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Abstract: TH-PO541

PiT-2 Is the Main Transporter Responsible for Intestinal Phosphate Absorption in Human

Session Information

Category: Bone and Mineral Metabolism

  • 401 Bone and Mineral Metabolism: Basic

Authors

  • Ichida, Yasuhiro, Chugai Pharmaceutical Co.,Ltd., Gotemba, SHIZUOKA, Japan
  • Weis, Daniel, RWTH University of Aachen, Aachen, Germany
  • Ohtomo, Shuichi, Chugai Pharmaceutical Co.,Ltd., Gotemba, SHIZUOKA, Japan
  • Kaesler, Nadine, RWTH University of Aachen, Aachen, Germany
  • Kuppe, Christoph, RWTH University of Aachen, Aachen, Germany
  • Yamamoto, Tessai, Chugai Pharmaceutical Co.,Ltd., Gotemba, SHIZUOKA, Japan
  • Murao, Naoaki, Chugai Pharmaceutical Co.,Ltd., Gotemba, SHIZUOKA, Japan
  • Segawa, Hiroko, University of Tokushima Graduate School, Tokushima, Japan
  • Kawabe, Yoshiki, Chugai Pharmaceutical Co.,Ltd., Gotemba, SHIZUOKA, Japan
  • Horiba, Naoshi, Chugai Pharmaceutical Co.,Ltd., Gotemba, SHIZUOKA, Japan
  • Miyamoto, Ken-ichi, University of Tokushima Graduate School, Tokushima, Japan
  • Floege, Jürgen, RWTH University of Aachen, Aachen, Germany
Background

In chronic kidney disease (CKD) patients, adequate management of hyperphosphatemia is critical. Phosphate is absorbed in the small intestine via passive and active transports. NaPi-IIb is thought to be the main transporter for the active route, but a selective NaPi-IIb inhibitor failed to ameliorate hyperphosphatemia in patients with CKD. Transporters besides NaPi-IIb are thought to contribute to active phosphate transport in humans.

Methods

We examined the protein expression levels of NaPi-IIb, PiT-1, and PiT-2 in the small intestine of humans and rats by mass spectrometry (LC-MS/MS). To evaluate the influence of kidney disease, these 3 transporters were also assessed in CKD/dialysis patients and CKD rat models. Phosphate metabolism including intestinal phosphate uptake was evaluated, and protein expression levels were compared in rats.

Results

In humans, intestinal NaPi-IIb protein expression was low and PiT-2 protein expression dominated. PiT-2 protein was mostly expressed in the duodenum and jejunum where most of the phosphate is absorbed. PiT-2 expression levels were similar in CKD or dialysis patients and normal subjects. Compared to humans, in normal rats NaPi-IIb was predominantly expressed in the upper small intestine. Expression levels significantly decreased with age, and this correlated with lower serum phosphate concentration and the velocity of phosphate uptake in intestinal brush border membrane vesicles (BBMV). In rat CKD models, NaPi-IIb protein expression decreased significantly and low-affinity sodium-dependent phosphate transport dominated in intestinal BBMV. The nature of this transport remains unknown, as PiT-1 or PiT-2 protein expression in these animals remained undetectable by LC-MS/MS.

Conclusion

Major species differences in the intestinal phosphate absorption system were identified between humans and rats. Unlike in rats, PiT-2 appears to be the dominant intestinal phosphate transporter in humans and its expression was unaltered in patients with CKD. Thus, we identify PiT-2 as a promising pharmacological target for the treatment of hyperphosphatemia in dialysis and/or CKD patients.