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Mechanisms and Regulation of Intestinal Phosphate Absorption

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ABSTRACT

States of hypo‐ and hyperphosphatemia have deleterious consequences including rickets/osteomalacia and renal/cardiovascular disease, respectively. Therefore, the maintenance of appropriate plasma levels of phosphate is an essential requirement for health. This control is executed by the collaborative action of intestine and kidney whose capacities to (re)absorb phosphate are regulated by a number of hormonal and metabolic factors, among them parathyroid hormone, fibroblast growth factor 23, 1,25(OH)2 vitamin D3, and dietary phosphate. The molecular mechanisms responsible for the transepithelial transport of phosphate across enterocytes are only partially understood. Indeed, whereas renal reabsorption entirely relies on well‐characterized active transport mechanisms of phosphate across the renal proximal epithelia, intestinal absorption proceeds via active and passive mechanisms, with the molecular identity of the passive component still unknown. The active absorption of phosphate depends mostly on the activity and expression of the sodium‐dependent phosphate cotransporter NaPi‐IIb (SLC34A2), which is highly regulated by many of the factors, mentioned earlier. Physiologically, the contribution of NaPi‐IIb to the maintenance of phosphate balance appears to be mostly relevant during periods of low phosphate availability. Therefore, its role in individuals living in industrialized societies with high phosphate intake is probably less relevant. Importantly, small increases in plasma phosphate, even within normal range, associate with higher risk of cardiovascular disease. Therefore, therapeutic approaches to treat hyperphosphatemia, including dietary phosphate restriction and phosphate binders, aim at reducing intestinal absorption. Here we review the current state of research in the field. © 2017 American Physiological Society. Compr Physiol 8:1065‐1090, 2018.

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Figure 1. Figure 1. Phosphate balance in healthy subjects. The cartoon shows the main organs involved in phosphate homeostasis, namely, intestine, kidney, and bones. In healthy adults, the daily amount of phosphate ingested with the diet is excreted by the intestine and kidneys.
Figure 2. Figure 2. Hormonal changes triggered high dietary phosphate/plasma phosphate and hormonal feedback loops. An increase in plasma phosphate stimulates the production PTH and FGF23 whereas it blunts synthesis of 1,25(OH)2 vitamin D3. PTH activates the production of FGF23 and 1,25(OH)2 vitamin D3, FGF23 inactivates the synthesis of PTH as well as 1,25(OH)2 vitamin D3 and this later one activates FGF23 whereas inhibits PTH production. Green and red arrows indicated positive and negative effects, respectively. The identity of intestinal and renal Na+‐dependent phosphate cotransporters in indicated in the boxes. High dietary phosphate/hyperphosphatemia downregulates the expression of cotransporters both in the gut and in the proximal tubules; downregulation is indicated in red.
Figure 3. Figure 3. Transepithelial transport of phosphate across enterocytes. Dietary phosphate is transported via secondary active Na+‐dependent phosphate cotransporters (NaPi‐IIb, PiT‐1, and PiT‐2) located in the apical membrane of enterocytes as well as via a paracellular route. The active route is energized by the activity of the basolateral Na+/K+ pump. The identity of the molecules responsible for the basolateral efflux as well as for the paracellular transport remains unknown.
Figure 4. Figure 4. Structure of intestinal villi and microvilli and distribution of NaPi‐IIb along the intestinal villi of mice. (A) The intestinal lumen contains may folds or villi consisting of different cell types, from which enterocytes (gray) are the most abundant. (B) The apical membrane of enterocytes contains abundant actin‐based protrusions, the microvilli or brush border membrane that are stabilized by different types of protein‐protein (and protein‐lipid) interactions: F‐actin bundling, membrane‐cytoskeleton crosslinking and intermicrovillar adhesion (adapted, with permission, from Crawley et al., Ref. ). (C) Actin staining and immunofluorescence of NaPi‐IIb along the intestinal villi of mice: NaPi‐IIb is expressed along the villi but is absent from crypts (taken from Hattenhauer et al., Ref. , with permission).


Figure 1. Phosphate balance in healthy subjects. The cartoon shows the main organs involved in phosphate homeostasis, namely, intestine, kidney, and bones. In healthy adults, the daily amount of phosphate ingested with the diet is excreted by the intestine and kidneys.


Figure 2. Hormonal changes triggered high dietary phosphate/plasma phosphate and hormonal feedback loops. An increase in plasma phosphate stimulates the production PTH and FGF23 whereas it blunts synthesis of 1,25(OH)2 vitamin D3. PTH activates the production of FGF23 and 1,25(OH)2 vitamin D3, FGF23 inactivates the synthesis of PTH as well as 1,25(OH)2 vitamin D3 and this later one activates FGF23 whereas inhibits PTH production. Green and red arrows indicated positive and negative effects, respectively. The identity of intestinal and renal Na+‐dependent phosphate cotransporters in indicated in the boxes. High dietary phosphate/hyperphosphatemia downregulates the expression of cotransporters both in the gut and in the proximal tubules; downregulation is indicated in red.


Figure 3. Transepithelial transport of phosphate across enterocytes. Dietary phosphate is transported via secondary active Na+‐dependent phosphate cotransporters (NaPi‐IIb, PiT‐1, and PiT‐2) located in the apical membrane of enterocytes as well as via a paracellular route. The active route is energized by the activity of the basolateral Na+/K+ pump. The identity of the molecules responsible for the basolateral efflux as well as for the paracellular transport remains unknown.


Figure 4. Structure of intestinal villi and microvilli and distribution of NaPi‐IIb along the intestinal villi of mice. (A) The intestinal lumen contains may folds or villi consisting of different cell types, from which enterocytes (gray) are the most abundant. (B) The apical membrane of enterocytes contains abundant actin‐based protrusions, the microvilli or brush border membrane that are stabilized by different types of protein‐protein (and protein‐lipid) interactions: F‐actin bundling, membrane‐cytoskeleton crosslinking and intermicrovillar adhesion (adapted, with permission, from Crawley et al., Ref. ). (C) Actin staining and immunofluorescence of NaPi‐IIb along the intestinal villi of mice: NaPi‐IIb is expressed along the villi but is absent from crypts (taken from Hattenhauer et al., Ref. , with permission).
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Teaching Material

N. Hernando, C. A. Wagner. Mechanisms and Regulation of Intestinal Phosphate Absorption. Compr Physiol 8: 2018, 1065-1090.

Didactic Synopsis

Major Teaching Points:

  • Phosphate homeostasis is essential for health, and therefore plasma phosphate levels must be kept within a normal range. This regulation is achieved by the combined action of intestine, kidneys, and bones.
  • In adults under zero phosphate balance, the daily amount of phosphate absorbed by the intestine is excreted by the kidneys.
  • The epithelia of the small intestine and renal proximal tubules contain Na+-dependent phosphate cotransporters responsible for the active transport of phosphate. These active transporters belong to the SLC34 and SLC20 families of solute carriers, with the SLC34 family probably playing a major quantitative role.
  • In addition to the active component, the intestine also transports phosphate via a passive/paracellular pathway which identity remains unknown.
  • Hyperphosphatemia correlates with increased risk of cardiovascular disease in the normal population as well as in patients with chronic kidney disease.

Didactic Legends

The figures—in a freely downloadable PowerPoint format—can be found on the Images tab along with the formal legends published in the article. The following legends to the same figures are written to be useful for teaching.

Figure 1 Teaching points: Phosphate balance in healthy subjects. This figure shows the main organs involved in phosphate homeostasis, namely intestine, kidney, and bones. Dietary phosphate is absorbed in the small intestine and upon entering the circulation is in constant exchange with bones and soft tissues. Only about 1% of total body phosphate remains in plasma. Because phosphate is freely filtered in the glomerulus, it must be then reabsorbed along the renal tubule, a process that takes place mostly along the proximal segment. Bones represent the major phosphate storage site. Green arrows indicate shift of phosphate from plasma, whereas purple arrows indicate incorporation of phosphate to the plasma pool. In healthy adults, the daily amount of phosphate ingested with the diet is excreted by the intestine and kidneys.

Figure 2 Teaching points: Hormonal changes triggered high dietary phosphate/plasma phosphate and hormonal feedback loops. High plasma phosphate stimulates the production of PTH by the parathyroid glands as well as the synthesis of FGF23 by osteocytes. Both hormones have phosphaturic effects, since they downregulate the expression of renal phosphate cotransporters, thus promoting the excretion of phosphate in excess. In contrast, hyperphosphatemia inhibits the renal formation of 1,25(OH)2 vitamin D3. Since one of the roles of 1,25(OH)2 vitamin D3 is to burst the intestinal absorption of phosphate by increasing the expression of NaPi-IIb, its inhibition results in blunt intestinal phosphate uptake. Additionally, these three hormones are engaged in feed-back loops, such that PTH activates the production of FGF23 and 1,25(OH)2 vitamin D3, FGF23 inactivates the synthesis of PTH as well as 1,25(OH)2 vitamin D3 and this later one activates FGF23 whereas inhibits PTH production. Green and red arrows indicated positive and negative effects, respectively. The identity of intestinal and renal Na+-dependent phosphate cotransporters in indicated in the boxes. High dietary phosphate/hyperphosphatemia downregulates the expression of cotransporters both in the gut and in the proximal tubules; downregulation is indicated in red. These changes result in increased renal excretion of phosphate and blunted intestinal absorption. High PTH and FGF23 are responsible for the renal response whereas the low 1,25(OH)2 vitamin D3 contributes to the reduced NaPi-IIb expression (its effect on Pits has not been tested).

Figure 3 Teaching points: Transepithelial transport of phosphate across enterocytes. This figure shows that dietary phosphate is transported across the intestinal epithelia via secondary active as well as passive/paracellular routes. The active transporters which expression has been reported in enterocytes are NaPi-IIb/SLC34A2, PiT1/SLC20A1, and PiT-2/SLC20A2. All these three proteins are Na+-dependent phosphate cotransporters expressed in the apical membrane of enterocytes, a membrane domain characterized by the presence of many actin-based protrusions, the microvilli, or brush-border membrane. The active route is energized by the activity of the basolateral Na+/K+ pump that keeps an Na+-electrochemical gradient. The identity of the molecules responsible for the basolateral efflux as well as for the paracellular transport remains unknown.

Figure 4 Teaching points: Structure of intestinal villi and microvilli and distribution of NaPi-IIb along the intestinal villi of mice. (A) The intestinal lumen contains may folds or villi which function is to increase the surface for nutrient absorption. Each villus consists of different cell types, from which enterocytes (gray) are the most abundant and the ones responsible for absorption. (B) The apical membrane of enterocytes contains abundant actin-based protrusions, the microvilli, or brush-border membrane that further increase the luminal surface. These protrusions are stabilized by different types of protein-protein (and protein-lipid) interactions: F-actin bundling (mediated by EPS8, villin, espin, and fimbrin), membrane-cytoskeleton crosslinking (mediated by myosin-1a, myosin-6, and ezrin) and intermicrovillar adhesion (mediated by PCDH24/MLPCDH, harmonin, and myosin 7b), (adapted from Crawley et al., 2014). (C) Actin staining and immunofluorescence of NaPi-IIb along the intestinal villi of mice: NaPi-IIb is expressed along the villi but is absent from crypts (taken from Hattenhauer et al., 1999, with permission).

 


Related Articles:

Inorganic Phosphate Absorption in Small Intestine
Kidney and Bone: Physiological and Pathophysiological Relationships
Mendelian Phenotypes as “Probes” of Renal Transport Systems for Amino Acids and Phosphate
Phosphate Homeostasis
PTH and Vitamin D
Renal Handling of Phosphate and Sulfate
Vitamin D Endocrine System and Calcium and Phosphorus Homeostasis

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How to Cite

Nati Hernando, Carsten A. Wagner. Mechanisms and Regulation of Intestinal Phosphate Absorption. Compr Physiol 2018, 8: 1065-1090. doi: 10.1002/cphy.c170024