Novel amiloride-sensitive sodium-dependent proton secretion in the mouse proximal convoluted tubule

The proximal convoluted tubule (PCT) reabsorbs most of the filtered bicarbo nate. Proton secretion is believed to be mediated predominantly by an epica l membrane Na+/H+ exchanger (NHE). Several NHE isoforms have been cloned, b ut only NHE3 and NHE2 are known to be present on the apical membrane of the PCT. Here we examined apical membrane PCT sodium-dependent proton secretio n of wild-type (NHE3(+/+)/NHE2(+/+)), NHE3(-/-), NHE2(-/-), and double-knoc kout NNE3(-/-)/NHE2(-/-) mice to determine their relative contribution to l uminal proton secretion. NHE2(-/-) and wild-type mice had comparable rates of sodium-dependent proton secretion. Sodium-dependent proton secretion in NHE3(-/-) mice was approximately 50% that of wild-type mice. The residual s odium-dependent proton secretion was inhibited by 100 mu M 5-(N-ethyl-N-iso propyl) amiloride (EIPA). Luminal sodium-dependent proton secretion was the same in NHE3(-/-)/NHE2(-/-) as in NHE3(-/-) mice. These data point to a pr eviously unrecognized Na+-dependent EIPA-sensitive proton secretory mechani sm in the proximal tubule that may play an important role in acid-base home ostasis.