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

Abstract

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.