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.