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. 2021 Jan 1;36(1):68-75.
doi: 10.1093/ndt/gfaa156.

Evidence of an intestinal phosphate transporter alternative to type IIb sodium-dependent phosphate transporter in rats with chronic kidney disease

Yasuhiro Ichida  1 , Shuichi Ohtomo  1 , Tessai Yamamoto  2 , Naoaki Murao  2 , Yoshinori Tsuboi  1 , Yoshiki Kawabe  1 , Hiroko Segawa  3 , Naoshi Horiba  1 , Ken-Ichi Miyamoto  3 , Jürgen Floege  4
Affiliations

Evidence of an intestinal phosphate transporter alternative to type IIb sodium-dependent phosphate transporter in rats with chronic kidney disease

Yasuhiro Ichida et al. Nephrol Dial Transplant. .

Abstract

Background: Phosphate is absorbed in the small intestine via passive flow and active transport.NaPi-IIb, a type II sodium-dependent phosphate transporter, is considered to mediate active phosphate transport in rodents. To study the regulation of intestinal phosphate transport in chronic kidney disease (CKD), we analyzed the expression levels of NaPi-IIb, pituitary-specific transcription factor 1 (PiT-1) and PiT-2 and the kinetics of intestinal phosphate transport using two CKD models.

Methods: CKD was induced in rats via adenine orThy1 antibody injection. Phosphate uptake by intestinal brush border membrane vesicles (BBMV) and the messenger RNA (mRNA) expression of NaPi-IIb, PiT-1 and PiT-2 were analyzed. The protein expression level of NaPi-IIb was measured by mass spectrometry (e.g. liquid chromatography tandem mass spectrometry).

Results: In normal rats, phosphate uptake into BBMV consisted of a single saturable component and its Michaelis constant (Km) was comparable to that of NaPi-IIb. The maximum velocity (Vmax) correlated with mRNA and protein levels of NaPi-IIb. In the CKD models, intestinal phosphate uptake consisted of two saturable components. The Vmax of the higher-affinity transport, which is thought to be responsible for NaPi-IIb, significantly decreased and the decrease correlated with reduced NaPi-IIb expression. The Km of the lower-affinity transport was comparable to that of PiT-1 and -2. PiT-1 mRNA expression was much higher than that of PiT-2, suggesting that PiT-1 was mostly responsible for phosphate transport.

Conclusions: This study suggests that the contribution of NaPi-IIb to intestinal phosphate absorption dramatically decreases in rats with CKD and that a low-affinity alternative to NaPi-IIb, in particular PiT-1, is upregulated in a compensatory manner in CKD.

Keywords: NaPi-IIb; PiT; chronic kidney disease; intestine; phosphate.

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Figures

FIGURE 1
FIGURE 1
Changes in phosphate uptake by rat intestinal BBMVs with age (A) 4 weeks old, (B) 9 weeks old and (C) 15 weeks old. Dots represent the actual values and the Michaelis–Menten curve was generated using JMP 11.2.1. Inset shows an Eadie–Hofstee plot of the uptake. Each point in the inset represents the mean of three measurement points.
FIGURE 2
FIGURE 2
Changes in NaPi-IIb (A) mRNA or (B) protein expression level in rat upper intestine with age. Values are normalized by villin-1 protein or mRNA, respectively. The actual values are represented as dots and the columns represent mean ± SE. *P < 0.05, significant difference versus 4 weeks old; #P < 0.05, significant difference versus 9 weeks old (Tukey–Kramer test).
FIGURE 3
FIGURE 3
Phosphate uptake by intestinal BBMVs in (A) normal rats and (B) adenine-induced CKD rats. Dots represent the actual values and the Michaelis–Menten curve was generated using JMP 11.2.1. Inset shows an Eadie–Hofstee plot of the uptake. Each point represents the mean of three measurement points. Normal, normal rats; CKD, adenine-induced CKD rats.
FIGURE 4
FIGURE 4
Changes in NaPi-IIb (A) mRNA and (B) protein expression levels in the upper intestine of rats with adenine-induced CKD. Values are normalized by villin-1 protein and mRNA, respectively. The actual values are represented as dots and the columns represent mean + SE. *P < 0.05, significant difference versus normal (Student’s t-test). Normal, normal rats; CKD, adenine-induced CKD rats.
FIGURE 5
FIGURE 5
Phosphate uptake by intestinal BBMV in sham rats (A) and anti-Thy1-induced CKD rats (B). Dots represent the actual values and the Michaelis–Menten curve was generated using JMP11.2.1. Inset shows an Eadie–Hofstee plot of the uptake. Each point represents the mean of three measurement points. Sham, sham-operated rats; CKD, anti-Thy1 CKD rats.
FIGURE 6
FIGURE 6
Changes in NaPi-IIb (A) mRNA and (B) protein expression levels in the upper intestine of rats with anti-Thy1 CKD. Values are normalized by villin-1 protein and mRNA, respectively. The actual values are represented as dots and the columns represent mean + SE. *P < 0.05, significant difference versus sham (Student’s t-test). Sham, sham-operated rats; CKD, anti-Thy1 CKD rats.
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