The genetic and genomic evidence for an important role of the Na + /H + exchanger 3 in the blood pressure regulation and angiotensin II-induced hypertension.

The sodium (Na+ )/hydrogen (H+ ) exchanger 3 (NHE3) and sodium-potassium adenosine triphosphatase (Na+ /K+ -ATPase) are two of the most important Na+ transporters in the proximal tubules of the kidney. On the apical membrane side, NHE3 primarily mediates the entry of Na+ into and the exit of H+ from the proximal tubules, directly and indirectly being responsible for reabsorbing about 50% of filtered Na+ in the proximal tubules of the kidney. On the basolateral membrane side, Na+ /K+ -ATPase serves as a powerful engine driving Na+ out of, while pumping K+ into the proximal tubules against their concentration gradients. While the roles of NHE3 and Na+ /K+ -ATPase in proximal tubular Na+ transport in vitro preparations are well recognized, their respective contributions to the basal blood pressure regulation and angiotensin II (ANG II)-induced hypertension remain poorly understood. Recently, we have been fortunate to be able to use genetically modified mouse models with global, kidney- or proximal tubule-specific deletion of NHE3 to directly determine the cause and effect relationship between NHE3, basal blood pressure homeostasis, and ANG II-induced hypertension at the whole body, kidney and/or proximal tubule levels. The purpose of this article is to review the genetic and genomic evidence for an important role of NHE3 with a focus in the regulation of basal blood pressure and ANG II-induced hypertension, as we learnt from studies using global, kidney- or proximal tubule-specific NHE3 knockout mice. We hypothesize that NHE3 in the proximal tubules is necessary for maintaining basal blood pressure homeostasis and the development of ANG II-induced hypertension.