Effects of acid-base variables and the role of carbonic anhydrase on oxalate secretion by the mouse intestine in vitro

Hyperoxaluria is a major risk factor for calcium oxalate kidney stones and the intestine is recognized as an important extra-renal pathway for eliminating oxalate. The membrane-bound chloride/bicarbonate (Cl^-/HCO₃^-) exchangers are involved in the transcellular movement of oxalate, but little is understood about how they might be regulated. HCO₃^-, CO₂, and pH are established modulators of intestinal NaCl cotransport, involving Na⁺/H⁺ and Cl^-/HCO₃^- exchange, but their influence on oxalate transport is unknown. Measuring¹⁴C-oxalate and³⁶Cl fluxes across isolated, short-circuited segments of the mouse distal ileum and distal colon we examined the role of these acid-base variables and carbonic anhydrase (CA) in oxalate and Cl^- transport. In standard buffer both segments performed net oxalate secretion (and Cl^- absorption), but only the colon, and the secretory J^Ox_sm pathway were responsive to HCO₃^- and CO₂. Ethoxzolamide abolished net oxalate secretion by the distal colon, and when used in tandem with an impermeant CA inhibitor, signaled an intracellular CA isozyme was required for secretion. There was a clear dependence on HCO₃^- =CO₂ as their removal eliminated secretion, while at 42 mmol/L HCO₃^- J^Ox_sm was also decreased and J^Ox_net eradicated. Independent of pH, raising PCO₂ from 28 to 64 mmHg acutely stimulated net oxalate secretion 41%. In summary, oxalate secretion by the distal colon was dependent on HCO₃^-, CA and specifically modulated by CO₂, whereas the ileum was remarkably unresponsive. These findings highlight the distinct segmental heterogeneity along the intestine, providing new insights into the oxalate transport mechanism and how it might be regulated.