Defective Fluid Secretion and NaCl Absorption in the Parotid Glands of Na+/H+ Exchanger-deficient Mice

Abstract

Multiple Na؉ /H ؉ exchangers (NHEs) are expressed in salivary gland cells; however, their functions in the secretion of saliva by acinar cells and the subsequent modification of the ionic composition of this fluid by the ducts are unclear. Mice with targeted disruptions of the Nhe1, Nhe2, and Nhe3 genes were used to study the in vivo functions of these exchangers in parotid glands. Immunohistochemistry indicated that NHE1 was localized to the basolateral 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 duct cells of NHE1-deficient mice (Nhe1 ؊/؊ ). Salivation in response to pilocarpine stimulation was reduced significantly in both Nhe1 ؊/؊ and Nhe2 ؊/؊ mice, particularly during prolonged stimulation, whereas the loss of NHE3 had no effect on secretion. Expression of Na ؉ /K ؉ /2Cl ؊ cotransporter mRNA increased 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 contrast, Nhe1 ؊/؊ mice displayed impaired NaCl absorption. These results suggest that in parotid duct cells apical NHE2 and NHE3 do not play a major role in Na ؉ absorption. These results also demonstrate that basolateral NHE1 and apical NHE2 modulate saliva secretion in vivo, especially during sustained stimulation when secretion depends less on Na ؉ /K ؉ /2Cl ؊ cotransporter activity.

The Basolateral NHE1 Na+/H+ Exchanger Regulates Transepithelial HCO3− Absorption through Actin Cytoskeleton Remodeling in Renal Thick Ascending Limb

“…Our results thus raise the possibility that NHE1 acting via the cytoskeleton could influence a broad range of membrane transporters and epithelial functions, as it does NHE3 and HCO 3 Ϫ absorption in the MTAL. A loss of cross-talk between basolateral NHE1 and apical Na ϩ /H ϩ exchange has been suggested recently as a possible explanation for decreased NaCl absorption by parotid gland cells from NHE1 knockout mice (49). An effect of NHE1 to control NHE3 or other transporters also may be relevant to pathophysiological conditions in which NHE1 expression and activity are altered.…”

Traditional and emerging roles for the SLC9 Na+/H+ exchangers

“…Although, whether NHE2 activity is beneficial or detrimental remains to be determined [108,107]. A role for NHE2 in salivation responses has also been observed using the NHE2 KO mice [132]. Most recently, NHE2 expression was localized to the pituitary.…”

“…In addition, NHE1 constitutes a major pathway for Na + influx into the cell, which coupled to Cl -and H 2 O uptake, ensures restoration of cell volume following cell shrinkage, a process referred to as regulatory volume increase. In specialized secretory cell types like acinar cells of the parotid or sublingual glands, NHE1 is critical for secretagogue-induced fluid secretion [116,132]. The unique subcellular localization of NHE1 in certain cell types suggests that NHE1 has additional biological functions to those outlined above.…”

The NHX Family of Na+-H+ Exchangers in Caenorhabditis elegans

“…Consistent with NHE1 playing a "housekeeping" role in maintaining intracellular pH, fibroblasts and lacrimal and salivary acinar cells from NHE1 Ϫ/Ϫ mice appear to lack the means to recover effectively from an intracellular acid load (24 -27). Indeed, lack of NHE1 resulted in a dramatic reduction in salivation, consistent with a role in promoting chloride flux via functionally coupled Cl Ϫ -HCO 3 Ϫ exchangers by increasing the pH i during sustained secretion (28).…”