for genetic strain differences that do not contribute to ARPKD severity, gene expression of each cystic rat strain was compared to its parental strain.
2015-06-06 | E-GEOD-58229 | biostudies-arrayexpress
Project description:Autosomal recessive polycystic kidney disease (ARPKD) is caused by mutations in the PKHD1 gene in both humans and the orthologous PCK rat model. Although ARPKD results solely from PKHD1 mutations, the disease onset and severity are highly variable, indicating that other unknown genetic risk factor(s) modify ARPKD-associated phenotypes. To identify genetic modifiers of ARPKD severity, we created two genetically distinct Pkhd1 congenic rat strains on the Fawn-Hooded Hypertensive (FHH) and the Dahl S (SS) rat backgrounds (denoted FHH.Pkhd1 and SS.Pkhd1, respectively) that harbor the PCK-derived Pkhd1 allele. The FHH.Pkhd1 and SS.Pkhd1 strains had lower renal cyst formation at 30 days-of-age (5±2% and 8±2% cystic, respectively; P<0.001) compared to the PCK kidneys (26±4% cystic), which coincided with significantly reduced kidney weights in the FHH.Pkhd1 and SS.Pkhd1. Liver cyst formation and liver weight did not differ between PCK, FHH.Pkhd1, and SS.Pkhd1. These data indicated that the PCK genome harbors genetic modifier(s) of ARPKD severity that are not present in the FHH and SS genomes. Using high density SNP array genotyping and microarray expression analysis, we identified 50 potential modifiers of ARPKD severity in the PCK rat. Of these candidates, a damaging nonsynonymous variant in Nphp4 stood out as the most likely candidate based on variant segregation, protein modeling, network analysis, and gene ontology. Nphp4 is widely associated with the autosomal recessive cilliopathy and nephronopthisis, but had not been previously implicated in the molecular or cellular pathophysiology of ARPKD. Collectively, these data provide genetic evidence of disease modifier(s) in the PCK model of ARPKD and prioritized multiple candidates, including NPHP4, for further investigation in ARPKD pathogenesis.
2015-06-06 | GSE58229 | GEO
Project description:Electrolyte and Metabolite Composition of Cystic Fluid from a rat model of ARPKD
| PRJNA1087327 | ENA
Project description:Autosomal Recessive Polycystic Kidney Disease (ARPKD) is a rare paediatric disease primarily caused by mutations in the gene PKHD1. ARPKD presents with considerably clinical variability which is linked to the type of PKHD1 mutation but not position. Animal models of Polycystic Kidney Disease (PKD) suggest there is a complex genetic landscape with genetic modifiers as a potential cause of disease variability. Transcriptomic analysis identified a considerable number of genes linked to cellular metabolism and development. Amongst these genes were those linked to WNT signalling. Two individuals in this cohort had the same mutations in PKHD1 but different rates of kidney disease progression. Amongst the transcriptomic differences of these two individuals were differences in the expression changes of WNT genes.
2024-09-06 | GSE242476 | GEO
Project description:Polycystic Kidney Disease is characterized by the formation of large fluid-filled cysts that eventually destroy the renal parenchyma leading to end-stage renal failure. Although remarkable progress has been made in understanding the pathologic mechanism of the disease, the precise orchestration of the early events leading to cyst formation is still unclear. Abnormal cellular proliferation was traditionally considered to be one of the primary irregularities leading to cyst initiation and growth. Consequently, many therapeutic interventions have focused on targeting this abnormal proliferation, and some have even progressed to clinical trials. However, the role of proliferation in cyst development was primarily examined at stages where cysts are already visible in the kidneys and therefore at later stages of disease development. In this study we focused on the cystic phenotype since birth in an attempt to clarify the temporal contribution of cellular proliferation in cyst development. Using a PKD2 transgenic rat model (PKD2 (1-703)) of different ages (0-60 days after birth) we performed gene expression profiling and phenotype analysis by measuring various kidney parameters. Phenotype analysis demonstrated that renal cysts appear immediately after birth in the PKD2 transgenic rat model (PKD2 (1-703)). On the other hand, abnormal proliferation occurs at later stages of the disease as identified by gene expression profiling. Interestingly, other pathways appear to be deregulated at early stages of the disease in this PKD model. Our data suggest that cystogenesis precedes deregulation of proliferation-related pathways, suggesting that proliferation abnormalities may contribute in cyst growth rather than cyst formation. In this study we focused on the cystic phenotype since birth in an attempt to clarify the temporal contribution of cellular proliferation in cyst development. Using a PKD2 transgenic rat model (PKD2 (1-703)) of different ages (0,6 and 24 days after birth) we performed gene expression profiling of kidney cells.
2010-01-31 | E-GEOD-19460 | biostudies-arrayexpress
Project description:To facilitate the search for genetic modifiers that modulate ARPKD disease progression and severity, we sought to generate a congenic rat model that carries the PCK Pkhd1 mutation but is resistant to the development of ARPKD. We transferred the Pkhd1 mutation from the PCK rat onto the genetic background of the FHH (Fawn-Hooded Hypertensive) rat. This newly developed strain, called FHH.Pkhd1, showed significant amelioration of renal disease, and delayed onset of biliary abnormalities. To initiate the exploration for genes and pathways that modulate susceptibility to renal cystogenesis, we investigated transcriptional changes in kidneys from PCK, SD, FHH and FHH.Pkhd1 rats by microarray analysis.
2012-01-01 | GSE33056 | GEO
Project description:To facilitate the search for genetic modifiers that modulate ARPKD disease progression and severity, we sought to generate a congenic rat model that carries the PCK Pkhd1 mutation but is resistant to the development of ARPKD. We transferred the Pkhd1 mutation from the PCK rat onto the genetic background of the FHH (Fawn-Hooded Hypertensive) rat. This newly developed strain, called FHH.Pkhd1, showed significant amelioration of renal disease, and delayed onset of biliary abnormalities. To initiate the exploration for genes and pathways that modulate susceptibility to renal cystogenesis, we investigated transcriptional changes in kidneys from PCK, SD, FHH and FHH.Pkhd1 rats by microarray analysis. Both kidneys were harvested from 6 animals for each strain; SD, FHH, PCK, FHH.Pkhd1 (FHH.PCK-(D9Rat35-D9Rat70)/Mcwi, RGD ID 5147594) at 30 days of age. The kidneys were bisected and stored in RNAlater at 4C for 24hrs. RNA was extracted using the Trizol (Invitrogen) method according to manufacturer’s instructions. RNA from each strain was pooled together, reverse transcribed, and hybridized to three Affymetrix Rat 230 arrays (Affymetrix).
2012-01-01 | E-GEOD-33056 | biostudies-arrayexpress
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: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:Autosomal recessive polycystic kidney disease is a severe, monogenetically inherited kidney and liver disease and PCK rats carrying the orthologous mutant gene serve as a model of human disease. We combined selective MALDI imaging of sulfated kidney lipids and Fisher discriminant analysis of imaging data sets for identification of candidate lipid markers of progressive disease in PCK rats. Our study highlights strong increases in lower mass lipids as main classifiers of cystic disease. Structure determination by high resolution mass spectrometry identifies these altered lipids as taurine-conjugated bile acids. Beside increased levels of serum-cholesterol these sulfated lipids are selectively elevated in the PCK rat model but not in models of related hepatorenal fibrocystic diseases suggesting that they be molecular markers of the disease. Genome-scale gene expression profiling of PCK and SD livers as control was performed to attempt elucidation of some of the underlying mechanisms leading to increases of cholesterol and taurine-conjugated bile acids in the PCK rat. Several pathways were found to be changed in cystic livers with up regulation or down regulation of important gene sets. Enhanced expression of steroid biosynthesis genes might result in the observed increased levels of cholesterol. In contrast, primary bile acid biosynthesis was found to be down regulated in diseased livers. These findings might be explained by compensatory mechanisms of liver metabolism to reduce toxic levels of accumulated bile acids. Snap-frozen liver tissue of 10 week old rats were subjected for RNA extraction and hybridization on Affymetrix microarrays to perform genome-scale gene expression profiling of n = 6 diseased PCK and n = 6 Sprague Dawley rat livers as control.
2013-12-01 | E-GEOD-48357 | biostudies-arrayexpress