Defective fluid secretion and NaCl absorption in the parotid glands of Na+/H+ exchanger-deficient mice

Multiple Na+/H+ exchangers (NHEs) are expressed in salivary gland cells; ho wever, their functions in the secretion of saliva by acinar cells and the s ubsequent modification of the ionic composition of this-fluid by the ducts are unclear. Mice with targeted disruptions of the Nhe1, Nhe2, and Nhe3 gen es were used to study the,in vivo functions of these exchangers in parotid glands. Immunohistochemistry indicated that NHE1 was localized to the basol ateral and NHE2 to apical membranes of both acinar and duct cells, whereas NHE3 was restricted to the apical region of duct cells. Na+/H+ exchange was reduced more than 95% in acinar cells and greater than 80% in duet cells o f NKE1-deficient mice (Nhe1(-/-)). Salivation in response to pilocarpine st imulation was reduced significantly in both Nhe1(-/-) and Nhe2(-/-) mice, p articularly during prolonged stimulation, whereas the loss of NHE3 had no e ffect on secretion. Expression of Na+/K+/2Cl(-) cotransporter mRNA increase d dramatically in Nhe1(-/-) parotid glands but not in those of Nhe2(-/-) or Nhe3(-/-) mice, suggesting that compensation occurs for the Loss of NHE1. The sodium content, chloride activity and osmolality of saliva in Nhe2(-/-) or Nhe3(-/-) mice were comparable with those of wild-type mice. In contras t, Nhe1(-/-) mice displayed impaired NaCl absorption. These results suggest that in parotid duct cells apical NHE2 and NHE3 do not play a major role i n Na+ absorption. These results also demonstrate that basolateral NHE1 and apical NHE2 modulate saliva secretion in viva, especially during sustained stimulation when secretion depends less on Na+/K+/2Cl(-) cotransporter acti vity.