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Slc26a4 (Pds, pendrin) is an anion transporter expressed in the apical region of type B and non-A, non-B intercalated cells of the distal nephron. It is upregulated by aldosterone analogues and is critical in the development of mineralocorticoid-induced hypertension. Thus, Slc26a4 expression and its role in blood pressure and fluid and electrolyte homeostasis was explored during NaCl restriction, a treatment model in which aldosterone is appropriately increased. Ultrastructural immunolocalization, balance studies, and cortical collecting ducts (CCDs) perfused in vitro were used. With moderate physiological NaCl restriction, Slc26a4 expression in the apical plasma membrane increased 2- to 3-fold in type B intercalated cells. Because Slc26a4 transports Cl-, we tested whether NaCl balance differs in Slc26a4(+/+) and Slc26a4(-/-) mice during NaCl restriction. Cl- absorption was observed in CCDs from Slc26a4(+/+) but not from Slc26a4(-/-) mice. After moderate NaCl restriction, urinary volume and Cl- excretion were increased in Slc26a4(-/-) relative to Slc26a4(+/+) mice. Moreover, Slc26a4(-/-) mice had evidence of relative vascular volume depletion because they had a higher arterial pH, hematocrit, and blood urea nitrogen than wild-type mice. With moderate NaCl restriction, blood pressure was similar in Slc26a4(+/+) and Slc26a4(-/-) mice. However, on a severely restricted intake of NaCl, Slc26a4(-/-) mice were hypotensive relative to wild-type mice. We conclude that Slc26a4 is upregulated with NaCl restriction and is critical in the maintenance of acid-base balance and in the renal conservation of Cl- and water during NaCl restriction.