The proximal tubule is responsible for the reabsorption of 70 to 90% of filtered NaHCO₃ and 50% of filtered NaCl. Approximately 70% of H secretion across the apical or luminal membrane is mediated by an amiloride-inhibitable Na/H antiporter, while the remaining 30% is likely mediated by a vacuolar H-ATPase (Fig. 1) [1, 2]. All of apical membrane NaCl absorption is mediated by an amiloride-inhibitable Na/H antiporter functioning in parallel with Cl/base exchange [3, 4]. Thus the apical membrane Na/H antiporter plays pivotal roles in proximal tubular acidification (NaHCO₃ absorption) and NaCl absorption. Base generated within the cell exits the basolateral membrane on a Na-coupled electrogenic transporter which likely transports 1 Na, 1 HCO₃, and 1 carbonate ion (Na/HCO₃/CO₃ cotransporter) [5–8]. Na exits the basolateral membrane on an Na/K pump and the Na/HCO₃/CO₃ cotransporter; the mechanism of basolateral membrane Cl exit is unresolved. In addition to these processes, the proximal tubule is the major site of ammonia synthesis, and the major site of renal tubular citrate reabsorption. The latter is of relevance to acid/base physiology in that the excretion of one citrate ion in the urine is equivalent to the excretion of three bicarbonate ions.

All of the above processes are subject to acute and chronic regulation. While acute regulation is of significant interest, physiologically relevant regulation is more chronic in nature, and generally occurs over hours and days. In this review, we will discuss the chronic regulation of the proximal tubular Na/H antiporter. Chronic regulation of proximal tubular H secretion and Na absorption in most cases involves chronic regulation of the apical membrane Na/H antiporter.