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Gene expression of human keratinocyte (HaCaT) under the stress of high sodium concentration

ABSTRACT: The mechanisms by which the epidermis responds to disturbances in barrier function and restores homeostasis are unknown. With a disruption of the epidermal barrier, water is lost resulting in an increase in extracellular sodium concentration. We demonstrate that the sodium channel Nax functions as the sodium sensor. With increased extracellular sodium, Nax up-regulates prostasin which results in activation of the sodium channel ENaC, resulting in increased sodium flux and increased downstream mRNA synthesis of inflammatory mediators. The same pathways are present in lung epithelial cells. A signal transduction pathway mediated directly through Nax and secondarily through ENaC results in production of secretory inflammatory mediators. These mediators result in epithelial proliferation and restoration of epidermal homeostasis, but can also have negative effects including excess inflammation and ultimately leads to activation of fibroblasts.

ORGANISM(S): Homo sapiens

PROVIDER: GSE65366 | GEO | 2015/01/29

SECONDARY ACCESSION(S): PRJNA273807

REPOSITORIES: GEO

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Gene expression of human keratinocyte (HaCaT) under the stress of high sodium concentration

Project description:The mechanisms by which the epidermis responds to disturbances in barrier function and restores homeostasis are unknown. With a disruption of the epidermal barrier, water is lost resulting in an increase in extracellular sodium concentration. We demonstrate that the sodium channel Nax functions as the sodium sensor. With increased extracellular sodium, Nax up-regulates prostasin which results in activation of the sodium channel ENaC, resulting in increased sodium flux and increased downstream mRNA synthesis of inflammatory mediators. The same pathways are present in lung epithelial cells. A signal transduction pathway mediated directly through Nax and secondarily through ENaC results in production of secretory inflammatory mediators. These mediators result in epithelial proliferation and restoration of epidermal homeostasis, but can also have negative effects including excess inflammation and ultimately leads to activation of fibroblasts. Both wild type and Nax knockdown HaCaT cells were seeded in 12-well plates. 70-80% confluent cells were starved with fetal bovine serum (FBS) free Dulbecco's modiM-oM-,M-^Aed Eagle's medium (DMEM) overnight followed by a treatment with control medium (final150 mM sodium) or medium plus 10% more sodium (final 165 mM sodium). Cells were harvested at time point 0, 4, and 16 hours post treatment.

2015-01-29 | E-GEOD-65366 | biostudies-arrayexpress

Quantitative proteomic analysis of urinary exosomes from patients with primary aldosteronism that underwent fludrocortisone suppression test

Project description:The sodium chloride cotransporters (NCC) and the epithelial sodium channel (ENaC) have been reported to be the main effectors of aldosterone in Na+ and Cl- reabsorption in the distal nephron and dietary K+ downregulates NCC. The Cl-/HCO3- exchanger pendrin has been revealed as a key role in maintaining extracellular fluid and electrolyte homeostasis by regulating Cl- reabsorption in the aldosterone-sensitive distal nephron working in tandem with ENaC and perhaps NCC. Pendrin-mediated Cl-/HCO3- exchange is stimulated in models of metabolic alkalosis (e.g. aldosterone administration or dietary NaHCO3 intake), and plasma K+ level is thought to negatively influence pendrin. In this study we used high-throughput proteomics and bioinformatics approaches to analyze urinary exosome contents isolated from patients undergoing fludrocortisone suppression test (FST, as a means of confirming or excluding primary aldosteronism [PA]) to examine the actions of administration of aldosterone analogs, NaCl and KCl orally on transmembrane proteins existing in urinary exosomes.

2020-11-20 | PXD017083 | Pride

Tmprss2 maintains epithelial barrier integrity and transepithelial sodium transport

Project description:Membrane-bound serine proteases are well known regulators of ENaC. More recently, they have also been identified as regulators of tight junction complexes. Here, we demonstrate that within the kidney, the serine protease Tmprss2 is co-expressed with the alpha subunit of ENaC, whereas Furin is primarily expressed in ENaC-negative cortex cells. In mCCDcl1 kidney cells, aldosterone-induced ENaC and Scnn1a-specific overexpression is accompanied by increased Tmprss2 gene expression, whereas Scnn1a silencing does not alter Tmprss2 transcription, suggesting that ENaC depends on Tmprss2 expression. This was confirmed by CRISPR-Cas9 Tmprss2 knockout which significantly downregulates Scnn1a gene and protein expression, and thus ENaC-mediated transepithelial sodium transport. Additionally, RNA sequencing analyses unveiled a drastic downregulation in EpCAM and claudin-3 and -7 gene expression, resulting in reduced protein expression also confirmed by immunocytochemistry. In summary, our data clearly demonstrates that the serine protease Tmprss2 is important in maintaining the epithelial tight junction barrier, in addition to regulating ENaC function via Scnn1a expression.

2024-01-02 | GSE247775 | GEO

Transcription profiling of cortical collecting duct/connecting nephron tissue from mice treated with aldosterone, canrenoate vs. controls to identify gene products regulated by aldosterone in target cells

Project description:The mineralocorticoid hormone aldosterone controls sodium reabsorption and blood pressure largely by regulating the cell-surface expression and function of the epithelial sodium channel ENaC in target kidney tubules. Part of the stimulatory effect of aldosterone on ENaC is mediated by the induction of SGK1, a kinase that interferes with the ubiquitylation of ENaC by ubiquitin-protein ligase Nedd4-2. We performed a microarray study in order to investigate which other gene products are rapidly regulated by aldosterone in target cells that participate to the control of Na+ reabsorption and K+ secretion.

2007-03-07 | E-TABM-229 | biostudies-arrayexpress

Quantitative Phosphoproteomic Identification of Novel Vasopressin-mediated Signaling Networks in Kidney Distal Convoluted Tubule Cells

Project description:The kidney distal convoluted tubule (DCT) plays an important role in body sodium regulation and thus control of blood pressure. The main sodium reabsorption pathways in the DCT are the epithelial sodium channel (ENaC) and the thiazide-sensitive NaCl cotransporter (NCC), the functions of which can be modulated by the hormone vasopressin (VP) acting via uncharacterized signaling cascades. We performed large scale stable isotope labeling by amino acids in cell culture (SILAC) based quantitative phosphoproteomics of cultured mouse DCT cells (mpkDCT) to map global changes in protein phosphorylation events upon acute treatment with the VP type II receptor agonist 1-desamino-8-D-arginine vasopressin (dDAVP). The aim of this study is to identify unique VP signaling cascades in DCT cells that may be important for regulating ENaC or NCC activity. These pathways may be novel targets for modulation of blood pressure.

2015-08-04 | PXD001729 | Pride

Salt-deficient diet exacerbates cystogenesis in ARPKD via epithelial sodium channel (ENaC)

Project description:Salt-deficient diet exacerbates cystogenesis in ARPKD via epithelial sodium channel (ENaC)

| PRJNA544464 | ENA

Aldosterone-responsive genes in kidney cortical collecting duct cell line, mpkCCDc14

Project description:Aldosterone is arguably the single most important hormone implicated in the control of blood pressure and extracellular fluid volume in mammals. It acts primarily by increasing the rate of transepithelial sodium transport in the kidney tubules. Several monogenetic defects resulting in hypertension have now been attributed to abnormalities in sodium handling within the aldosterone-sensitive distal nephron, where the epithelial sodium channel, ENaC, constitutes the rate-limiting step of sodium transport. To date, the transcription-dependent aldosterone-signaling pathway between receptor and membrane transport effectors, remains incompletely understood. The broad aim of our study is to explore these intracellular signaling pathways that are critical to the functioning of sodium channels. Microarray analysis in an aldosterone-responsive kidney cortical collecting duct cell line (mpkCCDc14), allowed us to identify many potential aldosterone-regulated transcripts. The present study describes the identification, and possible physiological relevance of various aldosterone-regulated transcripts. The results of this study promise to extend our understanding of the molecular basis of aldosterone-regulated sodium transport in kidney epithelia, and provide approaches for regulating this process in disease states such as congestive heart failure and hypertension. Keywords: hormone effect

2005-07-15 | GSE2933 | GEO

Proteomic analysis of small extracellular vesicles (sEVs) derived from primary keratinocytes cultured in different calcium concentrations, treated with a peanut allergen extract and atopic dermatitis (AD)-relevant cytokines

Project description:Epidermal keratinocytes are key for maintenance of the integrity of the epidermis. One of the main drivers of keratinocyte differentiation is the calcium gradient; calcium concentration gradually increases towards the outer layers of the epidermis. Atopic dermatitis (AD) is a disorder associated with a chronic inflammatory state and a compromised epidermal barrier. Keratinocytes secrete lipid-rich small extracellular vesicles (sEVs) that acts as mediators of both local and long-distance signaling.

2022-06-07 | PXD031729 | Pride

Rapid Aldosterone Effects in Mouse Kidney Distal Convoluted Tubules Cells

Project description:Kidney distal convoluted tubules (DCT) are important for regulation of urinary salt excretion. Aldosterone is known to exert long-term effects in this segment, and regulate sodium reabsorption via increasing abundance of the Na+-Cl- cotransporter (NCC) and the epithelial Na channel ENaC. Whether acute effects of aldosterone occur in the DCT and the potential signaling networks remain unknown. Here in this study, we aim to identify the acute aldosterone-mediated signaling (rapid effects) in the DCT.

2019-06-24 | PXD010032 | Pride

ZFP750 regulates skin lipid metabolism and cutaneous barrier

Project description:A life-essential function of the epidermis is to provide a physical barrier that prevents the loss of water and electrolytes. Essential mediators of this permeability barrier function include ceramides, cholesterol and very long chain fatty acids. Accordingly, their alteration may lead to distinct human conditions, including psoriasis or atopic dermatitis. Recently, a frameshift mutation in the human ZNF750 gene, that encodes for a zinc finger transcription factor, causing a seborrhea-like dermatitis with psoriasiform element, has brought ZNF750 as a key element for the maintenance of the epidermal tissue homeostasis. To clarify this hypothesis, with its underlying molecular mechanism, we generated a novel mouse knockout by deleting exon 2. Here, we show that genetic deletion of the mouse homolog ZFP750 results in loss of epidermal permeability barrier function. ZFP750-/- mice die shortly after birth, within 12 hours. In the stratum corneum of ZFP750-/- mice levels of ceramides, nonpolar lipids and intercellular lipid lamellae are significantly reduced. The alteration of the epidermal lipid homeostasis is directly linked to the transcriptional activity of ZFP750. Indeed, in addition to epidermal differentiation genes, ZFP750 directly and/or indirectly regulates the expression of nearly 50 crucial enzymes in the biosynthesis of ceramides, such as SPTLC1, DGAT2, SMPD3, ELOVL7 and DEGS2. Overall, our study identifies the transcription factor ZFP750 as a master regulator of lipid biosynthesis and epidermal homeostasis and may contribute to our understanding of the pathogenesis of several human skin diseases.

2023-05-03 | GSE220813 | GEO

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