Role of NHE isoforms in mediating bicarbonate reabsorption along the nephron

Abstract

This study assessed the functional role of Na(+)/H(+) exchanger (NHE) isoforms NHE3 and NHE2 in the proximal tubule, loop of Henle, and distal convoluted tubule of the rat kidney by comparing sensitivity of transport to inhibition by Hoe-694 (an agent known to inhibit NHE2 but not NHE3) and S-3226 (an agent with much higher affinity for NHE3 than NHE2). Rates of transport of fluid (J(v)) and HCO(3)(-) (J(HCO3)) were studied by in situ microperfusion. In the proximal tubule, addition of ethylisopropylamiloride or S-3226 significantly reduced J(v) and J(HCO3), but addition of Hoe-694 caused no significant inhibition. In the loop of Henle, J(HCO3) was also inhibited by S-3226 and not by Hoe-694, although much higher concentrations of S-3226 were required than what was necessary to inhibit transport in the proximal tubule. In contrast, in the distal convoluted tubule, J(HCO3) was inhibited by Hoe-694 but not by S-3226. These results are consistent with the conclusion that NHE2 rather than NHE3 is the predominant isoform responsible for apical membrane Na(+)/H(+) exchange in the distal convoluted tubule, whereas NHE3 is the predominant apical isoform in the proximal tubule and possibly also in the loop of Henle.

Chloride-Dependent Intracellular pH Regulation via Extracellular Calcium-Sensing Receptor in the Medullary Thick Ascending Limb of the Mouse Kidney

“…The H + -ATPase is selectively localized to luminal membranes and submembranous vesicles. It has also been demonstrated that the luminal membranes of the TALs possess NHE3 and another Na + /H + exchanger NHE2 in rat kidneys (Wang et al 2001;Capasso et al 2002). In our experimental protocol, we examined the involvement of these Na + /H + exchangers in the luminal membranes of the mTALs by either inhibiting ambient Na + with a high dose of amiloride or eliminating ambient Na + .…”

Renal Vacuolar H+-ATPase

“…As for the proximal tubule, proton and bicarbonate transport in the thick ascending limb of Henle's loop are mediated by the vacuolar H ϩ -ATPase, along with other transporters including the Na ϩ /H ϩ exchanger NHE-3 (96,554). Both the electroneutral NBC(N)1 (538) and electrogenic NBC4 (577) are expressed in the thick ascending limb (TAL).…”

“…The main Na ϩ /H ϩ exchanger isoform is NHE-3, but NHE-2 may also play a role (98,554). The reabsorbed HCO 3 Ϫ is excreted into blood possi-bly through a K ϩ -dependent HCO 3 Ϫ pathway (56), the molecular identity of which is not resolved.…”

Molecular detection and immunological localization of gill Na+/H+exchanger in the dogfish (Squalus acanthias)

“…In mammals, NHE2 is primarily found in skeletal muscle, kidney, and the gastrointestinal tract, whereas NHE3 is mainly in the renal tubule, intestine, and stomach (39,70). NHE3 is the predominant apical exchanger in the renal proximal tubule and is upregulated during metabolic acidosis (43,68), whereas NHE2 may be the predominant isoform in the distal convoluted tubule (63) and apical membranes of colonic crypts (30). Phylogenetic analysis of the NHE family indicates that NHE1, NHE2, and NHE4 are closely related (all belonging to the resident plasma membrane NHE clade; see Ref.…”