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

Area of Science:

• Physiology
• Nephrology
• Gastroenterology

Background:

• The kidneys are crucial for maintaining phosphate (P_i) homeostasis.
• Chronic kidney disease (CKD) often leads to hyperphosphatemia.
• Tenapanor, an intestinal-specific NHE3 inhibitor, is a novel treatment for hyperphosphatemia.

Purpose of the Study:

• To investigate the mechanistic role of intestinal sodium-hydrogen exchanger 3 (NHE3) in P_i homeostasis.
• To compare the effects of tenapanor and NHE3 knockout on intestinal P_i absorption.

Main Methods:

• Studied tamoxifen-inducible intestinal epithelial cell-specific NHE3 knockout (NHE3^IEC-KO) mice.
• Performed dietary P_i challenges, hormone level determination, and urinary/plasma P_i measurements.
• Conducted in vivo intestinal ³³ P uptake studies, ex vivo P_i transport assays, and measured P_i transporter protein expression.

Main Results:

• NHE3^IEC-KO mice exhibited enhanced intestinal P_i uptake, linked to increased Npt2b expression.
• Acute P_i loading in NHE3^IEC-KO mice resulted in higher plasma P_i levels.
• Tenapanor acutely inhibited intestinal ³³ P uptake but led to hyper-absorption later; NHE3^IEC-KO mice showed enhanced P_i absorption compared to tenapanor treatment.

Conclusions:

• Intestinal NHE3 significantly contributes to P_i homeostasis.
• NHE3^IEC-KO mice demonstrate enhanced intestinal P_i uptake, contrasting with the expected effects of tenapanor.