Effect of variations in dietary Pi intake on intestinal Pi transporters (NaPi-IIb, PiT-1, and PiT-2) and phosphate-regulating factors (PTH, FGF-23, and MEPE)

Abstract

Hyperphosphatemia is a common condition in patients with chronic kidney disease (CKD) and can lead to bone disease, vascular calcification, and increased risks of cardiovascular disease and mortality. Inorganic phosphate (P) is absorbed in the intestine, an important step in the maintenance of homeostasis. In CKD, it is not clear to what extent P absorption is modulated by dietary P. Thus, we investigated 5/6 nephrectomized (Nx) Wistar rats to test whether acute variations in dietary P concentration over 2 days would alter hormones involved in P metabolism, expression of sodium-phosphate cotransporters, apoptosis, and the expression of matrix extracellular phosphoglycoprotein (MEPE) in different segments of the small intestine. The animals were divided into groups receiving different levels of dietary phosphate: low (Nx/LP), normal (Nx/NP), and high (Nx/HP). Serum phosphate, fractional excretion of phosphate, intact serum fibroblast growth factor 23 (FGF-23), and parathyroid hormone (PTH) were significantly higher and ionized calcium was significantly lower in the Nx/HP group than in the Nx/LP group. The expression levels of NaPi-IIb and PiT-1/2 were increased in the total jejunum mucosa of the Nx/LP group compared with the Nx/HP group. Modification of P concentration in the diet affected the apoptosis of enterocytes, particularly with P overload. MEPE expression was higher in the Nx/HP group than in the Nx/NP. These data reveal the importance of early control of P in uremia to prevent an increase in serum PTH and FGF-23. Uremia may be a determining factor that explains the expressional modulation of the cotransporters in the small intestine segments.

Calcium, Phosphate and Magnesium Disorders

“…Different species display diverse mechanisms for intestinal absorption of phosphate, and therefore the understanding of human intestinal phosphate handling is incomplete [34].…”

“…In healthy humans, 60-75% of dietary phosphorus is absorbed [4,21]. Paracellular transport involves passive diffusion of phosphate through tight junctions and occurs independently of any regulatory hormones [34]. The type II sodium-phosphate cotransporter, Npt2b (SLC34A2), and type III cotransporters, PiT1 and PiT2, modulate transcellular transport in the intestine.…”

“…The type II sodium-phosphate cotransporter, Npt2b (SLC34A2), and type III cotransporters, PiT1 and PiT2, modulate transcellular transport in the intestine. Npt2b is located on the apical membrane of enterocytes and is thought to be most abundant in the duodenum and jejunum in humans [1] although it is also found on lung, mammary, liver, and testis tissue [31,34]. Mutations in Npt2b transporters do not manifest in clinically significant hypophosphataemia in humans, and this is thought to be due to renal compensation [28].…”

“…FGF23 reduces the abundance and activity of sodium-phosphate cotransporters and will be discussed further in this chapter. Matrix extracellular phosphoglycoprotein (MEPE) produced by osteoblasts and osteocytes inhibits renal and intestinal phosphate absorption independent of PTH and FGF23 [34]. Other regulators of phosphate absorption are glucocorticoids, oestrogen and the presence of metabolic acidosis [28].…”

The role of SLC34A2 in intestinal phosphate absorption and phosphate homeostasis

“…The so called ‘intestinal phosphatonin’ was suggested to act independently of changes in plasma phosphate concentration or parathyroid hormone (PTH) [5]. The finding that matrix extracellular phosphoglycoprotein (MEPE), a protein typically secreted from bone [53] that has a phosphaturic effect on the kidney [59], is present in the intestinal epithelium, specifically the duodenum [3, 47], led to the suggestion that this may be the factor proposed by Berndt et al [47]. However, subsequent studies were unable to confirm the existence of this intestinal phosphatonin, but instead found that acute renal adaptation to an oral phosphate load requires PTH [40, 62].…”