Renal and intestinal absorptive defects in mice lacking the NHE3 Na⁺/H⁺ exchanger

NHE3 is one of five plasma membrane Na⁺/H⁺ exchangers^1-3 and is encoded by the mouse gene Slc9a3. It is expressed on apical membranes of renal proximal tubule^4,5 and intestinal epithelial cells^6,7 and is thought to play a major role in NaCl and HCO₃^- absorption^4-10. As the distribution of NHE3 overlaps with that of the NHE2 isoform in kidney^7,11 and intestine^7,12,13, the function and relative importance of NHE3 in vivo is unclear. To analyse its physiological functions, we generated mice lacking NHE3 function. Homozygous mutant (Slc9a3^-1-) mice survive, but they have slight diarrhoea and blood analysis revealed that they are mildly acidotic. HCO₃^- and fluid absorption are sharply reduced in proximal convoluted tubules, blood pressure is reduced and there is a severe absorptive defect in the intestine. Thus, compensatory mechanisms must limit gross perturbations of electrolyte and acid-base balance. Plasma aldosterone is increased in NHE3-deficient mice, and expression of both renin and the AE1 (Slc4a1) Cl^-/HCO₃^- exchanger mRNAs are induced in kidney. In the colon, epithelial Na⁺ channel activity is increased and colonic H⁺,K⁺-ATPase mRNA is massively induced. These data show that NHE3 is the major absorptive Na⁺/H⁺ exchanger in kidney and intestine, and that lack of the exchanger impairs acid-base balance and Na⁺-fluid volume homeostasis.