Proximal tubular NHEs: sodium, protons and calcium?

Na⁺/H⁺ exchange activity in the apical membrane of the proximal tubule is fundamental to the reabsorption of Na⁺ and water from the filtrate. The role of this exchange process in bicarbonate reclamation and, consequently, the maintenance of acid-base homeostasis has been appreciated for at least half a century and remains a pillar of renal tubular physiology. More recently, apical Na⁺/H⁺ exchange, mediated by Na⁺/H⁺ exchanger isoform 3 (NHE3), has been implicated in proximal tubular reabsorption of Ca²⁺ and Ca²⁺ homeostasis in general. Overexpression of NHE3 increased paracellular Ca²⁺ flux in a proximal tubular cell model. Consistent with this observation, mice with genetic deletion of Nhe3 have a noticable renal Ca²⁺ leak. These mice also display decreased intestinal Ca²⁺ uptake and osteopenia. This review highlights the traditional roles of proximal tubular Na⁺/H⁺ exchange and summarizes recent novel findings implicating the predominant isoform, NHE3, in Ca²⁺ homeostasis.