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

Aims: The kidneys play a major role in maintaining P 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 homeostasis, we studied tamoxifen-inducible intestinal epithelial cell-specific NHE3 knockout (NHE3 ) mice.

Methods: Mice underwent dietary P challenges, and hormones as well as urinary/plasma P were determined. Intestinal P uptake studies were conducted in vivo to compare the effects of tenapanor and NHE3 . Ex vivo P transport was measured in everted gut sacs and brush border membrane vesicles. Intestinal and renal protein expression of P transporters were determined.

Results: On the control diet, NHE3 mice had similar P homeostasis, but a ~25% reduction in FGF23 compared with control mice. Everted gut sacs and brush border membrane vesicles showed enhanced P uptake associated with increased Npt2b expression in NHE3 mice. Acute oral P loading resulted in higher plasma P in NHE3 mice. Tenapanor inhibited intestinal P uptake acutely but then led to hyper-absorption at later time points compared to vehicle. In response to high dietary P , plasma P and FGF23 increased to higher levels in NHE3 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 .

Conclusion: Intestinal NHE3 has a significant contribution to P homeostasis. In contrast to effects described for tenapanor on P homeostasis, NHE3 mice show enhanced, rather than reduced, intestinal P uptake.