Deficiency of Carbonic Anhydrase II Results in a Urinary Concentrating Defect.

Carbonic anhydrase II (CAII) is expressed along the nephron where it interacts with a number of transport proteins augmenting their activity. Aquaporin-1 (AQP1) interacts with CAII to increase water flux through the water channel. Both CAII and aquaporin-1 are expressed in the thin descending limb (TDL); however, the physiological role of a CAII-AQP1 interaction in this nephron segment is not known.

Carbonic anhydrase II binds to and increases the activity of the epithelial sodium-proton exchanger, NHE3.

Two-thirds of sodium filtered by the renal glomerulus is reabsorbed from the proximal tubule via a sodium/proton exchanger isoform 3 (NHE3)-dependent mechanism. Since sodium and bicarbonate reabsorption are coupled, we postulated that the molecules involved in their reabsorption [NHE3 and carbonic anhydrase II (CAII)] might physically and functionally interact. Consistent with this, CAII and NHE3 were closely associated in a renal proximal tubular cell culture model as revealed by a proximity ligation assay.

Increased water flux induced by an aquaporin-1/carbonic anhydrase II interaction.

Aquaporin-1 (AQP1) enables greatly enhanced water flux across plasma membranes. The cytosolic carboxy terminus of AQP1 has two acidic motifs homologous to known carbonic anhydrase II (CAII) binding sequences. CAII colocalizes with AQP1 in the renal proximal tubule.

Ezrin is required for the functional regulation of the epithelial sodium proton exchanger, NHE3.

The sodium hydrogen exchanger isoform 3 (NHE3) mediates absorption of sodium, bicarbonate and water from renal and intestinal lumina. This activity is fundamental to the maintenance of a physiological plasma pH and blood pressure. To perform this function NHE3 must be present in the apical membrane of renal tubular and intestinal epithelia.

The calmodulin antagonist W-7 inhibits the epithelial Na+/H+ exchanger via modulating membrane surface potential.

NHE3 is regulated via alterations in membrane surface charge. This is achieved through altered binding of cationic regions in the cytosolic-terminus of the exchanger with the inner leaflet of the plasma membrane. Calmodulin antagonists, including W-7, regulate surface potential and inhibit NHE3 activity.