Elucidation of the Mechanism for Intestinal Phosphate Absorption

概要

Blood phosphate levels are regulated by absorption in the intestines, release and utilization
by bones, and excretion from kidneys. Among them, the kidney plays an important role in
regulating blood phosphate concentration, which is maintained by adjusting the urinary
excretion of phosphate (1). Phosphate excretion into urine is performed via reabsorption by
NaPi-IIa and NaPi-IIc in kidneys, and FGF23 negatively regulates the translocation of
NaPi-IIa and NaPi-IIc into the renal tubular epithelium (2). However, in patients with
chronic kidney disease (CKD) and/or dialysis, urinary phosphate excretion decreases
remarkably as kidneys fail to remove dietary phosphate from the body, leading to
hyperphosphatemia (3). Hyperphosphatemia causes secondary hyperparathyroidism and
vascular calcification, which are known risk factors for death or a decline in the quality of life
(4, 5). Phosphate binders are used in patients with hyperphosphatemia to suppress
phosphate absorption in the gastrointestinal tract (6-8). In patients with CKD and/or
dialysis, blood phosphate levels are strongly influenced by uptake in the small intestine (9,
10).
Dietary phosphate is composed of organic phosphates and phosphoric acid, an inorganic
phosphate. Organic phosphate is metabolized into phosphoric acid by alkaline phosphatase
(ALP) in the digestive tract (11). In the gastrointestinal tract this phosphate is absorbed.
There are two pathways of phosphate absorption in the small intestine, active transport via
intestinal epithelial cells and passive transport via the tight junction between cells. Little is
known about the contribution between passive flow from tight junction and active transport,
but active transport has been thought to play an important role in maintaining phosphate
absorption in the small intestine (12-14). In humans and rats, the active transport of
phosphate mainly happens in the upper part of the small intestine where NaPi-IIb, a
sodium-dependent phosphate transporter, is thought to have an important function (15-18).
However, it was reported that the efficacy of a NaPi-IIb specific inhibitor was different
between rats and humans (19). And NaPi-IIb is also active in mice, but mainly in the lower
part of the small intestine (15, 16, 20). These reports indicate that there are species
differences in the intestinal phosphate absorption system among rats, mice, and humans.
NaPi-IIb which has a strong affinity for phosphate is highly expressed in the small intestine,
and it is well known that NaPi-IIb is regulated by 1,25(OH)2D3 in rodents, 1,25(OH)2D3
administration or 1,25(OH)2D3 receptor deletion causes the increase or decrease of NaPiIIb protein expression, respectively (21,22). ...

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