The role of NHE3 (Slc9a3) in oxalate and sodium transport by mouse intestine and regulation by cAMP

Intestinal oxalate transport involves Cl⁻/HCO₃⁻ exchangers but how this transport is regulated is not currently known. NHE3 (Slc9a3), an apical Na⁺/H⁺ exchanger, is an established target for regulation of electroneutral NaCl absorption working in concert with Cl⁻/HCO₃⁻ exchangers. To test whether NHE3 could be involved in regulation of intestinal oxalate transport and renal oxalate handling we compared urinary oxalate excretion rates and intestinal transepithelial fluxes of ¹⁴C-oxalate and ²²Na⁺ between NHE3 KO and wild-type (WT) mice. NHE3 KO kidneys had lower creatinine clearance suggesting reduced GFR, but urinary oxalate excretion rates (µmol/24 h) were similar compared to the WT but doubled when expressed as a ratio of creatinine. Intestinal transepithelial fluxes of ¹⁴C-oxalate and ²²Na⁺ were measured in the distal ileum, cecum, and distal colon. The absence of NHE3 did not affect basal net transport rates of oxalate or sodium across any intestinal section examined. Stimulation of intracellular cAMP with forskolin (FSK) and 3-isobutyl-1-methylxanthine (IBMX) led to an increase in net oxalate secretion in the WT distal ileum and cecum and inhibition of sodium absorption in the cecum and distal colon. In NHE3 KO cecum, cAMP stimulation of oxalate secretion was impaired suggesting the possibility of a role for NHE3 in this process. Although, there is little evidence for a role of NHE3 in basal intestinal oxalate fluxes, NHE3 may be important for cAMP stimulation of oxalate in the cecum and for renal handling of oxalate.