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J. Biol. Chem., Vol. 283, Issue 8, 4602-4611, February 22, 2008

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Defective ENaC Processing and Function in Tissue Kallikrein-deficient Mice^*

Nicolas Picard¹, Dominique Eladari¹², Soumaya El Moghrabi, Carole Planès^¶, Soline Bourgeois, Pascal Houillier, Qing Wang^||, Michel Burnier^||, Georges Deschenes^**, Mark A. Knepper³, Pierre Meneton, and Régine Chambrey⁴

From the INSERM U872 (Centre de Recherche des Cordeliers), Université Paris 5, Faculté de Médecine René Descartes F-75006, Paris, Département de Physiologie, Hôpital Necker-Enfants Malades, F-75015, Paris, ^¶INSERM U773 (CRB3), Universite Paris 7, UFR de Medecine, Site Bichat, F-75018, Paris, ^||Department of Nephrology, Centre Hospitalier Universitaire Vaudois, CH-1011, Lausanne, and ^**CNRS UMR 7134, UPMC, F-75006, Paris, France and Laboratory of Kidney and Electrolyte Metabolism, NHLBI, National Institutes of Health, Bethesda, Maryland 20892

An inverse relationship exists between urinary tissue kallikrein (TK) excretion and blood pressure in humans and rodents. In the kidney TK is synthesized in large amounts in the connecting tubule and is mainly released into the urinary fluid where its function remains unknown. In the present study mice with no functional gene coding for TK (TK^–/–) were used to test whether the enzyme regulates apically expressed sodium transporters. Semiquantitative immunoblotting of the renal cortex revealed an absence of the 70-kDa form of -ENaC in TK^–/– mice. Urinary Na⁺ excretion after amiloride injection was blunted in TK^–/– mice, consistent with reduced renal ENaC activity. Amiloride-sensitive transepithelial potential difference in the colon, where TK is also expressed, was decreased in TK^–/– mice, whereas amiloride-sensitive alveolar fluid clearance in the lung, where TK is not expressed, was unchanged. In mice lacking the B2 receptor for kinins, the abundance of the 70-kDa form of -ENaC was increased, indicating that its absence in TK^–/– mice is not kinin-mediated. Incubation of membrane proteins from renal cortex of TK^–/– mice with TK resulted in the appearance of the 70-kDa band of the -ENaC, indicating that TK was able to promote -ENaC cleavage in vitro. Finally, in mouse cortical collecting ducts isolated and microperfused in vitro, the addition of TK in the luminal fluid increased significantly intracellular Na⁺ concentration, consistent with an activation of the luminal entry of the cation. The results demonstrate that TK, like several other proteases, can activate ENaC in the kidney and the colon.

Received for publication, July 10, 2007 , and in revised form, December 12, 2007.

^* This work was supported in part by the INSERM and by the Société de Néphrologie (Ph.D. support to N. P. and S. E. M.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ These authors contributed equally to this work and share first authorship.

³ Supported by the intramural budget of the NHLBI, National Institutes of Health Project HL-001285.

² To whom correspondence may be addressed: INSERM Unité 872, Centre de Recherche des Cordeliers, 15 rue de l'Ecole de médecine, 75006, Paris, France. Tel.: 33-1-44-41-37-18; Fax: 33-1-44-41-37-17; E-mail: eladari{at}ccr.jussieu.fr. ⁴ To whom correspondence may be addressed: INSERM Unité 872, Centre de Recherche des Cordeliers, 15 rue de l'Ecole de médecine, 75006, Paris, France. Tel.: 33-1-44-41-37-18; Fax: 33-1-44-41-37-17; E-mail: chambrey{at}ccr.jussieu.fr.

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