Enhanced phosphate absorption in intestinal epithelial cell-specific NHE3 knockout mice.

Aims: The kidneys play a major role in maintaining P _i homeostasis. Patients in later stages of CKD develop hyperphosphatemia. One novel treatment option is tenapanor, an intestinal-specific NHE3 inhibitor. To gain mechanistic insight into the role of intestinal NHE3 in P _i homeostasis, we studied tamoxifen-inducible intestinal epithelial cell-specific NHE3 knockout (NHE3 ^IEC-KO ) mice.
Methods: Mice underwent dietary P _i challenges, and hormones as well as urinary/plasma P _i were determined. Intestinal ³³ P uptake studies were conducted in vivo to compare the effects of tenapanor and NHE3 ^IEC-KO . Ex vivo P _i transport was measured in everted gut sacs and brush border membrane vesicles. Intestinal and renal protein expression of P _i transporters were determined.
Results: On the control diet, NHE3 ^IEC-KO mice had similar P _i homeostasis, but a ~25% reduction in FGF23 compared with control mice. Everted gut sacs and brush border membrane vesicles showed enhanced P _i uptake associated with increased Npt2b expression in NHE3 ^IEC-KO mice. Acute oral P _i loading resulted in higher plasma P _i in NHE3 ^IEC-KO mice. Tenapanor inhibited intestinal ³³ P uptake acutely but then led to hyper-absorption at later time points compared to vehicle. In response to high dietary P _i , plasma P _i and FGF23 increased to higher levels in NHE3 ^IEC-KO mice which was associated with greater Npt2b expression. Reduced renal Npt2c and a trend for reduced Npt2a expression were unable to correct for higher plasma P _i .
Conclusion: Intestinal NHE3 has a significant contribution to P _i homeostasis. In contrast to effects described for tenapanor on P _i homeostasis, NHE3 ^IEC-KO mice show enhanced, rather than reduced, intestinal P _i uptake.
(© 2022 The Authors. Acta Physiologica published by John Wiley & Sons Ltd on behalf of Scandinavian Physiological Society.)