Renal salt wasting in mice lacking NHE3 Na+/H+ exchanger but not in mice lacking NHE2

To study the role of Na+/H+ exchanger isoform 2 (NHE2) and isoform 3 (NHE3) in sodium-fluid volume homeostasis and renal Na+ conservation, mice with N he2 (Nhe2(-/-)) and/or Nhe3 (Nhe3(-/-)) null mutations were fed a Na+-restr ieted diet, and urinary Na excretion, blood pressure, systemic acid-base an d electrolyte status, and renal function were analyzed. Na+-restricted Nhe2 (-/-) mice, on either a wild-type or Nhe3 heterozygous mutant (Nhe3(+/-)) b ackground, did not exhibit excess urinary Na+ excretion. After 15 days of N a+ restriction, blood pressure, fractional excretion of Na+, and the glomer ular filtration rate (GFR) of Nhe2(-/-)Nhe3(+/-) mice were similar to those of Nhe2(+/+) and Nhe3(+/-) mice, and no metabolic disturbances were observ ed. Nhe3(-/-) mice maintained on a Na+-restricted diet for 3 days exhibited hyperkalemia, urinary salt wasting, acidosis, sharply reduced blood pressu re and GFR, and evidence of hypovolemic shock. These results negate the hyp othesis that NHE2 plays an important renal function in sodium-fluid volume homeostasis; however, they demonstrate that NHE3 is critical for systemic e lectrolyte, acid-base, and fluid volume homeostasis during dietary Na+ rest riction and that its absence leads to renal salt wasting.