Membrane sodium-hydrogen exchangers (NHEs), found in virtually all cell types, appear to have diverse and essential roles in regulating cellular pH and mediating vectorial transport by epithelial cells. However, the functional and physiological role of the recently cloned isoform NHE-4 remains unknown. Unlike other Na-H exchanger isoforms, NHE-4 transfected into NHE-deficient mutant fibroblasts demonstrated no amiloride-inhibitable sodium uptake, under basal or acid-loaded isoosmotic conditions. By immunoblot analysis, only the NHE-4 transfectants synthesized a 100-kDa protein, which cross-reacted to polyclonal antibody made to an NHE-4 fusion protein. However, when cells were subjected to acute hyperosmolar cell shrinkage conditions, amiloride-sensitive NHE activity was readily detected at 420 mosm, exhibiting maximal activity at 490 mosm. By in situ hybridization, NHE-4 expression in the rat kidney was found to be limited to the inner renal medullary collecting tubules, the region of highest tissue osmolarity fluctuations in the body. We conclude that NHE-4 is an unusual isoform of sodium-hydrogen exchangers that may play a specialized supplementary role in cell volume regulation.
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