Salt-deficient diet exacerbates cystogenesis in ARPKD via epithelial sodium channel (ENaC)
Ontology highlight
ABSTRACT:
ORGANISM(S): Rattus norvegicus
PROVIDER: GSE131693 | GEO | 2019/05/24
REPOSITORIES: GEO
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Project description:BACKGROUND:Autosomal Recessive Polycystic Kidney Disease (ARPKD) is marked by cyst formation in the renal tubules, primarily in the collecting duct (CD) system, ultimately leading to end-stage renal disease. Patients with PKD are generally advised to restrict their dietary sodium intake. This study was aimed at testing the outcomes of dietary salt manipulation in ARPKD. METHODS:PCK/CrljCrlPkhd1pck/CRL (PCK) rats, a model of ARPKD, were fed a normal (0.4% NaCl; NS), high salt (4% NaCl; HS), and sodium-deficient (0.01% NaCl; SD) diets for 8 weeks. Immunohistochemistry, GFR measurements, balance studies, and molecular biology approaches were applied to evaluate the outcomes of the protocol. Renin-angiotensin-aldosterone system (RAAS) levels were assessed using LC-MS/MS, and renal miRNA profiles were studied. FINDINGS:Both HS and SD diets resulted in an increase in cystogenesis. However, SD diet caused extensive growth of cysts in the renal cortical area, and hypertrophy of the tissue; RAAS components were enhanced in the SD group. We observed a reduction in epithelial Na+ channel (ENaC) expression in the SD group, accompanied with mRNA level increase. miRNA assay revealed that renal miR-9a-5p level was augmented in the SD group; we showed that this miRNA decreases ENaC channel number in CD cells. INTERPRETATION:Our data demonstrate a mechanism of ARPKD progression during salt restriction that involves activity of ENaC. We further show that miR-9a-5p potentially implicated in this mechanism and that miR-9a-5p downregulates ENaC in cultured CD cells. Our findings open new therapeutic possibilities and highlight the importance of understanding salt reabsorption in ARPKD.
| S-EPMC6413684 | biostudies-other
Project description:Salt-deficient diet exacerbates cystogenesis in ARPKD via epithelial sodium channel (ENaC)
| PRJNA544464 | ENA
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:Polycystic Kidney Disease (PKD) is a devastating inherited kidney disease that is a major cause of kidney failure. Large fluid-filled cysts develop in the kidney and continually expand over time, damaging the surrounding tissue until renal replacement therapy is required. Because the development of cysts is the major feature of this disease, researchers have long sought to determine the composition of cystic fluid. To the best of our knowledge, no one has previously published the ion concentrations of cystic fluid from any PKD rodent models. The overall goal of this study was to characterize the cyst fluid composition of a rat model of ARPKD, the PCK rat. This model developed spontaneously from the Charles River Japan cesarean derived Sprague Dawley (Crj:CD/SD) strain and features a mutation in Pkhd1, the ortholog to the causative ARPKD gene in humans. In addition to analyzing cystic fluid, we complemented our metabolomics approach with transcriptomic analysis of male and female PCK rat kidney cortex tissue.
2024-03-30 | GSE261500 | GEO
Project description:Serum and glucocorticoid-induced kinase 1 (SGK1) activates the epithelial sodium channel (eNaC) in tubules. We examined renal SGK1 abundance in salt-adaptation and in salt-sensitive hypertension. Sprague-Dawley and Dahl salt-sensitive rats were placed on either 8% or 0.3% NaCl diets for 10 days. Plasma aldosterone levels were approximately 2.5-fold greater on 0.3% versus 8% NaCl diets in both rat strains. Both serum and glucocorticoid-induced kinase 1 transcript and protein abundance were less (P<0.01) in Sprague-Dawley rats and greater (P<0.01) in Dahl salt-sensitive rats on 8% versus 0.3% NaCl diets. The cDNA sequences of serum and glucocorticoid-induced kinase 1 in both strains of rat were the same. The present results provide evidence that the abundance of serum and glucocorticoid-induced kinase 1 in rat kidney may play a role in salt adaptation and the pathogenesis of hypertension and suggests that aldosterone is not the primary inducer of SGK1 in the Sprague-Dawley rat. Keywords = Rattus norvegicus, Sprague Dawley, Dahl SS/Jr, kidney, NaCl diet Keywords: other
2004-02-14 | GSE599 | GEO
Project description:Regulation of fin regeneration by a voltage-gated sodium channel
| PRJNA775662 | ENA
Project description:The voltage-gated sodium channel NaV1.7 plays a critical role in pain pathways. As well as action potential propagation, NaV1.7 regulates neurotransmitter release, integrates depolarizing inputs over long periods and regulates transcription. In order to better understand these functions, we generated an epitope-tagged NaV1.7 mouse that showed normal NaV1.7 channel activity and normal pain behavior. Analysis of NaV1.7 complexes affinity-purified under native conditions by mass spectrometry revealed 267 NaV1.7 associated proteins including known and novel interactors such as sodium channel β3 subunit (Scn3b) and collapsin response mediator protein (Crmp2). Selected NaV1.7 protein interactors, such as Crmp2, membrane-trafficking protein synapototagmin-2 (Syt2), G protein-regulated inducer of neurite outgrowth 1 (Gprin1), L-type amino acid transporter 1 (Lat1) and transmembrane P24 trafficking protein 10 (Tmed10) were validated using co-immunoprecipitation and functional assays. The information provided with this physiologically normal epitope-tagged mouse should provide useful insights into the downstream mechanisms associated with NaV1.7 channel function.
2018-01-15 | PXD005155 | Pride
Project description:As a histone deacetylase inhibitor, sodium butyrate and its derivative sodium phenylbutyrate involve in cellular events such as proliferation, differentiation, apoptosis and cell cycle control via reprogramming gene expression. However, the gene associated with the cell cycle control and molecular signaling triggering cell apopotosis and death are not well elucidated. Here, we treated A549 cells,a cell line belong to the non-small cells lung cancer,with high concentration of sodium butyrate or sodium phenylbutyrate and then used microarray identified differentially-expressed mRNA during this process.
2017-06-10 | GSE86928 | GEO
Project description:Serum and glucocorticoid-induced kinase 1 (SGK1) activates the epithselial sodium channel (eNaC) in tubules. We examined renal SGK1 abundance in salt-adaptation and in salt-sensitive hypertension. Sprague-Dawley and Dahl salt-sensitive rats were placed on either 8% or 0.3% NaCl diets for 10 days. Plasma aldosterone levels were approximately 2.5-fold greater on 0.3% versus 8% NaCl diets in both rat strains. Both serum and glucocorticoid-induced kinase 1 transcript and protein abundance were less (P<0.01) in Sprague-Dawley rats and greater (P<0.01) in Dahl salt-sensitive rats on 8% versus 0.3% NaCl diets. The cDNA sequences of serum and glucocorticoid-induced kinase 1 in both strains of rat were the same. The present results provide evidence that the abundance of serum and glucocorticoid-induced kinase 1 in rat kidney may play a role in salt adaptation and the pathogenesis of hypertension and suggests that aldosterone is not the primary inducer of SGK1 in the Sprague-Dawley rat.
2007-10-11 | E-GEOD-599 | biostudies-arrayexpress