Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress 2023 EHA Congress 2023 ASCO Annual Meeting
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on sleep in brain health

LIVE: Thursday 2nd May 2024, 18:00-19:30 (CEST)

Quality sleep is essential for health. But what happens to our brains when sleep patterns are disturbed? Join our experts to explore the interplay between sleep disruption and neurological diseases, and the questions that you need to be asking your patients to help you prevent the harmful effects of sleep deprivation.
ADVANCED SEARCH
Log in
Top
Clinical and Experimental Nephrology
Published in: Clinical and Experimental Nephrology 5/2010

01-10-2010 | Review Article

Regulation of renal sodium handling through the interaction between serine proteases and serine protease inhibitors

Authors: Kenichiro Kitamura, Kimio Tomita

Published in: Clinical and Experimental Nephrology | Issue 5/2010

Login to get access

Abstract

Sodium balance, extracellular fluid volume, and ultimately blood pressure are maintained by precise regulation of the activity of epithelial sodium channels (ENaC). Multiple mechanisms such as hormones, intracellular factors, and other regulatory factors contribute to regulation of ENaC activity. Prostasin, a glycosylphosphatidylinositol-anchored serine protease, has been identified as an activator of ENaC that increases its open probability. Furin cleaves αENaC at two sites and γENaC at one site at the Golgi. Prostasin cleaves γENaC at one site that is distinct from the furin site at the plasma membrane. Dual cleavage of α- and γ-subunit releases inhibitory segments from ENaC, leading to channel activation. Protease nexin-1 (PN-1), an endogenous prostasin inhibitor, inhibits ENaC activity through suppression of prostasin activity. Aldosterone and transforming growth factor-β1 reciprocally regulate expression of prostasin, PN-1, and ENaC in renal epithelial cell, resulting in sodium retention or natriuresis, respectively. These findings strongly suggest the possibility that coordinated regulation of serine protease, serpin, and ENaC expression plays a key role in sodium handling in the kidney.
Literature
1.
Barbry P, Lazdunski M. Structure and regulation of the amiloride-sensitive epithelial sodium channel. Ion Channels. 1996;4:115–67.PubMed
2.
Garty H, Palmer LG. Epithelial sodium channels: function, structure, and regulation. Physiol Rev. 1997;77(2):359–96.PubMed
3.
Rossier BC. 1996 Homer Smith Award Lecture. Cum grano salis: the epithelial sodium channel and the control of blood pressure. J Am Soc Nephrol. 1997;8(6):980–92.PubMed
4.
Firsov D, Schild L, Gautschi I, Merillat AM, Schneeberger E, Rossier BC. Cell surface expression of the epithelial Na channel and a mutant causing Liddle syndrome: a quantitative approach. Proc Natl Acad Sci USA. 1996;93(26):15370–5.CrossRefPubMed
5.
Hansson JH, Schild L, Lu Y, Wilson TA, Gautschi I, Shimkets R, Nelson-Williams C, Rossier BC, Lifton RP. A de novo missense mutation of the beta subunit of the epithelial sodium channel causes hypertension and Liddle syndrome, identifying a proline-rich segment critical for regulation of channel activity. Proc Natl Acad Sci USA. 1995;92(25):11495–9.CrossRefPubMed
6.
Oh YS, Warnock DG. Disorders of the epithelial Na(+) channel in Liddle’s syndrome and autosomal recessive pseudohypoaldosteronism type 1. Exp Nephrol. 2000;8(6):320–5.CrossRefPubMed
7.
Vallet V, Chraibi A, Gaeggeler HP, Horisberger JD, Rossier BC. An epithelial serine protease activates the amiloride-sensitive sodium channel. Nature. 1997;389(6651):607–10.CrossRefPubMed
8.
Vallet V, Pfister C, Loffing J, Rossier BC. Cell-surface expression of the channel activating protease xCAP-1 is required for activation of ENaC in the Xenopus oocyte. J Am Soc Nephrol. 2002;13(3):588–94.PubMed
9.
Chraibi A, Vallet V, Firsov D, Hess SK, Horisberger JD. Protease modulation of the activity of the epithelial sodium channel expressed in Xenopus oocytes. J Gen Physiol. 1998;111(1):127–38.CrossRefPubMed
10.
Yu JX, Chao L, Chao J. Prostasin is a novel human serine proteinase from seminal fluid. Purification, tissue distribution, and localization in prostate gland. J Biol Chem. 1994;269(29):18843–8.PubMed
11.
Yu JX, Chao L, Chao J. Molecular cloning, tissue-specific expression, and cellular localization of human prostasin mRNA. J Biol Chem. 1995;270(22):13483–9.PubMed
12.
Chen LM, Skinner ML, Kauffman SW, Chao J, Chao L, Thaler CD, Chai KX. Prostasin is a glycosylphosphatidylinositol-anchored active serine protease. J Biol Chem. 2001;276(24):21434–42.CrossRefPubMed
13.
Chen LM, Chai KX. Prostasin serine protease inhibits breast cancer invasiveness and is transcriptionally regulated by promoter DNA methylation. Int J Cancer. 2002;97(3):323–9.CrossRefPubMed
14.
Chen LM, Zhang X, Chai KX. Regulation of prostasin expression and function in the prostate. Prostate. 2004;59(1):1–12.CrossRefPubMed
15.
Chen LM, Hodge GB, Guarda LA, Welch JL, Greenberg NM, Chai KX. Down-regulation of prostasin serine protease: a potential invasion suppressor in prostate cancer. Prostate. 2001;48(2):93–103.CrossRefPubMed
16.
Mok SC, Chao J, Skates S, Wong K, Yiu GK, Muto MG, Berkowitz RS, Cramer DW. Prostasin, a potential serum marker for ovarian cancer: identification through microarray technology. J Natl Cancer Inst. 2001;93(19):1458–64.CrossRefPubMed
17.
Netzel-Arnett S, Currie BM, Szabo R, Lin CY, Chen LM, Chai KX, Antalis TM, Bugge TH, List K. Evidence for a matriptase–prostasin proteolytic cascade regulating terminal epidermal differentiation. J Biol Chem. 2006;281(44):32941–5.CrossRefPubMed
18.
Chen M, Chen LM, Lin CY, Chai KX. The epidermal growth factor receptor (EGFR) is proteolytically modified by the matriptase–prostasin serine protease cascade in cultured epithelial cells. Biochim Biophys Acta Mol Cell Res. 2008;1783(5):896–903.CrossRef
19.
Chen LM, Wang C, Chen M, Marcello MR, Chao J, Chao L, Chai KX. Prostasin attenuates inducible nitric oxide synthase expression in lipopolysaccharide-induced urinary bladder inflammation. Am J Physiol Ren Physiol. 2006;291(3):F567–77.CrossRef
20.
Leyvraz C, Charles RP, Rubera I, Guitard M, Rotman S, Breiden B, Sandhoff K, Hummler E. The epidermal barrier function is dependent on the serine protease CAP1/Prss8. J Cell Biol. 2005;170(3):487–96.CrossRefPubMed
21.
Adachi M, Kitamura K, Miyoshi T, Narikiyo T, Iwashita K, Shiraishi N, Nonoguchi H, Tomita K. Activation of epithelial sodium channels by prostasin in Xenopus oocytes. J Am Soc Nephrol. 2001;12(6):1114–21.PubMed
22.
Masilamani S, Kim GH, Mitchell C, Wade JB, Knepper MA. Aldosterone-mediated regulation of ENaC alpha, beta, and gamma subunit proteins in rat kidney. J Clin Investig. 1999;104(7):R19–23.CrossRefPubMed
23.
Caldwell RA, Boucher RC, Stutts MJ. Neutrophil elastase activates near-silent epithelial Na+ channels and increases airway epithelial Na+ transport. Am J Physiol Lung Cell Mol Physiol. 2005;288(5):L813–9.CrossRefPubMed
24.
Passero CJ, Mueller GM, Rondon-Berrios H, Tofovic SP, Hughey RP, Kleyman TR. Plasmin activates epithelial Na+ channels by cleaving the γ subunit. J Biol Chem. 2008;283(52):36586–91.CrossRefPubMed
25.
Bruns JB, Carattino MD, Sheng S, Maarouf AB, Weisz OA, Pilewski JM, Hughey RP, Kleyman TR. Epithelial Na+ channels are fully activated by furin- and prostasin-dependent release of an inhibitory peptide from the gamma-subunit. J Biol Chem. 2007;282(9):6153–60.CrossRefPubMed
26.
Hughey RP, Bruns JB, Kinlough CL, Harkleroad KL, Tong Q, Carattino MD, Johnson JP, Stockand JD, Kleyman TR. Epithelial sodium channels are activated by furin-dependent proteolysis. J Biol Chem. 2004;279(18):18111–4.CrossRefPubMed
27.
Rossier BC. The epithelial sodium channel: activation by membrane-bound serine proteases. Proc Am Thorac Soc. 2004;1(1):4–9.CrossRefPubMed
28.
Vuagniaux G, Vallet V, Jaeger NF, Hummler E, Rossier BC. Synergistic activation of ENaC by three membrane-bound channel-activating serine proteases (mCAP1, mCAP2, and mCAP3) and serum- and glucocorticoid-regulated kinase (Sgk1) in Xenopus oocytes. J Gen Physiol. 2002;120(2):191–201.CrossRefPubMed
29.
Carattino MD, Sheng S, Bruns JB, Pilewski JM, Hughey RP, Kleyman TR. The epithelial Na+ channel is inhibited by a peptide derived from proteolytic processing of its α subunit. J Biol Chem. 2006;281(27):18901–7.CrossRefPubMed
30.
Sheng S, Carattino MD, Bruns JB, Hughey RP, Kleyman TR. Furin cleavage activates the epithelial Na+ channel by relieving Na+ self-inhibition. Am J Physiol Ren Physiol. 2006;290(6):F1488–96.CrossRef
31.
Carattino MD, Passero CJ, Steren CA, Maarouf AB, Pilewski JM, Myerburg MM, Hughey RP, Kleyman TR. Defining an inhibitory domain in the alpha-subunit of the epithelial sodium channel. Am J Physiol Ren Physiol. 2008;294(1):F47–52.CrossRef
32.
Hughey RP, Bruns JB, Kinlough CL, Kleyman TR. Distinct pools of epithelial sodium channels are expressed at the plasma membrane. J Biol Chem. 2004;279(47):48491–4.CrossRefPubMed
33.
Caldwell RA, Boucher RC, Stutts MJ. Serine protease activation of near-silent epithelial Na+ channels. Am J Physiol Cell Physiol. 2004;286(1):C190–4.CrossRefPubMed
34.
Baker JB, Low DA, Simmer RL, Cunningham DD. Protease-nexin: a cellular component that links thrombin and plasminogen activator and mediates their binding to cells. Cell. 1980;21(1):37–45.CrossRefPubMed
35.
Gronke RS, Bergman BL, Baker JB. Thrombin interaction with platelets. Influence of a platelet protease nexin. J Biol Chem. 1987;262(7):3030–6.PubMed
36.
Scott RW, Bergman BL, Bajpai A, Hersh RT, Rodriguez H, Jones BN, Barreda C, Watts S, Baker JB. Protease nexin. Properties and a modified purification procedure. J Biol Chem. 1985;260(11):7029–34.PubMed
37.
Wakida N, Kitamura K, Tuyen DG, Maekawa A, Miyoshi T, Adachi M, Shiraishi N, Ko T, Ha V, Nonoguchi H, Tomita K. Inhibition of prostasin-induced ENaC activities by PN-1 and regulation of PN-1 expression by TGF-beta1 and aldosterone. Kidney Int. 2006;70(8):1432–8.CrossRefPubMed
38.
Myerburg MM, McKenna EE, Luke CJ, Frizzell RA, Kleyman TR, Pilewski JM. Prostasin expression is regulated by airway surface liquid volume and is increased in cystic fibrosis. Am J Physiol Lung Cell Mol Physiol. 2008;294(5):L932–41.CrossRefPubMed
39.
40.
Verrey F. Early aldosterone action: toward filling the gap between transcription and transport. Am J Physiol. 1999;277(3 Pt 2):F319–27.PubMed
41.
Chen SY, Bhargava A, Mastroberardino L, Meijer OC, Wang J, Buse P, Firestone GL, Verrey F, Pearce D. Epithelial sodium channel regulated by aldosterone-induced protein sgk. Proc Natl Acad Sci USA. 1999;96(5):2514–9.CrossRefPubMed
42.
Varez de la RD, Canessa CM. Role of SGK in hormonal regulation of epithelial sodium channel in A6 cells. Am J Physiol Cell Physiol. 2003;284(2):C404–14.
43.
Mastroberardino L, Spindler B, Forster I, Loffing J, Assandri R, May A, Verrey F. Ras pathway activates epithelial Na+ channel and decreases its surface expression in Xenopus oocytes. Mol Biol Cell. 1998;9(12):3417–27.PubMed
44.
Stockand JD, Spier BJ, Worrell RT, Yue G, Al-Baldawi N, Eaton DC. Regulation of Na(+) reabsorption by the aldosterone-induced small G protein K-Ras2A. J Biol Chem. 1999;274(50):35449–54.CrossRefPubMed
45.
Kemendy AE, Kleyman TR, Eaton DC. Aldosterone alters the open probability of amiloride-blockable sodium channels in A6 epithelia. Am J Physiol. 1992;263(4 Pt 1):C825–37.PubMed
46.
Bhalla V, Soundararajan R, Pao AC, Li H, Pearce D. Disinhibitory pathways for control of sodium transport: regulation of ENaC by SGK1 and GILZ. Am J Physiol Ren Physiol. 2006;291(4):F714–21.CrossRef
47.
Soundararajan R, Zhang TT, Wang J, Vandewalle A, Pearce D. A novel role for glucocorticoid-induced leucine zipper protein in epithelial sodium channel-mediated sodium transport. J Biol Chem. 2005;280(48):39970–81.CrossRefPubMed
48.
Narikiyo T, Kitamura K, Adachi M, Miyoshi T, Iwashita K, Shiraishi N, Nonoguchi H, Chen LM, Chai KX, Chao J, Tomita K. Regulation of prostasin by aldosterone in the kidney. J Clin Investig. 2002;109(3):401–8.PubMed
49.
Liu L, Hering-Smith KS, Schiro FR, Hamm LL. Serine protease activity in m-1 cortical collecting duct cells. Hypertension. 2002;39(4):860–4.CrossRefPubMed
50.
Fukushima K, Naito H, Funayama Y, Yonezawa H, Haneda S, Shibata C, Sasaki I. ) In vivo induction of prostasin mRNA in colonic epithelial cells by dietary sodium depletion and aldosterone infusion in rats. J Gastroenterol. 2004;39(10):940–7.CrossRefPubMed
51.
Fukushima K, Sato S, Naito H, Funayama Y, Haneda S, Shibata C, Sasaki I. Comparative study of epithelial gene expression in the small intestine among total proctocolectomized, dietary sodium-depleted, and aldosterone-infused rats. J Gastrointest Surg. 2005;9(2):236–44.CrossRefPubMed
52.
Olivieri O, Castagna A, Guarini P, Chiecchi L, Sabaini G, Pizzolo F, Corrocher R, Righetti PG. Urinary prostasin: a candidate marker of epithelial sodium channel activation in humans. Hypertension. 2005;46(4):683–8.CrossRefPubMed
53.
Asher C, Wald H, Rossier BC, Garty H. Aldosterone-induced increase in the abundance of Na+ channel subunits. Am J Physiol. 1996;271(2 Pt 1):C605–11.PubMed
54.
May A, Puoti A, Gaeggeler HP, Horisberger JD, Rossier BC. Early effect of aldosterone on the rate of synthesis of the epithelial sodium channel alpha subunit in A6 renal cells. J Am Soc Nephrol. 1997;8(12):1813–22.PubMed
55.
Lyons RM, Moses HL. Transforming growth factors and the regulation of cell proliferation. Eur J Biochem. 1990;187(3):467–73.CrossRefPubMed
56.
Massague J. Transforming growth factor-alpha. A model for membrane-anchored growth factors. J Biol Chem. 1990;265(35):21393–6.PubMed
57.
Husted RF, Sigmund RD, Stokes JB. Mechanisms of inactivation of the action of aldosterone on collecting duct by TGF-beta. Am J Physiol Ren Physiol. 2000;278(3):F425–33.
58.
Husted RF, Matsushita K, Stokes JB. Induction of resistance to mineralocorticoid hormone in cultured inner medullary collecting duct cells by TGF-beta 1. Am J Physiol. 1994;267(5 Pt 2):F767–75.PubMed
59.
Husted RF, Stokes JB. Separate regulation of Na+ and anion transport by IMCD: location, aldosterone, hypertonicity, TGF-beta 1, and cAMP. Am J Physiol. 1996;271(2 Pt 2):F433–9.PubMed
60.
61.
Houlihan CA, Akdeniz A, Tsalamandris C, Cooper ME, Jerums G, Gilbert RE. Urinary transforming growth factor-beta excretion in patients with hypertension, type 2 diabetes, and elevated albumin excretion rate: effects of angiotensin receptor blockade and sodium restriction. Diabetes Care. 2002;25(6):1072–7.CrossRefPubMed
62.
Tuyen DG, Kitamura K, Adachi M, Miyoshi T, Wakida N, Nagano J, Nonoguchi H, Tomita K. Inhibition of prostasin expression by TGF-beta1 in renal epithelial cells. Kidney Int. 2005;67(1):193–200.CrossRefPubMed
63.
Arsura M, Wu M, Sonenshein GE. TGF beta 1 inhibits NF-kappa B/Rel activity inducing apoptosis of B cells: transcriptional activation of I kappa B alpha. Immunity. 1996;5(1):31–40.CrossRefPubMed
64.
Sovak MA, Arsura M, Zanieski G, Kavanagh KT, Sonenshein GE. The inhibitory effects of transforming growth factor beta1 on breast cancer cell proliferation are mediated through regulation of aberrant nuclear factor-kappaB/Rel expression. Cell Growth Differ. 1999;10(8):537–44.PubMed
65.
Frank J, Roux J, Kawakatsu H, Su G, Dagenais A, Berthiaume Y, Howard M, Canessa CM, Fang X, Sheppard D, Matthay MA, Pittet JF. Transforming growth factor-beta1 decreases expression of the epithelial sodium channel alphaENaC and alveolar epithelial vectorial sodium and fluid transport via an ERK1/2-dependent mechanism. J Biol Chem. 2003;278(45):43939–50.CrossRefPubMed
66.
Ying WZ, Sanders PW. Dietary salt modulates renal production of transforming growth factor-beta in rats. Am J Physiol. 1998;274(4 Pt 2):F635–41.PubMed
67.
Juknevicius I, Segal Y, Kren S, Lee R, Hostetter TH. Effect of aldosterone on renal transforming growth factor-beta. Am J Physiol Ren Physiol. 2004;286(6):F1059–62.CrossRef
Metadata
Title
Regulation of renal sodium handling through the interaction between serine proteases and serine protease inhibitors
Authors
Kenichiro Kitamura
Kimio Tomita
Publication date
01-10-2010
Publisher
Springer Japan
Published in
Clinical and Experimental Nephrology / Issue 5/2010
Print ISSN: 1342-1751
Electronic ISSN: 1437-7799
DOI
https://doi.org/10.1007/s10157-010-0299-7

Other articles of this Issue 5/2010

Clinical and Experimental Nephrology 5/2010 Go to the issue

Original Article

Incidence of symptomatic stroke and cancer in chronic kidney disease patients treated with epoetins

Case Report

Rapidly progressive lupus nephritis and concomitant thrombotic microangiopathy

Original Article

Effect of changes in renal circulation on serum uric acid levels in women with twin pregnancy

Letter to the Editor

Clinical improvement in patients with autosomal recessive pseudohypoaldosteronism and the necessity for salt supplementation

Original Article

Association between IGF-1 and chronic kidney disease among US adults

Case Report

Rapidly progressive cryoglobulinemic glomerulonephritis

ACC 2024 Congress Coverage

Heart Failure Video

Year in Review: Heart failure and cardiomyopathies

Watch now

Watch this official video from ACC.24 to hear Dr. Biykem Bozkurt discuss last year's major advances in heart failure and cardiomyopathies.

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

16-04-2024 Type 2 Diabetes News

Incentivised to exercise

11-04-2024 Lifestyle Modifications News

New intervention for STEMI-related cardiogenic shock

10-04-2024 Myocardial Infarction News

» View more highlights on the ACC 2024 congress hub page

Image Credits