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Transmembrane serine protease 2 and proteolytic activation of the epithelial sodium channel in mouse kidney: Late effects of aldosterone

ABSTRACT: Transmembrane serine protease 2 and proteolytic activation of the epithelial sodium channel in mouse kidney: Late effects of aldosterone

PROVIDER: PRJNA1145911 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR30172714_1.fastq.gz	Fastqsanger.gz
	SRR30172714_2.fastq.gz	Fastqsanger.gz
	SRR30172715_1.fastq.gz	Fastqsanger.gz
	SRR30172715_2.fastq.gz	Fastqsanger.gz
	SRR30172716_1.fastq.gz	Fastqsanger.gz

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Transmembrane serine protease 2 and proteolytic activation of the epithelial sodium channel in mouse kidney: Late effects of aldosterone

Project description:The appropriate regulation of the epithelial sodium channel (ENaC) in the aldosterone-sensitive distal nephron is required for sodium homeostasis and thereby for the long-term regulation of arterial blood pressure. A unique feature of ENaC is its activation by proteolytic cleavage. However, the relevant proteases involved in proteolytic ENaC activation in the kidney remain elusive. Here, we examined a potential role of transmembrane serine protease 2 (TMPRSS2). A mouse cortical collecting duct cell line (mCCDcl1) was used as a model system. We performed RNA-Seq transcriptome analysis of mCCDcl1 cells, which confirmed coexpression of Tmprss2 and all three ENaC subunits (Scnn1a, Scnn1b, Scnn1g) in this cell line. Importantly, high baseline expression of TMPRSS2 was detected in these cells without a stimulatory effect of aldosterone on its function or transcription. TMPRSS2 knockout in mCCDcl1 cells compromised γ-ENaC cleavage and reduced baseline and aldosterone-stimulated transepithelial short-circuit currents, which could be rescued by chymotrypsin. A compensatory transcriptional upregulation of other proteases was not observed. From these findings we conclude that TMPRSS2 is likely to contribute to proteolytic ENaC activation in the kidney.

2024-10-30 | GSE274305 | GEO

Transmembrane serine protease 2 and proteolytic activation of the epithelial sodium channel in mouse kidney: Early effects of aldosterone

2024-10-30 | GSE274304 | GEO

Transmembrane serine protease 2 and proteolytic activation of the epithelial sodium channel in mouse kidney: Effects of TMPRSS2 knockout

2024-10-30 | GSE274306 | GEO

Transmembrane serine protease 2 and proteolytic activation of the epithelial sodium channel in mouse kidney: Early effects of aldosterone

Project description:Transmembrane serine protease 2 and proteolytic activation of the epithelial sodium channel in mouse kidney: Early effects of aldosterone

| PRJNA1145910 | ENA

Transmembrane serine protease 2 and proteolytic activation of the epithelial sodium channel in mouse kidney: Effects of TMPRSS2 knockout

Project description:Transmembrane serine protease 2 and proteolytic activation of the epithelial sodium channel in mouse kidney: Effects of TMPRSS2 knockout

| PRJNA1145912 | ENA

Transmembrane serine protease 2 (TMPRSS2) proteolytically activates the epithelial sodium channel (ENaC) by cleaving the channel's γ-subunit.

Project description:The epithelial sodium channel (ENaC) is a heterotrimer consisting of α-, β-, and γ-subunits. Channel activation requires proteolytic release of inhibitory tracts from the extracellular domains of α-ENaC and γ-ENaC; however, the proteases involved in the removal of the γ-inhibitory tract remain unclear. In several epithelial tissues, ENaC is coexpressed with the transmembrane serine protease 2 (TMPRSS2). Here, we explored the effect of human TMPRSS2 on human αβγ-ENaC heterologously expressed in Xenopus laevis oocytes. We found that coexpression of TMPRSS2 stimulated ENaC-mediated whole-cell currents by approximately threefold, likely because of an increase in average channel open probability. Furthermore, TMPRSS2-dependent ENaC stimulation was not observed using a catalytically inactive TMPRSS2 mutant and was associated with fully cleaved γ-ENaC in the intracellular and cell surface protein fractions. This stimulatory effect of TMPRSS2 on ENaC was partially preserved when inhibiting its proteolytic activity at the cell surface using aprotinin but was abolished when the γ-inhibitory tract remained attached to its binding site following introduction of two cysteine residues (S155C-Q426C) to form a disulfide bridge. In addition, computer simulations and site-directed mutagenesis experiments indicated that TMPRSS2 can cleave γ-ENaC at sites both proximal and distal to the γ-inhibitory tract. This suggests a dual role of TMPRSS2 in the proteolytic release of the γ-inhibitory tract. Finally, we demonstrated that TMPRSS2 knockdown in cultured human airway epithelial cells (H441) reduced baseline proteolytic activation of endogenously expressed ENaC. Thus, we conclude that TMPRSS2 is likely to contribute to proteolytic ENaC activation in epithelial tissues in vivo.

| S-EPMC9163703 | biostudies-literature

Proteolytic cleavage of human acid-sensing ion channel 1 by the serine protease matriptase.

Project description:Acid-sensing ion channel 1 (ASIC1) is a H(+)-gated channel of the amiloride-sensitive epithelial Na(+) channel (ENaC)/degenerin family. ASIC1 is expressed mostly in the central and peripheral nervous system neurons. ENaC and ASIC function is regulated by several serine proteases. The type II transmembrane serine protease matriptase activates the prototypical alphabetagammaENaC channel, but we found that matriptase is expressed in glioma cells and its expression is higher in glioma compared with normal astrocytes. Therefore, the goal of this study was to test the hypothesis that matriptase regulates ASIC1 function. Matriptase decreased the acid-activated ASIC1 current as measured by two-electrode voltage clamp in Xenopus oocytes and cleaved ASIC1 expressed in oocytes or CHO K1 cells. Inactive S805A matriptase had no effect on either the current or the cleavage of ASIC1. The effect of matriptase on ASIC1 was specific, because it did not affect the function of ASIC2 and no matriptase-specific ASIC2 fragments were detected in oocytes or in CHO cells. Three matriptase recognition sites were identified in ASIC1 (Arg-145, Lys-185, and Lys-384). Site-directed mutagenesis of these sites prevented matriptase cleavage of ASIC1. Our results show that matriptase is expressed in glioma cells and that matriptase specifically cleaves ASIC1 in heterologous expression systems.

| S-EPMC2930712 | biostudies-literature

Virtual Screening of Transmembrane Serine Protease Inhibitors.

Project description:The human family of type II transmembrane serine proteases includes 17 members. The defining features of these proteases are an N-terminal transmembrane domain and a C-terminal serine protease of the chymotrypsin (S1) fold, separated from each other by a variable stem region. Recently accumulated evidence suggests a critical role for these proteases in development of cancer and metastatic capacity. Both the cancer relevance and the accessibility of the extracellularly oriented catalytic domain for therapeutic and imaging agents have fueled drug discovery interest in the type II class of transmembrane serine proteases. Typically, the initial hit discovery processes aim to identify molecules with verifiable activity at the drug target and with sufficient drug-like characters. We present here protocols for structure-based virtual screening of candidate ligands for transmembrane serine protease hepsin. The methods describe use of the 3D structure of the catalytic site of hepsin for molecular docking with ZINC, which is a molecular database of > 30 million purchasable compounds. Small candidate subsets were experimentally tested with demonstrable hits, which provided meaningful cues of the ligand structures for further lead development.

| S-EPMC8410343 | biostudies-literature

Cardiac aldosterone regulated genes in mice

Project description:Aldosterone excess is involved in cardiac diseases. The mechanisms are still unclears. Mice were treated for 7 days with aldosterone and a whole genome microarray analysis was performed. Two-group experiment: Untreated mice (Ctrl), mice + aldosterone treatment (Aldo). One comparisons: Ctrl vs Aldo

2016-09-08 | E-GEOD-50709 | biostudies-arrayexpress

Cardiac aldosterone regulated genes in mice

2016-09-08 | GSE50709 | GEO