SLC26 Cl-/HCO3- exchangers in the kidney: roles in health and disease

Abstract

Solute-linked carrier 26 (SLC26) isoforms constitute a conserved family of anion transporters with 10 distinct members. Except for SLC26A5 (prestin), all can operate as multifunctional anion exchangers, with three members (SLC26A7, SLC26A9, and SLC26A11) also capable of functioning as chloride channels. Several SLC26 isoforms can specifically mediate Cl(-)/HCO(3)(-) exchange. These include SLC26A3, A4, A6, A7, A9, and A11, which are expressed in the kidney except for SLC26A3 (DRA), which is predominantly expressed in the intestine. SLC26 Cl(-)/HCO(3)(-) exchanger isoforms display unique nephron segment distribution patterns with distinct subcellular localization in the kidney tubules. Together with studies in pathophysiologic states and the examination of genetically engineered mouse models, the evolving picture points to important roles for the SLC26 family in health and disease states. This review summarizes recent advances in the characterization of the SLC26 Cl(-)/HCO(3)(-) exchangers in the kidney with emphasis on their essential role in diverse physiological processes, including chloride homeostasis, oxalate excretion and kidney stone formation, vascular volume and blood pressure regulation, and acid-base balance.

Figure 1.. A dendrogram of the SLC26 isoforms.

SAT1: Sulfate Anion Transporter 1; DTDST: diastrophic dysplasia sulfate transporter; DRA: Down Regulated in Adenoma; CLD; Chloride Losing Diarrhea; PDS: Pendred Syndrome; PAT1: Putative Anion Transporter 1; CFEX: Chloride-Formate Exchange; KBAT: Kidney Brain Anion Transporter. SLC26A10 is a pseudogene and therefore not discussed.

Figure 2.. A schematic diagram depicting the nephron segment distribution of SLC26A4 (pendrin), SLC26A6 (PAT-1; CFEX), SLC26A7, SLC26A9, and SLC26A11 (KBAT).

SLC26A6 is primarily detected in the proximal tubule whereas the other SLC26 Cl⁻/HCO₃⁻ exchangers are expressed in the collecting duct.

Figure 3.. A schematic diagram depicting the localization of pendrin in cortical collecting duct cells.

Pendrin protein is primarily detected on the apical membrane of B-and non-A, non-B intercalated cells in the cortical collecting duct.

Figure 4.. A schematic diagram highlighting the synergistic effects of pendrin and Na-Cl cotransport (NCC) inhibition on salt and water excretion.

Combined inactivation or inhibition of pendrin and NCC should result in severe salt wasting.

Figure 5.. An immunofluorescence labeling of Slc26a6 (PAT1) in the kidney proximal tubule.

SLC26A6 is exclusively detected on the apical membrane of kidney proximal tubules.

Figure 6.. A schematic diagram depicting the localization of Slc26a7 and Slc26a9 in the kidney OMCD (and IMCD).

SLC26A7 is primarily detected on the basolateral membrane of A-intercalated cells in the OMCD whereas SLC26A9 is located on the apical membrane of principal cells in OMCD and the initial portion of IMCD. Slc26a9 is likely functioning as a chloride channel and not a Cl⁻/HCO₃⁻ exchange, given the electrochemical gradients for chloride and bicarbonate across the apical membrane. Slc26a7 is likely a Cl⁻/HCO₃⁻ exchanger based on the presence of distal renal tubular acidosis and functional studies in microperfused OMCD in Slc26a7 null mice.

Figure 7.. Localization of Slc26a11 in the kidney.

Top panel: Double immunofluorescence labeling of Slc26a11 and AQP2 in the kidney CCD. Slc26a11 and AQP2 localize to two distinct cell types in the collecting duct. Bottom panel: Double immunofluorescence labeling of Slc26a11 and H⁺-ATPase in the kidney CCD. Slc26a11 co-localizes with H⁺-ATPase in the collecting duct.

Figure 7.. Localization of Slc26a11 in the kidney.

Top panel: Double immunofluorescence labeling of Slc26a11 and AQP2 in the kidney CCD. Slc26a11 and AQP2 localize to two distinct cell types in the collecting duct. Bottom panel: Double immunofluorescence labeling of Slc26a11 and H⁺-ATPase in the kidney CCD. Slc26a11 co-localizes with H⁺-ATPase in the collecting duct.

Fig. 8.. A schematic diagram depicting Slc26a11 as an apical chloride channel in intercalated cells in the CCD.

Slc26a11 is expressed on the apical membrane of A-intercalated cells and the basolateral membrane of B-intercalated cells in the CCD. Whether the basolateral Slc26a11 can also function as a chloride channel remains speculative.