Zymogen-locked mutant prostasin (Prss8) leads to incomplete proteolytic activation of the epithelial sodium channel (ENaC) and severely compromises triamterene tolerance in mice.
ENaC
Prostasin
Prss8
Prss8-R44Q
Prss8-S238A
epithelial sodium channel
Journal
Acta physiologica (Oxford, England)
ISSN: 1748-1716
Titre abrégé: Acta Physiol (Oxf)
Pays: England
ID NLM: 101262545
Informations de publication
Date de publication:
05 2021
05 2021
Historique:
revised:
15
02
2021
received:
18
11
2020
accepted:
26
02
2021
pubmed:
3
3
2021
medline:
8
7
2021
entrez:
2
3
2021
Statut:
ppublish
Résumé
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. 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. 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. 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.
Identifiants
pubmed: 33650216
doi: 10.1111/apha.13640
pmc: PMC8159854
mid: NIHMS1680213
doi:
Substances chimiques
Enzyme Precursors
0
Epithelial Sodium Channels
0
Serine Endopeptidases
EC 3.4.21.-
prostasin
EC 3.4.21.-
Triamterene
WS821Z52LQ
Types de publication
Journal Article
Research Support, N.I.H., Intramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e13640Subventions
Organisme : Intramural NIH HHS
ID : Z01 DE000699
Pays : United States
Commentaires et corrections
Type : CommentIn
Informations de copyright
© 2021 The Authors. Acta Physiologica published by John Wiley & Sons Ltd on behalf of Scandinavian Physiological Society.
Références
Annu Rev Physiol. 2009;71:361-79
pubmed: 18928407
J Am Soc Nephrol. 2014 Jul;25(7):1453-64
pubmed: 24480829
Am J Nephrol. 2004 Nov-Dec;24(6):595-605
pubmed: 15564765
Am J Physiol Renal Physiol. 2019 Dec 1;317(6):F1612-F1622
pubmed: 31566425
Proc Natl Acad Sci U S A. 1996 Nov 12;93(23):13362-6
pubmed: 8917596
Acta Physiol (Oxf). 2018 Sep;224(1):e13060
pubmed: 29489063
J Biol Chem. 2021 Feb 9;:100404
pubmed: 33577799
J Biol Chem. 2006 Nov 3;281(44):32941-5
pubmed: 16980306
Acta Physiol (Oxf). 2019 Dec;227(4):e13286
pubmed: 31006168
Eur J Biochem. 1988 Feb 15;172(1):17-25
pubmed: 3278905
Annu Rev Physiol. 2018 Feb 10;80:263-281
pubmed: 29120692
Pflugers Arch. 2018 Apr;470(4):649-660
pubmed: 29397423
Kidney Blood Press Res. 2009;32(2):119-27
pubmed: 19401625
J Am Soc Nephrol. 2018 Mar;29(3):977-990
pubmed: 29371419
Biochem Biophys Res Commun. 2004 Nov 12;324(2):953-63
pubmed: 15474520
J Biol Chem. 2007 Mar 2;282(9):6153-60
pubmed: 17199078
Pflugers Arch. 2017 Jun;469(5-6):655-667
pubmed: 28233126
J Clin Invest. 2002 Feb;109(3):401-8
pubmed: 11828000
J Proteomics. 2021 Jan 6;230:103981
pubmed: 32927112
J Biol Chem. 2014 Jul 4;289(27):19067-78
pubmed: 24841206
Am J Physiol Renal Physiol. 2017 Jan 1;312(1):F65-F76
pubmed: 27413200
J Biol Chem. 1994 Jul 22;269(29):18843-8
pubmed: 8034638
J Biol Chem. 2014 May 23;289(21):14740-9
pubmed: 24706745
Am J Physiol Renal Physiol. 2021 Mar 1;320(3):F485-F491
pubmed: 33522411
Nephrol Dial Transplant. 2015 May;30(5):781-9
pubmed: 25609736
Science. 2018 May 18;360(6390):758-763
pubmed: 29622724
PLoS One. 2018 Apr 4;13(4):e0194660
pubmed: 29617460
J Clin Invest. 1999 Oct;104(7):R19-23
pubmed: 10510339
Acta Physiol (Oxf). 2021 Jan;231(1):e13512
pubmed: 32455507
J Gen Physiol. 2012 Oct;140(4):375-89
pubmed: 22966015
J Biol Chem. 1995 Jun 2;270(22):13483-9
pubmed: 7768952
J Biol Chem. 2009 Jul 31;284(31):20447-51
pubmed: 19401469
J Physiol. 2008 Oct 1;586(19):4587-608
pubmed: 18669538
Am J Physiol Renal Physiol. 2014 Nov 1;307(9):F1080-7
pubmed: 25209858
PLoS One. 2013;8(2):e55796
pubmed: 23405214
J Clin Invest. 2016 May 2;126(5):1773-82
pubmed: 27043284
J Biol Chem. 2016 Sep 16;291(38):19835-47
pubmed: 27489102
J Am Soc Nephrol. 2006 Apr;17(4):968-76
pubmed: 16524950
Proc Natl Acad Sci U S A. 2017 Nov 14;114(46):E9989-E9998
pubmed: 29089413
Am J Respir Crit Care Med. 2016 Sep 15;194(6):701-10
pubmed: 27014936
J Cell Biol. 2005 Aug 1;170(3):487-96
pubmed: 16061697
J Am Soc Nephrol. 2018 May;29(5):1411-1425
pubmed: 29483157
J Am Soc Nephrol. 2000 May;11(5):828-834
pubmed: 10770960
Hypertension. 2016 Jun;67(6):1256-62
pubmed: 27170740
J Biol Chem. 2016 Feb 5;291(6):2577-82
pubmed: 26719335
J Am Soc Nephrol. 2001 Jun;12(6):1114-1121
pubmed: 11373334
Am J Physiol Renal Physiol. 2000 Aug;279(2):F252-8
pubmed: 10919843
J Am Soc Nephrol. 2015 Nov;26(11):2669-77
pubmed: 25817355