Renal Proteinase-activated Receptor 2, a New Actor in the Control of Blood Pressure and Plasma Potassium Level

Proteinase-activated receptor 2 (PAR2) is a G protein-coupled membrane receptor that is activated upon cleavage of its extracellular N-terminal domain by trypsin and related proteases. PAR2 is expressed in kidney collecting ducts, a main site of control of Na+ and K+ homeostasis, but its function re...

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Published in:The Journal of biological chemistry 2013-04, Vol.288 (14), p.10124-10131
Main Authors: Morla, Luciana, Brideau, Gaëlle, Fila, Marc, Crambert, Gilles, Cheval, Lydie, Houillier, Pascal, Ramakrishnan, Sureshkrishna, Imbert-Teboul, Martine, Doucet, Alain
Format: Article
Language:English
Subjects:
Aldosterone
Aldosterone - metabolism
Animals
Blood Pressure
Calcium
Calcium - metabolism
Diuretics
Diuretics - pharmacology
Gene Expression Regulation
Homeostasis
Kidney
Kidney - metabolism
Life Sciences
Male
Metabolism
Mice
Mice, Transgenic
Perfusion
Plasma Potassium Concentration
Potassium
Potassium - blood
Potassium Transport
Protease
Proteinase-activated Receptor
Rats
Rats, Sprague-Dawley
Receptor, PAR-2
Receptor, PAR-2 - metabolism
Sodium
Sodium - blood
Sodium Transport
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Summary:Proteinase-activated receptor 2 (PAR2) is a G protein-coupled membrane receptor that is activated upon cleavage of its extracellular N-terminal domain by trypsin and related proteases. PAR2 is expressed in kidney collecting ducts, a main site of control of Na+ and K+ homeostasis, but its function remains unknown. We evaluated whether and how PAR2 might control electrolyte transport in collecting ducts, and thereby participate in the regulation of blood pressure and plasma K+ concentration. PAR2 is expressed at the basolateral border of principal and intercalated cells of the collecting duct where it inhibits K+ secretion and stimulates Na+ reabsorption, respectively. Invalidation of PAR2 gene impairs the ability of the kidney to control Na+ and K+ balance and promotes hypotension and hypokalemia in response to Na+ and K+ depletion, respectively. This study not only reveals a new role of proteases in the control of blood pressure and plasma potassium level, but it also identifies a second membrane receptor, after angiotensin 2 receptor, that differentially controls sodium reabsorption and potassium secretion in the late distal tubule. Conversely to angiotensin 2 receptor, PAR2 is involved in the regulation of sodium and potassium balance in the context of either stimulation or nonstimulation of the renin/angiotensin/aldosterone system. Therefore PAR2 appears not only as a new actor of the aldosterone paradox, but also as an aldosterone-independent modulator of blood pressure and plasma potassium. Background: The function of proteinase-activated receptor 2 (PAR2) in the distal nephron remains unknown. Results: PAR2 activation increases electroneutral sodium reabsorption and inhibits potassium secretion in collecting ducts and thereby controls blood pressure and plasma potassium. Conclusion: PAR2 controls sodium and potassium homeostasis. Significance: PAR2 is a new actor of aldosterone paradox but also an aldosterone-independent modulator of blood pressure and plasma potassium.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M112.446393