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 NI ID 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 P-33 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, hut a similar to 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 P-33 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.