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Reduced ENaC protein abundance contributes to the lower blood pressure observed in pendrin-null mice

Departments of ¹Medicine and ²Physiology, Emory University, Atlanta, Georgia; ³Hypertension and Vascular Research Division, Henry Ford Hospital and Wayne State School of Medicine, Detroit, Michigan; ⁴The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, United Kingdom; ⁵Genome Technology Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland; ⁶Department of Medicine, University of Florida, Gainesville, Florida; and ⁷Atlanta Veterans Affairs Medical Center, Atlanta, Georgia

Submitted 2 April 2007 ; accepted in final form 2 August 2007

Pendrin (encoded by Pds, Slc26a4) is a Cl^–/HCO₃^– exchanger expressed in the apical regions of type B and non-A, non-B intercalated cells of kidney and mediates renal Cl^– absorption, particularly when upregulated. Aldosterone increases blood pressure by increasing absorption of both Na⁺ and Cl^– through increased protein abundance and function of Na⁺ transporters, such as the epithelial Na⁺ channel (ENaC) and the Na⁺-Cl^– cotransporter (NCC), as well as Cl^– transporters, such as pendrin. Because aldosterone analogs do not increase blood pressure in Slc26a4^–/– mice, we asked whether Na⁺ excretion and Na⁺ transporter protein abundance are altered in kidneys from these mutant mice. Thus wild-type and Slc26a4-null mice were given a NaCl-replete, a NaCl-restricted, or NaCl-replete diet and aldosterone or aldosterone analogs. Abundance of the major renal Na⁺ transporters was examined with immunoblots and immunohistochemistry. Slc26a4-null mice showed an impaired ability to conserve Na⁺ during dietary NaCl restriction. Under treatment conditions in which circulating aldosterone is increased, -, -, and 85-kDa -ENaC subunit protein abundances were reduced 15–35%, whereas abundance of the 70-kDa fragment of -ENaC was reduced 70% in Slc26a4-null relative to wild-type mice. Moreover, ENaC-dependent changes in transepithelial voltage were much lower in cortical collecting ducts from Slc26a4-null than from wild-type mice. Thus, in kidney, ENaC protein abundance and function are modulated by pendrin or through a pendrin-dependent downstream event. The reduced ENaC protein abundance and function observed in Slc26a4-null mice contribute to their lower blood pressure and reduced ability to conserve Na⁺ during NaCl restriction.

intercalated cell; Slc26a4; apical Cl^–/HCO₃^– exchanger; epithelial sodium channel; aldosterone

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