Loss of the NHE2 Na+/H+ exchanger has no apparent effect on diarrheal state of NHE3-deficient mice

The expression of NHE2 and NHE3 on intestinal-brush border membranes sugges ts that both Na+/H+ exchangers serve absorptive functions. Studies with kno ckout mice showed that the loss of NHE3, but not NHE2, causes diarrhea, dem onstrating that NHE3 is the major absorptive exchanger and indicating that any remaining absorptive capacity contributed by NHE2 is not sufficient to compensate fully for the loss of NHE3. To test the hypothesis that NHE2 pro vides partial compensation for the diarrheal state of NHE3-deficient mice, we crossed doubly heterozygous mice carrying null mutations in the Nhe2 and Nhe3 genes and analyzed the phenotypes of their offspring. The additional loss of NHE2 in NHE3-deficient mice caused no apparent reduction in viabili ty, no further impairment of systemic acid-base status or increase in aldos terone levels, and no apparent worsening of the diarrheal state. These in v ivo phenotypic correlates of the absorptive defect suggest that the NaCl, H CO3-, and fluid absorption that is dependent on apical Na+/H+ exchange is d ue overwhelmingly to the activity of NHE3, with little contribution from NH E2.