Pendrin modulates ENaC function by changing luminal HCO3-.
The epithelial Na(+) channel, ENaC, and the Cl(-)/HCO(3)(-) exchanger, pendrin, mediate NaCl absorption within the cortical collecting duct and the connecting tubule. Although pendrin and ENaC localize to different cell types, ENaC subunit abundance and activity are lower in aldosterone-treated pendrin-null mice relative to wild-type mice. Because pendrin mediates HCO(3)(-) secretion, we asked if increasing distal delivery of HCO(3)(-) through a pendrin-independent mechanism "rescues" ENaC function in pendrin-null mice. We gave aldosterone and NaHCO(3) to increase pendrin-dependent HCO(3)(-) secretion within the connecting tubule and cortical collecting duct, or gave aldosterone and NaHCO(3) plus acetazolamide to increase luminal HCO(3)(-) concentration, [HCO(3)(-)], independent of pendrin. Following treatment with aldosterone and NaHCO(3), pendrin-null mice had lower urinary pH and [HCO(3)(-)] as well as lower renal ENaC abundance and function than wild-type mice. With the addition of acetazolamide, however, acid-base balance as well as ENaC subunit abundance and function was similar in pendrin-null and wild-type mice. We explored whether [HCO(3)(-)] directly alters ENaC abundance and function in cultured mouse principal cells (mpkCCD). Amiloride-sensitive current and ENaC abundance rose with increased [HCO(3)(-)] on the apical or the basolateral side, independent of the substituting anion. However, ENaC was more sensitive to changes in [HCO(3)(-)] on the basolateral side of the monolayer. Moreover, increasing [HCO(3)(-)] on the apical and basolateral side of Xenopus kidney cells increased both ENaC channel density and channel activity. We conclude that pendrin modulates ENaC abundance and function, at least in part by increasing luminal [HCO(3)(-)] and/or pH.
Department of Medicine, Emory University School of Medicine, Atlanta, GA 30322, USA.
Vladimir
V
Pech
Truyen D
TD
Pham
Seongun
S
Hong
Alan M
AM
Weinstein
Kathryn B
KB
Spencer
Billy Jean
BJ
Duke
Eric
E
Walp
Young Hee
YH
Kim
Roy L
RL
Sutliff
Hui-Fang
HF
Bao
Douglas C
DC
Eaton
Susan M
SM
Wall
D000086:Acetazolamide / Q000494:pharmacology; D000450:Aldosterone / Q000494:pharmacology; D000818:Animals; D027321:Anion Transport Proteins / Q000235:genetics / Q000378:metabolism*; D001639:Bicarbonates / Q000378:metabolism*; D001794:Blood Pressure / Q000502:physiology; D002460:Cell Line; D004232:Diuretics / Q000494:pharmacology; D053503:Epithelial Sodium Channels / Q000378:metabolism*; D005260:Female; D006863:Hydrogen-Ion Concentration; D007672:Kidney Cortex / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D007685:Kidney Tubules, Collecting / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D023421:Models, Animal; D018408:Patch-Clamp Techniques; D017693:Sodium Bicarbonate / Q000494:pharmacology; D000076988:Sulfate Transporters; D014981:Xenopus
D027321:Anion Transport Proteins; D001639:Bicarbonates; D004232:Diuretics; D053503:Epithelial Sodium Channels; C494849:Slc26a4 protein, mouse; D000076988:Sulfate Transporters; D000450:Aldosterone; D017693:Sodium Bicarbonate; D000086:Acetazolamide