Mechanisms of chloride transport in the proximal tubule

The major fraction of filtered Cl- is reabsorbed in the proximal tubule. An important component of Cl- reabsorption is passive and paracellular, driven by the lumen-negative potential difference in the early proximal tubule and the outwardly directed concentration gradient for Cl- in the later proximal tubule. Evidence suggests that a significant additional component of NaCl reabsorption in the proximal tubule is active and transcellular. Cl-/formate and Cl-/oxalate exchangers have been identified as mechanisms of uphill Cl(-)entry across the apical membrane. For steady-state Cl- absorption to occur by these mechanisms, formate and oxalate must recycle from lumen to cell. Recent studies indicate that recycling of formate occurs by H+-coupled formate transport in parallel with Na+/H+ exchange, whereas oxalate recycling takes place by oxalate/sulfate exchange in parallel with Naf-sulfate cotransport. The predominant route for Cl- exit across the basolateral membrane is via Cl- channels. Unresolved issues include the adequacy of formate recycling to sustain Cl- absorption by Cl-/formate exchange, the existence and contributions of additional mechanisms for apical Cl(-)entry and basolateral Cl- exit, and the relative magnitudes of transcellular and paracellular transport under physiological conditions. In addition, the molecular identification and mechanisms of regulation of the Cl-/formate and Cl-/oxalate exchangers remain to be defined.