Ichida Yasuhiro, Hosokawa Naoto, Takemoto Ryushi, Koike Takafumi, Nakatogawa Tasuku, Hiranuma Mayumi, Arakawa Hitoshi, Miura Yukihito, Azabu Hiroko, Ohtomo Shuichi, Horiba Naoshi
Research Division, Chugai Pharmaceutical Co., Ltd.
Chugai Research Institute for Medical Science, Inc.
J Nutr Sci Vitaminol (Tokyo). 2020;66(1):60-67. doi: 10.3177/jnsv.66.60.
A treatment for hyperphosphatemia would be expected to reduce mortality rates for CKD and dialysis patients. Although rodent studies have suggested sodium-dependent phosphate transporter type IIb (NaPi-IIb) as a potential target for hyperphosphatemia, NaPi-IIb selective inhibitors failed to achieve efficacy in human clinical trials. In this study, we analyzed phosphate metabolism in rats, dogs, and monkeys to confirm the species differences. Factors related to phosphate metabolism were measured and intestinal phosphate absorption rate was calculated from fecal excretion in each species. Phosphate uptake by intestinal brush border membrane vesicles (BBMV) and the mRNA expression of NaPi-IIb, PiT-1, and PiT-2 were analyzed. In addition, alkaline phosphatase (ALP) activity was evaluated. The intestinal phosphate absorption rate, including phosphate uptake by BBMV and NaPi-IIb expression, was the highest in dogs. Notably, urinary phosphate excretion was the lowest in monkeys, and their intestinal phosphate absorption rate was by far the lowest. Dogs and rats showed positive correlations between V/K of phosphate uptake in BBMV and NaPi-IIb expression. Although phosphate uptake was observed in the BBMV of monkeys, NaPi-IIb expression was not detected and ALP activity was low. This study revealed significant species differences in intestinal phosphate absorption. NaPi-IIb contributes to intestinal phosphate uptake in rats and dogs. However, in monkeys, phosphate is poorly absorbed due to the slight degradation of organic phosphate in the intestine.
高磷血症的治疗有望降低慢性肾脏病（CKD）患者和透析患者的死亡率。尽管啮齿动物研究表明，IIb型钠依赖性磷酸盐转运体（NaPi-IIb）是高磷血症的一个潜在靶点，但NaPi-IIb选择性抑制剂在人体临床试验中未能取得疗效。在本研究中，我们分析了大鼠、犬和猴的磷酸盐代谢情况，以确认种属差异。测量了与磷酸盐代谢相关的因素，并根据每个物种的粪便排泄量计算肠道磷酸盐吸收率。分析了肠道刷状缘膜囊泡（BBMV）对磷酸盐的摄取以及NaPi-IIb、PiT-1和PiT-2的mRNA表达。此外，还评估了碱性磷酸酶（ALP）活性。包括BBMV对磷酸盐的摄取和NaPi-IIb表达在内的肠道磷酸盐吸收率在犬中最高。值得注意的是，猴的尿磷酸盐排泄量最低，其肠道磷酸盐吸收率也是迄今为止最低的。犬和大鼠的BBMV中磷酸盐摄取的V/K与NaPi-IIb表达之间呈正相关。尽管在猴的BBMV中观察到了磷酸盐摄取，但未检测到NaPi-IIb表达，且ALP活性较低。本研究揭示了肠道磷酸盐吸收存在显著的种属差异。NaPi-IIb有助于大鼠和犬的肠道磷酸盐摄取。然而，在猴中，由于肠道中有机磷酸盐的轻微降解，磷酸盐吸收较差。
