Expression of NaPi-IIb in rodent and human kidney and upregulation in a model of chronic kidney disease

Motta, Sarah E.; Silva, Pedro Henrique Imenez; Daryadel, Arezoo; Haykir, Betül; Pastor-Arroyo, Eva M.; Bettoni, Carla; Hernando, Nati; Wagner, Carsten A.

doi:10.1007/s00424-020-02370-9

Cited by 17 publications

(22 citation statements)

References 77 publications

(118 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…2002) cotransporters, whereas the role of the recently described renal Slc34a2 /NaPi‐IIb remains unclear (Motta et al . 2020). The quantitative role of the Slc20 family in the intestinal and/or renal transcellular transport of P i is probably minor, at least in mice (Pastor‐Arroyo et al .…”

Section: Introductionmentioning

confidence: 99%

1,25(OH)₂ vitamin D₃ stimulates active phosphate transport but not paracellular phosphate absorption in mouse intestine

Hernando

Pastor-Arroyo

Marks

et al. 2020

The Journal of Physiology

Self Cite

View full text Add to dashboard Cite

Key points Intestinal absorption of phosphate proceeds via an active/transcellular route mostly mediated by NaPi‐IIb/Slc34a2 and a poorly characterized passive/paracellular pathway. Intestinal phosphate absorption and expression of NaPi‐IIb are stimulated by 1,25(OH)2 vitamin D3 but whether NaPi‐IIb is the only target under hormonal control remains unknown. We report that administration of 1,25(OH)2 vitamin D3 to wild‐type mice resulted in the expected increase in active transport of phosphate in jejunum, without changing paracellular fluxes. Instead, the same treatment failed to alter phosphate transport in intestinal‐depleted Slc34a2‐deficient mice. In both genotypes, 1,25(OH)2 vitamin D3 induced similar hyperphosphaturic responses and changes in the plasma levels of FGF23 and PTH. While urinary phosphate loss induced by administration of 1,25(OH)2 vitamin D3 did not alter plasma phosphate, further studies should investigate whether chronic administration would lead to phosphate imbalance in mice with reduced active intestinal absorption. Abstract Intestinal absorption of phosphate is stimulated by 1,25(OH)2 vitamin D3. At least two distinct mechanisms underlie phosphate absorption in the gut, an active transcellular transport requiring the Na+/phosphate cotransporter NaPi‐IIb/Slc34a2, and a poorly characterized paracellular passive pathway. 1,25(OH)2 vitamin D3 stimulates NaPi‐IIb expression and function, and loss of NaPi‐IIb reduces intestinal phosphate absorption. However, it is remains unknown whether NaPi‐IIb is the only target for hormonal regulation by 1,25(OH)2 vitamin D3. Here we compared the effects of intraperitoneal administration of 1,25(OH)2 vitamin D3 (2 days, once per day) in wild‐type and intestinal‐specific Slc34a2‐deficient mice, and analysed trans‐ vs. paracellular routes of phosphate absorption. We found that treatment stimulated active transport of phosphate only in jejunum of wild‐type mice, though NaPi‐IIb protein expression was upregulated in jejunum and ileum. In contrast, 1,25(OH)2 vitamin D3 administration had no effect in Slc34a2‐deficient mice, suggesting that the hormone specifically regulates NaPi‐IIb expression. In both groups, 1,25(OH)2 vitamin D3 elicited the expected increase of plasma fibroblast growth factor 23 (FGF23) and reduction of parathyroid hormone (PTH). Treatment resulted in hyperphosphaturia (and hypercalciuria) in both genotypes, though mice remained normophosphataemic. While increased intestinal absorption and higher FGF23 can trigger the hyperphosphaturic response in wild types, only higher FGF23 can explain the renal response in Slc34a2‐deficient mice. Thus, 1,25(OH)2 vitamin D3 stimulates intestinal phosphate absorption by acting on the active transcellular pathway mostly mediated by NaPi‐IIb while the paracellular pathway appears not to be affected.

show abstract

Section: Introductionmentioning

confidence: 99%

1,25(OH)₂ vitamin D₃ stimulates active phosphate transport but not paracellular phosphate absorption in mouse intestine

Hernando

Pastor-Arroyo

Marks

et al. 2020

The Journal of Physiology

Self Cite

View full text Add to dashboard Cite

show abstract

“…NPT2B (SLC34A2) is expressed in the enterocyte brush border membrane, where it is upregulated by calcitriol [ 41 ], and in alveolar type II cells in the lungs. The mRNA expression of NPT2B in human lung is 30-fold higher than in the small intestine [ 42 , 43 ]. NPT2B has also recently been localized in the kidney medullary thick ascending limb in humans, although levels are ~100-fold lower than in lung [ 42 ].…”

Section: Phosphate Transporters: Knowledge From Animal Models and Human Physiologymentioning

confidence: 99%

“…NPT2B has also recently been localized in the kidney medullary thick ascending limb in humans, although levels are ~100-fold lower than in lung [ 42 ]. Whereas it has been shown that renal NPT2B transcripts are upregulated in a mouse model of chronic kidney disease (CKD) [ 43 ], its overall role in normal renal phosphate handling remains unknown. Diseases that have the potential to impact NPT2B function would be expected to cause an imbalance in phosphate homeostasis if this protein plays a critical role in intestinal phosphate absorption.…”

Section: Phosphate Transporters: Knowledge From Animal Models and Human Physiologymentioning

confidence: 99%

“…The thick ascending limb is the main site of renal CaSR expression [ 78 ], where phosphate absorption is negligible. Interestingly, recent studies have demonstrated the expression of NPT2B in this segment, but its function remains unknown [ 42 , 43 ]. In this segment, calcitriol inhibits bicarbonate absorption via a synergic action of aldosterone resulting in stimulation of the ERK pathway [ 79 ].…”

Section: Phosphate Sensing: the Knowns And Unknownsmentioning

confidence: 99%

See 1 more Smart Citation

The Complexities of Organ Crosstalk in Phosphate Homeostasis: Time to Put Phosphate Sensing Back in the Limelight

Figueres

Beck-Cormier

Beck

et al. 2021

IJMS

View full text Add to dashboard Cite

Phosphate homeostasis is essential for health and is achieved via interaction between the bone, kidney, small intestine, and parathyroid glands and via intricate processes involving phosphate transporters, phosphate sensors, and circulating hormones. Numerous genetic and acquired disorders are associated with disruption in these processes and can lead to significant morbidity and mortality. The role of the kidney in phosphate homeostasis is well known, although it is recognized that the cellular mechanisms in murine models and humans are different. Intestinal phosphate transport also appears to differ in humans and rodents, with recent studies demonstrating a dominant role for the paracellular pathway. The existence of phosphate sensing has been acknowledged for decades; however, the underlying molecular mechanisms are poorly understood. At least three phosphate sensors have emerged. PiT2 and FGFR1c both act as phosphate sensors controlling Fibroblast Growth Factor 23 secretion in bone, whereas the calcium-sensing receptor controls parathyroid hormone secretion in response to extracellular phosphate. All three of the proposed sensors are expressed in the kidney and intestine but their exact function in these organs is unknown. Understanding organ interactions and the mechanisms involved in phosphate sensing requires significant research to develop novel approaches for the treatment of phosphate homeostasis disorders.

show abstract

“…However, little is understood about the mechanism of phosphate reabsorption in the distal nephron. Recently, NPT2b has been localized to the apical membrane of the TAL in the kidney, but its purpose requires further investigation (125) . Furthermore, data concerning the effect of aging on phosphate homeostasis are limited.…”

Section: Role Of the Kidney In Phosphate Homeostasismentioning

confidence: 99%

Renal Contributions to Age‐Related Changes in Mineral Metabolism

2021

View full text Add to dashboard Cite

Aging results in a general decline in function in most systems. This is particularly true with respect to the skeleton and renal systems, impacting mineral homeostasis. Calcium and phosphate regulation requires tight coordination among the intestine, bone, parathyroid gland, and kidney.The role of the intestine is to absorb calcium and phosphate from the diet. The bone stores or releases calcium and phosphate depending on the body's needs. In response to low plasma ionized calcium concentration, the parathyroid gland produces parathyroid hormone which modulates bone turnover. The kidney reabsorbs or excretes the minerals and serves as the final regulator of plasma concentration. Many hormones are involved in this process in addition to parathyroid hormone, including fibroblast growth factor 23 produced by the bone, and calcitriol synthesized by the kidney. Sclerostin, calcitonin, osteoprotegerin and receptor activator of nuclear factor κ-B ligand also contribute to tissue-specific regulation. Changes in the function of organs due to aging or disease can perturb this balance. During aging, the intestine cannot absorb calcium efficiently due to decreased expression of key proteins. In the bone, the balance between bone formation and bone resorption tends toward the latter in older individuals. The kidney may not filter blood as efficiently in the later decades of life and the expression of certain proteins necessary for mineral homeostasis declines with age. These changes often lead to dysregulation of organismal mineral homeostasis. This review will focus on how mineral homeostasis is impacted by aging with a particular emphasis on the kidney's role in this process.

show abstract

Expression of NaPi-IIb in rodent and human kidney and upregulation in a model of chronic kidney disease

Cited by 17 publications

References 77 publications

1,25(OH)₂ vitamin D₃ stimulates active phosphate transport but not paracellular phosphate absorption in mouse intestine

1,25(OH)₂ vitamin D₃ stimulates active phosphate transport but not paracellular phosphate absorption in mouse intestine

The Complexities of Organ Crosstalk in Phosphate Homeostasis: Time to Put Phosphate Sensing Back in the Limelight

Renal Contributions to Age‐Related Changes in Mineral Metabolism

Contact Info

Product

Resources

About

Expression of NaPi-IIb in rodent and human kidney and upregulation in a model of chronic kidney disease

Cited by 17 publications

References 77 publications

1,25(OH)2 vitamin D3 stimulates active phosphate transport but not paracellular phosphate absorption in mouse intestine

1,25(OH)2 vitamin D3 stimulates active phosphate transport but not paracellular phosphate absorption in mouse intestine

The Complexities of Organ Crosstalk in Phosphate Homeostasis: Time to Put Phosphate Sensing Back in the Limelight

Renal Contributions to Age‐Related Changes in Mineral Metabolism

Contact Info

Product

Resources

About

1,25(OH)₂ vitamin D₃ stimulates active phosphate transport but not paracellular phosphate absorption in mouse intestine

1,25(OH)₂ vitamin D₃ stimulates active phosphate transport but not paracellular phosphate absorption in mouse intestine