| First Author | Xue J | Year | 2022 |
| Journal | Acta Physiol (Oxf) | Volume | 234 |
| Issue | 2 | Pages | e13756 |
| PubMed ID | 34978760 | Mgi Jnum | J:341288 |
| Mgi Id | MGI:7431326 | Doi | 10.1111/apha.13756 |
| Citation | Xue J, et al. (2022) Enhanced phosphate absorption in intestinal epithelial cell-specific NHE3 knockout mice. Acta Physiol (Oxf) 234(2):e13756 |
| abstractText | 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. |
