Genetic and genomic evidence for an important role of the Na/H exchanger 3 in 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 ~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 under in vitro conditions 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 learned 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.