Proximal tubule Na⁺/H⁺ exchanger activity in adult NHE8^-/-, NHE3^-/-, and NHE3^-/-/NHE8^-/- mice

NHE3 is the predominant Na⁺/H⁺ exchanger on the brush-border membrane (BBM) of the proximal tubule in adults. However, NHE3 null mice still have significant renal BBM Na⁺/H⁺ activity. NHE8 has been localized to the BBM of proximal tubules and is more highly expressed in neonates than adult animals. The relative role of NHE8 in adult renal H⁺ transport is unclear. This study examined whether there was compensation by NHE8 in NHE3^-/- mice and by NHE3 in NHE8^-/- mice. NHE3^-/- mice had significant metabolic acidosis, and renal BBM NHE8 protein abundance was greater in NHE3^-/- mice than control mice, indicating that there may be compensation by NHE8 in NHE3^-/- mice. NHE8^-/- mice had serum bicarbonate levels and pH that were not different from controls. NHE3 protein expression on the BBM was greater in NHE8^-/- mice than in wild-type mice, indicating that there may be compensation by NHE3 in NHE8^-/- mice. Both BBM NHE3 and NHE8 protein abundance increased in response to acidosis. Blood pressure and Na⁺/H⁺ exchanger activity were comparable in NHE8^-/- mice to that of controls, but both were significantly lower in NHE3^-/- mice compared with control mice. Compared with NHE3^-/- mice, NHE3^-/-/ NHE8^-/- mice had lower blood pressures. While serum bicarbonate was comparable in NHE3^-/- mice and NHE3^-/-/NHE8^-/- mice, proximal tubule Na⁺/H⁺ exchange activity was less in NHE3^-/-/ NHE8^-/- mice compared with NHE3^-/- mice. In conclusion, NHE3 is the predominant Na⁺/H⁺ exchanger in adult mice. NHE8 may play a compensatory role in renal acidification and blood pressure regulation in NHE3^-/- mice.