A UNIQUE SODIUM-HYDROGEN EXCHANGE ISOFORM (NHE-4) OF THE INNER MEDULLA OF THE RAT-KIDNEY IS INDUCED BY HYPEROSMOLARITY

Membrane sodium-hydrogen exchangers (NHEs), found in virtually all cel l types, appear to have diverse and essential roles in regulating cell ular 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 tr ansfected into NHE-deficient mutant fibroblasts demonstrated no amilor ide-inhibitable sodium uptake, under basal or acid-loaded isoosmotic c onditions. By immunoblot analysis, only the NHE-4 transfectants synthe sized a 100-kDa protein, which cross-reacted to polyclonal antibody ma de to an NHE-4 fusion protein. However, when cells were subjected to a cute hyperosmolar cell shrinkage conditions, amiloride-sensitive NHE a ctivity was readily detected at 420 mosm, exhibiting maximal activity at 490 mosm. By in situ hybridization, NHE-4 expression in the rat kid ney was found to be Limited to the inner renal medullary collecting t ubules, the region of highest tissue osmolarity fluctuations in the bo dy. We conclude that NHE-4 is an unusual isoform of sodium-hydrogen ex changers that may play a specialized supplementary role in cell volume regulation.