Journal
ACTA PHYSIOLOGICA
Volume 234, Issue 2, Pages -Publisher
WILEY
DOI: 10.1111/apha.13756
Keywords
chronic kidney disease; homeostasis; inhibitor; intestine; phosphate; sodium-hydrogen exchanger 3
Categories
Funding
- National Institute of Diabetes and Digestive and Kidney Diseases [1R01DK110621, DK076169, DK115255]
- American Heart Association [18PRE33990236, 19POST34400026, 19TPA34850116, 828731]
- Department of Veterans Affairs [IBX004968A]
- Novo Nordisk Fonden [NNF17OC0028812, NNF19OC0058439]
- Det Frie Forskningsrad [0134-00018B]
Ask authors/readers for more resources
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.
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 NI ID 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 P-33 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, hut a similar to 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 P-33 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.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available