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Enhanced phosphate absorption in intestinal epithelial cell-specific NHE3
knockout mice.
Authors Xue J, Thomas L, Murali SK, Levi M, Fenton RA, Dominguez Rieg JA, Rieg T
Submitted By Submitted Externally on 3/9/2022
Status Published
Journal Acta physiologica (Oxford, England), REFERENCES
Year 2022
Date Published 2/1/2022
Volume : Pages 234 : e13756
PubMed Reference 34978760
Abstract The 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., Mice underwent dietary Pi challenges, and hormones as well
as urinary/plasma Pi were determined. Intestinal 33 P 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., On 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 33 P 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 ., Intestinal 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.


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