The role of carbonic anhydrases in renal physiology

Carbonic anhydrase (CA) catalyzes the reversible hydration of CO2. CA is expressed in most segments of the kidney. CAII and CAIV predominate in human and rabbit kidneys; in rodent kidneys, CAXII, and CAXIV are also present. CAIX is expressed by renal cell carcinoma (RCC). Most of these isoforms, except for rodent CAIV, have high turnover rates. CAII is a cytoplasmic enzyme, whereas the others are membrane-associated; CAIV is anchored by glycosylphosphatidylinositol linkage. Membrane polarity is apical for CAXIV, basolateral for CAXII, and apical and basolateral for CAIV. Luminal membrane CAs facilitate the dehydration of carbonic acid (H2CO3) that is formed when secreted protons combine with filtered bicarbonate. Basolateral CA enhances the efflux of bicarbonate via dehydration of H2CO3. CAII and CAIV can associate with bicarbonate transporters (e.g., AE1, kNBC1, NBC3, and SCL26A6), and proton antiporter, NHE1 in a membrane protein complex called a transport metabolon. CAXII and CAXIV may also be associated with transporters in normal kidney and CAIX in RCCs. The multiplicity of CAs implicates their importance in acid–base and other solute transport along the nephron. For example, CAII on the cytoplasmic face and CAIV on the extracellular surface provide the ‘push’ and ‘pull’ for bicarbonate transport by supplying and dissipating substrate respectively