Elevated luminal inorganic phosphate suppresses intestinal Zn absorption in 5/6 nephrectomized rats

Zinc (Zn) is an essential trace element in various biological processes. Chronic kidney disease (CKD) often leads to hypozincemia, resulting in further progression of CKD. In CKD, intestinal Zn absorption, the main regulator of systemic Zn metabolism, is often impaired; however, the mechanism underlying Zn malabsorption remains unclear. Here, we evaluated intestinal Zn absorption capacity in a rat model of CKD induced by 5/6 nephrectomy (5/6 Nx). Rats were given Zn and the incremental area under the plasma Zn concentration-time curve (iAUC) was measured as well as the expression of ZIP4, an intestinal Zn transporter. We found that 5/6 Nx rats showed lower iAUC than sham-operated rats, but expression of ZIP4 protein was upregulated. We therefore focused on other Zn absorption regulators to explore the mechanism by which Zn absorption was substantially decreased. Because some phosphate compounds inhibit Zn absorption by coprecipitation and hyperphosphatemia is a common symptom in advanced CKD, we measured inorganic phosphate (P_i) levels. P_i was elevated in not only serum but also the intestinal lumen of 5/6 Nx rats. Furthermore, intestinal intraluminal P_i administration decreased the iAUC in a dose-dependent manner in normal rats. In vitro, increased P_i concentration decreased Zn solubility under physiological conditions. Furthermore, dietary P_i restriction ameliorated hypozincemia in 5/6 Nx rats. We conclude that hyperphosphatemia or excess P_i intake is a factor in Zn malabsorption and hypozincemia in CKD. Appropriate management of hyperphosphatemia will be useful for prevention and treatment of hypozincemia in patients with CKD.NEW & NOTEWORTHY We demonstrated that elevated intestinal luminal P_i concentration can suppress intestinal Zn absorption activity without decreasing the expression of the associated Zn transporter. Increased intestinal luminal P_i led to the formation of an insoluble complex with Zn while dietary P_i restriction or administration of a P_i binder ameliorated hypozincemia in chronic kidney disease model rats. Therefore, modulation of dietary P_i by P_i restriction or a P_i binder might be useful for the treatment of hypozincemia and hyperphosphatemia.