Dataset Information

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

ABSTRACT:

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.

SUBMITTER: Xue J

PROVIDER: S-EPMC9286053 | biostudies-literature |

REPOSITORIES: biostudies-literature

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