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1 Department of Medicine, Emory University, Atlanta, GA, USA
2 Department of Medicine, University of Florida College of Medicine, Gainesville, FL, USA
3 Division of Nephrology, University of California, Los Angeles, Los Angeles, LA, USA
4 Nephrology and Hypertension Section, North Florida/South Georgia Veterans Health System, Gainesville, FL, USA
5 Wellcome Trust Genome Campus, The Wellcome Trust Sanger Institute, Cambridge, United Kingdom
6 Genome Technology Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA
7 The Water and Salt Research Center, Aarhus University, Aarhus, Denmark
* To whom correspondence should be addressed. E-mail: smwall{at}emory.edu.
Pendrin is a Cl-/HCO3 - exchanger, encoded by Slc26a4 (Pds), which is expressed in the apical regions of type B and non-A, non-B cells of the kidney and mediates secretion of OH- equivalents. With genetic disruption of Slc26a4, net OH- secretion and net Cl- absorption are reduced within the CCD which leads to systemic alkalosis in some treatment models. Thus pendrin is critical in the regulation of arterial and probably intracellular pH (pHi). However, humans and mice with genetic disruption of Slc26a4 have normal acid-base balance and normal kidney function under basal conditions. Thus, we asked the following questions: 1) Is net acid excretion the same in Slc26a4 (-/-) and Slc26a4 (+/+) mice under basal conditions? 2) In the absence of Slc26a4-mediated OH- secretion, are cellular and systemic alkalosis minimized through changes either in the relative abundance of the various intercalated cell subtypes or through changes in abundance of H+/OH- transporters expressed within intercalated cells? To answer these questions, net acid excretion and H+-ATPase, NBC3 (Slc4a6), RhBG and RhCG protein expression were examined in Slc26a4 (-/-) and Slc26a4 (+/+) mice using balance studies, immunolocalization and immunoblotting. Ammonium excretion, titratable acid and citrate excretion were the same in Slc26a4 null and wild type mice. However, urinary pH and pCO2 were much lower in Slc26a4 null relative to wild type mice, consistent with reduced HCO3 - available to buffer secreted H+. Type A intercalated cell abundance was unchanged, although the abundance of non-A intercalated cells was reduced within the CCD of Slc26a4 null mice. H+-ATPase and RhBG total protein expression were significantly decreased in kidneys from Slc26a4 null mice, although RhCG protein expression was unchanged. However H+-ATPase, as well as NBC3 protein expression were decreased much more in type B and non-A, non-B than in type A intercalated cells. Conclusions: Reduced expression of H+/OH- transporters that localize to renal intercalated cells is observed in Slc26a4 null mice. This adaptive change likely attenuates the rise in intracellular and systemic pH expected with genetic disruption of Slc26a4.
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