Hernando, N. & Wagner, C. A. Mechanisms and regulation of intestinal phosphate absorption. Compr. Physiol. 8(3), 1065–1090 (2018).
Knoepfel, T. et al. Paracellular transport of phosphate along the intestine. Am. J. Physiol. Gastr. L. 317(2), G233–G241 (2019).
Danisi, G. & Straub, R. W. Unidirectional influx of phosphate across the mucosal membrane of rabbit small intestine. Pflugers Arch. 385(2), 117–122 (1980).
Harrison, H. E. & Harrison, H. C. Intestinal transport of phosphate: action of vitamin D, calcium, and potassium. Am. J. Physiol. 201, 1007–1012 (1961).
Mc, H. G. & Parsons, D. S. The absorption of water and salt from the small intestine of the rat. Q. J. Exp. Physiol. Cogn. Med. Sci. 42(1), 33–48 (1957).
Marks, J., Lee, G. J., Nadaraja, S. P., Debnam, E. S. & Unwin, R. J. Experimental and regional variations in Na+-dependent and Na+-independent phosphate transport along the rat small intestine and colon. Physiol. Rep. 3(1), e12281 (2015).
Hernando, N. et al. 1,25(OH)2 vitamin D3 stimulates active phosphate transport but not paracellular phosphate absorption in mouse intestine. J. Physiol. 599, 1131–1150 (2020).
Walton, J. & Gray, T. K. Absorption of inorganic phosphate in the human small intestine. Clin. Sci. (Lond.) 56(5), 407–412 (1979).
Candeal, E., Caldas, Y. A., Guillen, N., Levi, M. & Sorribas, V. Na+-independent phosphate transport in Caco2BBE cells. Am. J. Physiol. Cell Physiol. 307(12), C1113-1122 (2014).
Ichida, Y. et al. Evidence of an intestinal phosphate transporter alternative to type IIb sodium-dependent phosphate transporter in rats with chronic kidney disease. Nephrol. Dial Transpl. 36, 68–75 (2020).
Tsuboi, Y. et al. EOS789, a novel pan-phosphate transporter inhibitor, is effective for the treatment of chronic kidney disease-mineral bone disorder. Kidney Int. 98(2), 343–354 (2020).
Pastor-Arroyo, E. M. et al. Intestinal epithelial ablation of Pit-2/Slc20a2 in mice leads to sustained elevation of vitamin D(3)upon dietary restriction of phosphate. Acta Physiol. 230, e13526 (2020).
Hilfiker, H. et al. Characterization of a murine type II sodium-phosphate cotransporter expressed in mammalian small intestine. Proc. Natl. Acad. Sci. USA 95(24), 14564–14569 (1998).
Fenollar-Ferrer, C. et al. Structural fold and binding sites of the human Na(+)-phosphate cotransporter NaPi-II. Biophys. J. 106(6), 1268–1279 (2014).
Nishimura, M. & Naito, S. Tissue-specific mRNA expression profiles of human solute carrier transporter superfamilies. Drug Metab. Pharmacokinet. 23(1), 22–44 (2008).
Corut, A. et al. Mutations in SLC34A2 cause pulmonary alveolar microlithiasis and are possibly associated with testicular microlithiasis. Am. J. Hum. Genet. 79(4), 650–656 (2006).
Saito, A. et al. Modeling pulmonary alveolar microlithiasis by epithelial deletion of the Npt2b sodium phosphate cotransporter reveals putative biomarkers and strategies for treatment. Sci. Transl. Med. 7(313), 313ra181 (2015).
Samrah, S., Shraideh, H., Rawashdeh, S. & Khassawneh, B. Tricuspid valve calcification in familial pulmonary alveolar microlithiasis: a case report. Ann. Med. Surg. (Lond.) 55, 256–259 (2020).
Lacerda-Abreu, M. A., Russo-Abrahao, T., Monteiro, R. Q., Rumjanek, F. D. & Meyer-Fernandes, J. R. Inorganic phosphate transporters in cancer: functions, molecular mechanisms and possible clinical applications. Biochim. Biophys Acta Rev Cancer 1870(2), 291–298 (2018).
Traebert, M., Hattenhauer, O., Murer, H., Kaissling, B. & Biber, J. Expression of type II Na-P(i) cotransporter in alveolar type II cells. Am. J. Physiol. 277(5), L868-873 (1999).
Frei, P. et al. Identification and localization of sodium-phosphate cotransporters in hepatocytes and cholangiocytes of rat liver. Am. J. Physiol. Gastrointest. Liver Physiol. 288(4), G771-778 (2005).
Motta, S. E. et al. Expression of NaPi-IIb in rodent and human kidney and upregulation in a model of chronic kidney disease. Pflugers Arch. 472(4), 449–460 (2020).
Magagnin, S. et al. Expression cloning of human and rat renal cortex Na/Pi cotransport. Proc. Natl. Acad. Sci. USA 90(13), 5979–5983 (1993).
Segawa, H. et al. Growth-related renal type II Na/Pi cotransporter. J. Biol. Chem. 277(22), 19665–19672 (2002).
Schlingmann, K. P. et al. Autosomal-recessive mutations in SLC34A1 encoding sodium-phosphate cotransporter 2A cause idiopathic infantile hypercalcemia. J. Am. Soc. Nephrol. 27(2), 604–614 (2016).
Dinour, D. et al. Loss of function of NaPiIIa causes nephrocalcinosis and possibly kidney insufficiency. Pediatr. Nephrol. 31(12), 2289–2297 (2016).
Bergwitz, C. et al. SLC34A3 mutations in patients with hereditary hypophosphatemic rickets with hypercalciuria predict a key role for the sodium-phosphate cotransporter NaPi-IIc in maintaining phosphate homeostasis. Am. J. Hum. Genet. 78(2), 179–192 (2006).
Ichikawa, S. et al. Intronic deletions in the SLC34A3 gene cause hereditary hypophosphatemic rickets with hypercalciuria. J. Clin. Endocrinol. Metab. 91(10), 4022–4027 (2006).
Lorenz-Depiereux, B. et al. Hereditary hypophosphatemic rickets with hypercalciuria is caused by mutations in the sodium-phosphate cotransporter gene SLC34A3. Am. J. Hum. Genet. 78(2), 193–201 (2006).
Hattenhauer, O., Traebert, M., Murer, H. & Biber, J. Regulation of small intestinal Na-P(i) type IIb cotransporter by dietary phosphate intake. Am. J. Physiol. 277(4), G756-762 (1999).
Levi, M. et al. Mechanisms of phosphate transport. Nat. Rev. Nephrol. 15(8), 482–500 (2019).
Giral, H. et al. Regulation of rat intestinal Na-dependent phosphate transporters by dietary phosphate. Am. J. Physiol. Renal Physiol. 297(5), F1466-1475 (2009).
Marks, J. et al. Intestinal phosphate absorption and the effect of vitamin D: a comparison of rats with mice. Exp. Physiol. 91(3), 531–537 (2006).
Radanovic, T., Wagner, C. A., Murer, H. & Biber, J. Regulation of intestinal phosphate transport. I. Segmental expression and adaptation to low-P(i) diet of the type IIb Na(+)-P(i) cotransporter in mouse small intestine. Am. J. Physiol. Gastrointest. Liver Physiol. 288(3), 496–500 (2005).
Pastor-Arroyo, E. M. et al. Intestinal epithelial ablation of Pit-2/Slc20a2 in mice leads to sustained elevation of vitamin D3 upon dietary restriction of phosphate. Acta Physiol. (Oxf.) 230, e13526 (2020).
Walling, M. W. Intestinal Ca and phosphate transport: differential responses to vitamin D3 metabolites. Am. J. Physiol. 233(6), E488-494 (1977).
Juan, D., Liptak, P. & Gray, T. K. Absorption of inorganic phosphate in the human jejunum and its inhibition by salmon calcitonin. J. Clin. Endocrinol. Metab. 43(3), 517–522 (1976).
Dogan, O. T. et al. A frame-shift mutation in the SLC34A2 gene in three patients with pulmonary alveolar microlithiasis in an inbred family. Intern. Med. 49(1), 45–49 (2010).
Caffrey, P. R. & Altman, R. S. Pulmonary alveolar microlithiasis occurring in premature twins. J. Pediatr US 66(4), 758 (1965).
Dahabreh, M. & Najada, A. Pulmonary alveolar microlithiasis in an 8-month-old infant. Ann. Trop. Paediatr. 29(1), 55–59 (2009).
Takahashi, H., Chiba, H., Shiratori, M., Tachibana, T. & Abe, S. Elevated serum surfactant protein A and D in pulmonary alveolar microlithiasis. Respirology 11(3), 330–333 (2006).
Shibasaki, Y. et al. Targeted deletion of the tybe IIb Na(+)-dependent Pi-co-transporter, NaPi-IIb, results in early embryonic lethality. Biochem. Biophys. Res. Commun. 381(4), 482–486 (2009).
Sabbagh, Y. et al. Intestinal npt2b plays a major role in phosphate absorption and homeostasis. J. Am. Soc. Nephrol. 20(11), 2348–2358 (2009).
Hernando, N. et al. Intestinal depletion of NaPi-IIb/Slc34a2 in mice: renal and hormonal adaptation. J. Bone Miner. Res. 30(10), 1925–1937 (2015).
Knopfel, T. et al. The intestinal phosphate transporter NaPi-IIb (Slc34a2) is required to protect bone during dietary phosphate restriction. Sci. Rep. UK 7, 11018 (2017).
Uribarri, J. Phosphorus homeostasis in normal health and in chronic kidney disease patients with special emphasis on dietary phosphorus intake. Semin. Dial. 20(4), 295–301 (2007).
Sherman, R. A. & Mehta, O. Phosphorus and potassium content of enhanced meat and poultry products: implications for patients who receive dialysis. Clin. J. Am. Soc. Nephrol. 4(8), 1370–1373 (2009).
Dhingra, R. et al. Relations of serum phosphorus and calcium levels to the incidence of cardiovascular disease in the community. Arch. Intern. Med. 167(9), 879–885 (2007).
Foley, R. N., Collins, A. J., Herzog, C. A., Ishani, A. & Kalra, P. A. Serum phosphorus levels associate with coronary atherosclerosis in young adults. J. Am. Soc. Nephrol. 20(2), 397–404 (2009).
Vervloet, M. G. et al. The role of phosphate in kidney disease. Nat. Rev. Nephrol. 13(1), 27–38 (2017).
Beck, L. et al. Targeted inactivation of Npt2 in mice leads to severe renal phosphate wasting, hypercalciuria, and skeletal abnormalities. Proc. Natl. Acad. Sci. USA 95(9), 5372–5377 (1998).
Myakala, K. et al. Renal-specific and inducible depletion of NaPi-IIc/Slc34a3, the cotransporter mutated in HHRH, does not affect phosphate or calcium homeostasis in mice. Am. J. Physiol. Renal Physiol. 306(8), F833-843 (2014).
Segawa, H. et al. Type IIc sodium-dependent phosphate transporter regulates calcium metabolism. J. Am. Soc. Nephrol. 20(1), 104–113 (2009).
Shimada, T. et al. FGF-23 transgenic mice demonstrate hypophosphatemic rickets with reduced expression of sodium phosphate cotransporter type IIa. Biochem. Biophys. Res. Commun. 314(2), 409–414 (2004).
Gattineni, J. et al. FGF23 decreases renal NaPi-2a and NaPi-2c expression and induces hypophosphatemia in vivo predominantly via FGF receptor 1. Am. J. Physiol. Renal Physiol. 297(2), F282-291 (2009).
Tomoe, Y. et al. Phosphaturic action of fibroblast growth factor 23 in Npt2 null mice. Am. J. Physiol. Renal Physiol. 298(6), F1341-1350 (2010).
Xu, H., Bai, L., Collins, J. F. & Ghishan, F. K. Age-dependent regulation of rat intestinal type IIb sodium-phosphate cotransporter by 1,25-(OH)(2) vitamin D(3). Am. J. Physiol. Cell Physiol. 282(3), C487-493 (2002).
Noah, T. K., Donahue, B. & Shroyer, N. F. Intestinal development and differentiation. Exp. Cell Res. 317(19), 2702–2710 (2011).
Schittny, J. C. Development of the lung. Cell Tissue Res. 367(3), 427–444 (2017).
Vainio, S. & Lin, Y. Coordinating early kidney development: lessons from gene targeting. Nat. Rev. Genet. 3(7), 533–543 (2002).
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