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1 Medicine, Emory University, Atlanta, Georgia, United States
2 Medicine, Emory University School of Medicine, Atlanta, Georgia, United States
3 Hypertension and Vascular Research Division, Henry Ford Hospital and Wayne State School of Medicine, Detroit, Michigan, United States
4 The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Cambridge, United Kingdom
5 NHGRI
6 Medicine, University of Florida, Gainesville, Florida, United States
7 Medicine, Emory University School of Medicine, Atlanta, Georgia, United States; Medicine, Atlanta VA Medical Center, Decatur, Georgia, United States
8 Medicine, Emory University School of Medicine, Atlanta, Georgia, United States; Physiology, Emory University School of Medicine, Atlanta, Georgia, United States
* To whom correspondence should be addressed. E-mail: ajprenal{at}emory.edu.
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 ENaC and NCC, and Cl- transporters, such as pendrin. Because aldosterone analogues do not increase blood pressure in Slc26a4 (-/-) mice, we asked if Na+ excretion and Na+ transporter protein abundance is altered in kidneys from these mutant mice. Thus, wild type and Slc26a4 null mice were given a NaCl-replete, a NaCl-restricted, or a NaCl-replete diet and aldosterone or aldosterone analogues. Abundance of the major renal Na+ transporters was examined using immunoblots and immunohistochemistry. Slc26a4 null mice showed an impaired ability to conserve Na+ during dietary NaCl restriction. Under conditions where circulating aldosterone is increased, 
, 
and 85 kD 
ENaC subunit protein abundance were reduced 15-35%, while abundance of the 70 kD fragment of ENaC protein abundance was reduced ~ 70% in Slc26a4 null relative to wild type mice. Moreover, ENaC-dependent changes in transepithelial voltage were much lower in CCDs from Slc26a4 null than 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 contributes to their lower blood pressure and reduced ability to conserve Na+ during NaCl restriction.
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