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 | 2022 Feb

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

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

Xue Jianxiang J Thomas Linto L Murali Sathish Kumar SK Levi Moshe M Fenton Robert A RA Dominguez Rieg Jessica A JA Rieg Timo T

Acta physiologica (Oxford, England) 20220111 2

<h4>Aims</h4>The kidneys play a major role in maintaining P<sub>i</sub> 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<sub>i</sub> homeostasis, we studied tamoxifen-inducible intestinal epithelial cell-specific NHE3 knockout (NHE3<sup>IEC-KO</sup> ) mice.<h4>Methods</h4>Mice underwent dietary P<sub>i</sub> challenges, and hormo ...[more]

PMID: 34978760

Similar Datasets

Project description:Many of the pathological consequences of chronic kidney disease can be attributed to an elevation in serum phosphate levels. Current therapies focused on decreasing intestinal phosphate absorption to treat hyperphosphatemia are inadequate. The most effective therapeutic strategy may be to target multiple absorptive pathways. In this study, the ability of a novel inhibitor of the intestinal sodium hydrogen exchanger 3 (NHE3), LY3304000, which inhibits paracellular, diffusional uptake of phosphate, to work in combination with an inhibitor of the active transporter, sodium dependent phosphate cotransporter 2b (NPT2b), LY3358966, was explored. LY3304000 modestly inhibited the acute uptake of phosphate into plasma of rats, while surprisingly, it doubled the rate of phosphate uptake in mice, an animal model dominated by NPT2b mediated acute phosphate uptake. In rats, LY3004000 and LY3358966 work in concert to inhibit acute phosphate uptake. On top of LY3358966, LY3304000 further decreased the acute uptake of phosphate into plasma. Studies measuring the recovery of radiolabeled phosphate in the intestine demonstrated LY3304000 and LY3358966 synergistically inhibited the absorption of phosphate in rats. We hypothesize the synergism is because the NHE3 inhibitor, LY3304000, has two opposing effects on intestinal phosphate absorption in rats, first it decreases diffusion mediated paracellular phosphate absorption, while second, it simultaneously increases phosphate absorption through the NPT2b pathway. NHE3 inhibition decreases proton export from enterocytes and raises the cell surface pH. In vitro, NPT2b mediated phosphate transport is increased at higher pHs. The increased NPT2b mediated transport induced by NHE3 inhibition is masked in rats which have relatively low levels of NPT2b mediated phosphate transport, by the more robust inhibition of diffusion mediated phosphate absorption. Thus, the inhibition of NPT2b mediated phosphate transport in rats in the presence of NHE3 inhibition has an effect that exceeds its effect in the absence of NHE3 inhibition, leading to the observed synergism on phosphate absorption between NPT2b and NHE3 inhibition.

Dataset Information

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

Aims

Methods

Results

Conclusion

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets