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.
J Am Soc Nephrol
2009 Feb 01;202:299-310. doi: 10.1681/ASN.2008040364.
Show Gene links
Show Anatomy links
Plasmin in nephrotic urine activates the epithelial sodium channel.
Svenningsen P
,
Bistrup C
,
Friis UG
,
Bertog M
,
Haerteis S
,
Krueger B
,
Stubbe J
,
Jensen ON
,
Thiesson HC
,
Uhrenholt TR
,
Jespersen B
,
Jensen BL
,
Korbmacher C
,
Skøtt O
.
???displayArticle.abstract???
Proteinuria and increased renal reabsorption of NaCl characterize the nephrotic syndrome. Here, we show that protein-rich urine from nephrotic rats and from patients with nephrotic syndrome activate the epithelial sodium channel (ENaC) in cultured M-1 mouse collecting duct cells and in Xenopus laevis oocytes heterologously expressing ENaC. The activation depended on urinary serine protease activity. We identified plasmin as a urinary serine protease by matrix-assisted laser desorption/ionization time of-flight mass spectrometry. Purified plasmin activated ENaC currents, and inhibitors of plasmin abolished urinary protease activity and the ability to activate ENaC. In nephrotic syndrome, tubular urokinase-type plasminogen activator likely converts filtered plasminogen to plasmin. Consistent with this, the combined application of urokinase-type plasminogen activator and plasminogen stimulated amiloride-sensitive transepithelial sodium transport in M-1 cells and increased amiloride-sensitive whole-cell currents in Xenopus laevis oocytes heterologously expressing ENaC. Activation of ENaC by plasmin involved cleavage and release of an inhibitory peptide from the ENaC gamma subunit ectodomain. These data suggest that a defective glomerular filtration barrier allows passage of proteolytic enzymes that have the ability to activate ENaC.
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
Bertog,
Basolateral proteinase-activated receptor (PAR-2) induces chloride secretion in M-1 mouse renal cortical collecting duct cells.
1999,
Pubmed
Bie,
Determinants of the natriuresis after acute, slow sodium loading in conscious dogs.
2000,
Pubmed
Bistrup,
Reduced activity of 11beta-hydroxysteroid dehydrogenase type 2 is not responsible for sodium retention in nephrotic rats.
2005,
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
Caldwell,
Neutrophil elastase activates near-silent epithelial Na+ channels and increases airway epithelial Na+ transport.
2005,
Pubmed
Caldwell,
Serine protease activation of near-silent epithelial Na+ channels.
2004,
Pubmed
Canessa,
Amiloride-sensitive epithelial Na+ channel is made of three homologous subunits.
1994,
Pubmed
,
Xenbase
Carattino,
Proteolytic processing of the epithelial sodium channel gamma subunit has a dominant role in channel activation.
2008,
Pubmed
,
Xenbase
Cervenka,
Effects of acute AT1 receptor blockade by candesartan on arterial pressure and renal function in rats.
1998,
Pubmed
Cervenka,
Renal responses of the nonclipped kidney of two-kidney/one-clip Goldblatt hypertensive rats to type 1 angiotensin II receptor blockade with candesartan.
1999,
Pubmed
Chandra,
Renal function in rats with unilateral proteinuria produced by renal perfusion with aminonucleoside.
1981,
Pubmed
Chraïbi,
Protease modulation of the activity of the epithelial sodium channel expressed in Xenopus oocytes.
1998,
Pubmed
,
Xenbase
Deschênes,
Collecting duct (Na+/K+)-ATPase activity is correlated with urinary sodium excretion in rat nephrotic syndromes.
2000,
Pubmed
Deschênes,
Collecting duct is a site of sodium retention in PAN nephrosis: a rationale for amiloride therapy.
2001,
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
Ecelbarger,
Vasopressin-mediated regulation of epithelial sodium channel abundance in rat kidney.
2000,
Pubmed
Frindt,
Surface expression of epithelial Na channel protein in rat kidney.
2008,
Pubmed
,
Xenbase
Harris,
A novel neutrophil elastase inhibitor prevents elastase activation and surface cleavage of the epithelial sodium channel expressed in Xenopus laevis oocytes.
2007,
Pubmed
,
Xenbase
Harris,
Preferential assembly of epithelial sodium channel (ENaC) subunits in Xenopus oocytes: role of furin-mediated endogenous proteolysis.
2008,
Pubmed
,
Xenbase
Hughey,
Distinct pools of epithelial sodium channels are expressed at the plasma membrane.
2004,
Pubmed
,
Xenbase
Ichikawa,
Role for intrarenal mechanisms in the impaired salt excretion of experimental nephrotic syndrome.
1983,
Pubmed
Jonassen,
Decreased vasopressin-mediated renal water reabsorption in rats with chronic aldosterone-receptor blockade.
2000,
Pubmed
Kleyman,
Regulation of ENaCs by proteases: An increasingly complex story.
2006,
Pubmed
,
Xenbase
Kleyman,
Plasmin and sodium retention in nephrotic syndrome.
2009,
Pubmed
Konstas,
Conservation of pH sensitivity in the epithelial sodium channel (ENaC) with Liddle's syndrome mutation.
2000,
Pubmed
,
Xenbase
Letz,
Amiloride-sensitive sodium channels in confluent M-1 mouse cortical collecting duct cells.
1995,
Pubmed
,
Xenbase
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,
Trypsin can activate the epithelial sodium channel (ENaC) in microdissected mouse distal nephron.
2008,
Pubmed
Nørregaard,
Stimulation of 11-beta-hydroxysteroid dehydrogenase type 2 in rat colon but not in kidney by low dietary NaCl intake.
2003,
Pubmed
Olivieri,
Urinary prostasin: a candidate marker of epithelial sodium channel activation in humans.
2005,
Pubmed
Piedagnel,
Urokinase (u-PA) is produced by collecting duct principal cells and is post-transcriptionally regulated by SV40 large-T, arginine vasopressin, and epidermal growth factor.
2006,
Pubmed
Planès,
Regulation of the epithelial Na+ channel by peptidases.
2007,
Pubmed
,
Xenbase
Rossier,
The epithelial sodium channel: activation by membrane-bound serine proteases.
2004,
Pubmed
Shevchenko,
Mass spectrometric sequencing of proteins silver-stained polyacrylamide gels.
1996,
Pubmed
Thiesson,
Renal sodium retention in cirrhotic rats depends on glucocorticoid-mediated activation of mineralocorticoid receptor due to decreased renal 11beta-HSD-2 activity.
2007,
Pubmed
Usberti,
Role of plasma vasopressin in the impairment of water excretion in nephrotic syndrome.
1984,
Pubmed
Vallet,
An epithelial serine protease activates the amiloride-sensitive sodium channel.
1997,
Pubmed
,
Xenbase
Vallet,
Epithelial sodium channel regulatory proteins identified by functional expression cloning.
1998,
Pubmed
,
Xenbase
Vande Walle,
Volume regulation in children with early relapse of minimal-change nephrosis with or without hypovolaemic symptoms.
1995,
Pubmed
Vassalli,
Amiloride selectively inhibits the urokinase-type plasminogen activator.
1987,
Pubmed
Vogt,
Na+,K(+)-ATPase activity and hormones in single nephron segments from nephrotic rats.
1991,
Pubmed
Wagner,
Sites of urokinase-type plasminogen activator expression and distribution of its receptor in the normal human kidney.
1996,
Pubmed
Wakida,
Inhibition of prostasin-induced ENaC activities by PN-1 and regulation of PN-1 expression by TGF-beta1 and aldosterone.
2006,
Pubmed
,
Xenbase
Xu,
Different expression of the plasminogen activation system in renal thrombotic microangiopathy and the normal human kidney.
1996,
Pubmed
Yang,
Stimulation of the epithelial sodium channel (ENaC) by cAMP involves putative ERK phosphorylation sites in the C termini of the channel's beta- and gamma-subunit.
2006,
Pubmed
,
Xenbase
Yu,
Regulation of epithelial sodium channel in puromycin aminonucleoside-induced unilateral experimental nephrotic syndrome in normal and analbuminemic Nagase rats.
2005,
Pubmed
