Click here to close
Hello! We notice that you are using Internet Explorer, which is not supported by Xenbase and may cause the site to display incorrectly.
We suggest using a current version of Chrome,
FireFox, or Safari.
Acta Physiol (Oxf)
2021 May 01;2321:e13640. doi: 10.1111/apha.13640.
Show Gene links
Show Anatomy links
Zymogen-locked mutant prostasin (Prss8) leads to incomplete proteolytic activation of the epithelial sodium channel (ENaC) and severely compromises triamterene tolerance in mice.
Essigke D
,
Ilyaskin AV
,
Wörn M
,
Bohnert BN
,
Xiao M
,
Daniel C
,
Amann K
,
Birkenfeld AL
,
Szabo R
,
Bugge TH
,
Korbmacher C
,
Artunc F
.
???displayArticle.abstract???
AIM: The serine protease prostasin (Prss8) is expressed in the distal tubule and stimulates proteolytic activation of the epithelial sodium channel (ENaC) in co-expression experiments in vitro. The aim of this study was to explore the role of prostasin in proteolytic ENaC activation in the kidney in vivo.
METHODS: We used genetically modified knockin mice carrying a Prss8 mutation abolishing proteolytic activity (Prss8-S238A) or a mutation leading to a zymogen-locked state (Prss8-R44Q). Mice were challenged with low sodium diet and diuretics. Regulation of ENaC activity by Prss8-S238A and Prss8-R44Q was studied in vitro using the Xenopus laevis oocyte expression system.
RESULTS: Co-expression of murine ENaC with Prss8-wt or Prss8-S238A in oocytes caused maximal proteolytic ENaC activation, whereas ENaC was activated only partially in oocytes co-expressing Prss8-R44Q. This was paralleled by a reduced proteolytic activity at the cell surface of Prss8-R44Q expressing oocytes. Sodium conservation under low sodium diet was preserved in Prss8-S238A and Prss8-R44Q mice but with higher plasma aldosterone concentrations in Prss8-R44Q mice. Treatment with the ENaC inhibitor triamterene over four days was tolerated in Prss8-wt and Prss8-S238A mice, whereas Prss8-R44Q mice developed salt wasting and severe weight loss associated with hyperkalemia and acidosis consistent with impaired ENaC function and renal failure.
CONCLUSION: Unlike proteolytically inactive Prss8-S238A, zymogen-locked Prss8-R44Q produces incomplete proteolytic ENaC activation in vitro and causes a severe renal phenotype in mice treated with the ENaC inhibitor triamterene. This indicates that Prss8 plays a role in proteolytic ENaC activation and renal function independent of its proteolytic activity.
387509280 - SFB 1350 Deutsche Forschungsgemeinschaft, AR 1092/2-2 Deutsche Forschungsgemeinschaft, National Institute of Dental and Craniofacial Research, Z01 DE000699 Intramural NIH HHS, NIDCR NIH HHS
Adachi,
Activation of epithelial sodium channels by prostasin in Xenopus oocytes.
2001, Pubmed,
Xenbase
Adachi,
Activation of epithelial sodium channels by prostasin in Xenopus oocytes.
2001,
Pubmed
,
Xenbase
Andersen,
Diabetic nephropathy is associated with increased urine excretion of proteases plasmin, prostasin and urokinase and activation of amiloride-sensitive current in collecting duct cells.
2015,
Pubmed
Andreasen,
Activation of epithelial sodium channels by mouse channel activating proteases (mCAP) expressed in Xenopus oocytes requires catalytic activity of mCAP3 and mCAP2 but not mCAP1.
2006,
Pubmed
,
Xenbase
Artunc,
Responses to diuretic treatment in gene-targeted mice lacking serum- and glucocorticoid-inducible kinase 1.
2009,
Pubmed
Bohnert,
Urokinase-type plasminogen activator (uPA) is not essential for epithelial sodium channel (ENaC)-mediated sodium retention in experimental nephrotic syndrome.
2019,
Pubmed
,
Xenbase
Boscardin,
Plasma Potassium Determines NCC Abundance in Adult Kidney-Specific γENaC Knockout.
2018,
Pubmed
Bruns,
Epithelial Na+ channels are fully activated by furin- and prostasin-dependent release of an inhibitory peptide from the gamma-subunit.
2007,
Pubmed
,
Xenbase
Carattino,
Prostasin interacts with the epithelial Na+ channel and facilitates cleavage of the γ-subunit by a second protease.
2014,
Pubmed
,
Xenbase
Chen,
Transcriptomes of major renal collecting duct cell types in mouse identified by single-cell RNA-seq.
2017,
Pubmed
Diakov,
Cleavage in the {gamma}-subunit of the epithelial sodium channel (ENaC) plays an important role in the proteolytic activation of near-silent channels.
2008,
Pubmed
,
Xenbase
Friis,
Distinct Developmental Functions of Prostasin (CAP1/PRSS8) Zymogen and Activated Prostasin.
2016,
Pubmed
Frindt,
Cleavage state of γENaC in mouse and rat kidneys.
2021,
Pubmed
Grahammer,
mTORC2 critically regulates renal potassium handling.
2016,
Pubmed
Haerteis,
Proteolytic activation of the human epithelial sodium channel by trypsin IV and trypsin I involves distinct cleavage sites.
2014,
Pubmed
,
Xenbase
Haerteis,
Plasma kallikrein activates the epithelial sodium channel in vitro but is not essential for volume retention in nephrotic mice.
2018,
Pubmed
,
Xenbase
Haerteis,
Plasmin and chymotrypsin have distinct preferences for channel activating cleavage sites in the γ subunit of the human epithelial sodium channel.
2012,
Pubmed
,
Xenbase
Harris,
Mechanism of Hyperkalemia-Induced Metabolic Acidosis.
2018,
Pubmed
Hummler,
The channel-activating protease CAP1/Prss8 is required for placental labyrinth maturation.
2013,
Pubmed
Ilyaskin,
Inhibition of the epithelial sodium channel (ENaC) by connexin 30 involves stimulation of clathrin-mediated endocytosis.
2021,
Pubmed
,
Xenbase
Ilyaskin,
Activation of the Human Epithelial Sodium Channel (ENaC) by Bile Acids Involves the Degenerin Site.
2016,
Pubmed
,
Xenbase
Kawabata,
Highly sensitive peptide-4-methylcoumaryl-7-amide substrates for blood-clotting proteases and trypsin.
1988,
Pubmed
Kim,
Long-term adaptation of renal ion transporters to chronic diuretic treatment.
2004,
Pubmed
Kleyman,
ENaC at the cutting edge: regulation of epithelial sodium channels by proteases.
2009,
Pubmed
Kleyman,
Epithelial Na+ Channel Regulation by Extracellular and Intracellular Factors.
2018,
Pubmed
Krueger,
The phosphorylation site T613 in the β-subunit of rat epithelial Na+ channel (ENaC) modulates channel inhibition by Nedd4-2.
2018,
Pubmed
,
Xenbase
Lee,
Deep Sequencing in Microdissected Renal Tubules Identifies Nephron Segment-Specific Transcriptomes.
2015,
Pubmed
Leyvraz,
The epidermal barrier function is dependent on the serine protease CAP1/Prss8.
2005,
Pubmed
Loffing,
Differential subcellular localization of ENaC subunits in mouse kidney in response to high- and low-Na diets.
2000,
Pubmed
Lorenz,
Heteromultimeric CLC chloride channels with novel properties.
1996,
Pubmed
,
Xenbase
Malsure,
Colon-specific deletion of epithelial sodium channel causes sodium loss and aldosterone resistance.
2014,
Pubmed
Masilamani,
Aldosterone-mediated regulation of ENaC alpha, beta, and gamma subunit proteins in rat kidney.
1999,
Pubmed
Narikiyo,
Regulation of prostasin by aldosterone in the kidney.
2002,
Pubmed
,
Xenbase
Nesterov,
In Liddle Syndrome, Epithelial Sodium Channel Is Hyperactive Mainly in the Early Part of the Aldosterone-Sensitive Distal Nephron.
2016,
Pubmed
Netzel-Arnett,
Evidence for a matriptase-prostasin proteolytic cascade regulating terminal epidermal differentiation.
2006,
Pubmed
Oxlund,
Albuminuria is associated with an increased prostasin in urine while aldosterone has no direct effect on urine and kidney tissue abundance of prostasin.
2017,
Pubmed
Park,
Single-cell transcriptomics of the mouse kidney reveals potential cellular targets of kidney disease.
2018,
Pubmed
Peters,
The membrane-anchored serine protease prostasin (CAP1/PRSS8) supports epidermal development and postnatal homeostasis independent of its enzymatic activity.
2014,
Pubmed
Reihill,
Inhibition of Protease-Epithelial Sodium Channel Signaling Improves Mucociliary Function in Cystic Fibrosis Airways.
2016,
Pubmed
Rossier,
Activation of the epithelial sodium channel (ENaC) by serine proteases.
2009,
Pubmed
Shipway,
Biochemical characterization of prostasin, a channel activating protease.
2004,
Pubmed
Szabo,
Loss of HAI-2 in mice with decreased prostasin activity leads to an early-onset intestinal failure resembling congenital tufting enteropathy.
2018,
Pubmed
Vuagniaux,
Activation of the amiloride-sensitive epithelial sodium channel by the serine protease mCAP1 expressed in a mouse cortical collecting duct cell line.
2000,
Pubmed
,
Xenbase
Wörn,
Proteasuria in nephrotic syndrome-quantification and proteomic profiling.
2021,
Pubmed
Xiao,
Plasminogen deficiency does not prevent sodium retention in a genetic mouse model of experimental nephrotic syndrome.
2021,
Pubmed
Yang,
SGK1-dependent ENaC processing and trafficking in mice with high dietary K intake and elevated aldosterone.
2017,
Pubmed
Yu,
Molecular cloning, tissue-specific expression, and cellular localization of human prostasin mRNA.
1995,
Pubmed
Yu,
Prostasin is a novel human serine proteinase from seminal fluid. Purification, tissue distribution, and localization in prostate gland.
1994,
Pubmed
Zachar,
Dietary Na+ intake in healthy humans changes the urine extracellular vesicle prostasin abundance while the vesicle excretion rate, NCC, and ENaC are not altered.
2019,
Pubmed
