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

Abstract

AimsThe kidneys play a major role in maintaining Pi 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 Pi homeostasis, we studied tamoxifen‐inducible intestinal epithelial cell‐specific NHE3 knockout (NHE3IEC‐KO) mice.MethodsMice underwent dietary Pi challenges, and hormones as well as urinary/plasma Pi were determined. Intestinal 33P uptake studies were conducted in vivo to compare the effects of tenapanor and NHE3IEC‐KO. Ex vivo Pi transport was measured in everted gut sacs and brush border membrane vesicles. Intestinal and renal protein expression of Pi transporters were determined.ResultsOn the control diet, NHE3IEC‐KO mice had similar Pi homeostasis, but a ~25% reduction in FGF23 compared with control mice. Everted gut sacs and brush border membrane vesicles showed enhanced Pi uptake associated with increased Npt2b expression in NHE3IEC‐KO mice. Acute oral Pi loading resulted in higher plasma Pi in NHE3IEC‐KO mice. Tenapanor inhibited intestinal 33P uptake acutely but then led to hyper‐absorption at later time points compared to vehicle. In response to high dietary Pi, plasma Pi and FGF23 increased to higher levels in NHE3IEC‐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 Pi.ConclusionIntestinal NHE3 has a significant contribution to Pi homeostasis. In contrast to effects described for tenapanor on Pi homeostasis, NHE3IEC‐KO mice show enhanced, rather than reduced, intestinal Pi uptake.