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Cellular |
Divisions of
1 Nephrology
2 Pulmonary and Critical Care Medicine
3 Departments of Medicine and Physiology and Biophysics
4 the Will Rogers Institute Pulmonary Research Center, University of Southern California Keck School of Medicine, Los Angeles, CA 90033, USA
Renal net acid excretion requires tubular reabsorption of filtered bicarbonate, followed by secretion of protons and ammonium in the collecting duct, generating steep transtubular gradients for these ions. To prevent passive backleak of these ions, the tight junctions in the collecting duct must be highly impermeable to these ions. We previously generated a Madin-Darby canine kidney (MDCK II) cell line with inducible expression of claudin-8, a tight junction protein expressed in the collecting duct. In these cells, claudin-8 was shown to function as a paracellular barrier to alkali metal and divalent cations. We have now used this model to test the hypothesis that claudin-8 also functions as a paracellular barrier to acidic or basic ions involved in renal acid excretion. We developed a series of precise and unbiased methods, based on a combination of diffusion potential, short-circuit current, and pH stat measurements, to estimate paracellular permeability to protons, ammonium and bicarbonate in MDCK II cells. We found that under control conditions (i.e. in the absence of claudin-8), these cells are highly permeable to the acidic and basic ions tested. Interestingly, proton permeation exhibited an unusually low activation energy similar to that in bulk solution. This suggests that paracellular proton transfer may occur by a Grotthuss mechanism, implying that the paracellular pores are sufficiently wide to accommodate water molecules in a freely mobile state. Induction of claudin-8 expression reduces permeability not only to protons, but also to ammonium and bicarbonate. We conclude that claudin-8 probably functions to limit the passive leak of these three ions via paracellular routes, thereby playing a permissive role in urinary net acid excretion.
(Received 21 September 2005;
accepted after revision 24 November 2005;
first published online 1 December 2005)
Corresponding author A. S. L. Yu: University of Southern California Keck School of Medicine, Division of Nephrology, 2025 Zonal Avenue, RMR 406, Los Angeles, CA 90033, USA. Email: alanyu{at}usc.edu
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