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Mechanisms and Regulation of Intestinal Phosphate Absorption

Nati Hernando, Carsten A. Wagner

10.1002/cphy.c170024

Source: Volume 8, Issue 3, July 2018

Published online: June 2018

Full Article on Wiley Online Library



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. 59). (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. 111, 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. 59). (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. 111, with permission).
References
 1.Abd Alamir M, Radulescu V, Goyfman M, Mohler ER, 3rd, Gao YL, Budoff MJ, Investigators CS. Prevalence and correlates of mitral annular calcification in adults with chronic kidney disease: Results from CRIC study. Atherosclerosis 242: 117‐122, 2015.
 2.Adams JS, Hewison M. Extrarenal expression of the 25‐hydroxyvitamin D‐1‐hydroxylase. Arch Biochem Biophys 523: 95‐102, 2012.
 3.Adeney KL, Siscovick DS, Ix JH, Seliger SL, Shlipak MG, Jenny NS, Kestenbaum BR. Association of serum phosphate with vascular and valvular calcification in moderate CKD. J Am Soc Nephrol 20: 381‐387, 2009.
 4.Alexandre MD, Jeansonne BG, Renegar RH, Tatum R, Chen YH. The first extracellular domain of claudin‐7 affects paracellular Cl‐ permeability. Biochem Biophys Res Commun 357: 87‐91, 2007.
 5.Almaden Y, Canalejo A, Hernandez A, Ballesteros E, Garcia‐Navarro S, Torres A, Rodriguez M. Direct effect of phosphorus on PTH secretion from whole rat parathyroid glands in vitro. J Bone Miner Res 11: 970‐976, 1996.
 6.Almaden Y, Hernandez A, Torregrosa V, Canalejo A, Sabate L, Fernandez Cruz L, Campistol JM, Torres A, Rodriguez M. High phosphate level directly stimulates parathyroid hormone secretion and synthesis by human parathyroid tissue in vitro. J Am Soc Nephrol 9: 1845‐1852, 1998.
 7.Almaden Y, Rodriguez‐Ortiz ME, Canalejo A, Canadillas S, Canalejo R, Martin D, Aguilera‐Tejero E, Rodriguez M. Calcimimetics normalize the phosphate‐induced stimulation of PTH secretion in vivo and in vitro. J Nephrol 22: 281‐288, 2009.
 8.Altman D, Sweeney HL, Spudich JA. The mechanism of myosin VI translocation and its load‐induced anchoring. Cell 116: 737‐749, 2004.
 9.Amasheh S, Meiri N, Gitter AH, Schoneberg T, Mankertz J, Schulzke JD, Fromm M. Claudin‐2 expression induces cation‐selective channels in tight junctions of epithelial cells. JCell Sci 115: 4969‐4976, 2002.
 10.Amstutz M, Mohrmann M, Gmaj P, Murer H. Effect of Ph on phosphate‐transport in rat renal brush‐border membrane‐vesicles. Am J Physiol 248: F705‐F710, 1985.
 11.Andrukhova O, Zeitz U, Goetz R, Mohammadi M, Lanske B, Erben RG. FGF23 acts directly on renal proximal tubules to induce phosphaturia through activation of the ERK1/2‐SGK1 signaling pathway. Bone 51: 621‐628, 2012.
 12.Arima K, Collins JF, Hines ER, Bai L, Ghishan FK. Molecular cloning of murine sodium‐phosphate cotransporter type IIb (Na/P(i)‐IIb) gene promoter and characterization of gene structure. Biochim Biophys Acta 1494: 149‐154, 2000.
 13.Arima K, Hines ER, Kiela PR, Drees JB, Collins JF, Ghishan FK. Glucocorticoid regulation and glycosylation of mouse intestinal type IIb Na‐P(i) cotransporter during ontogeny. Am J Physiol Gastrointest Liver Physiol 283: G426‐G434, 2002.
 14.Ash SL, Goldin BR. Effects of age and estrogen on renal vitamin D metabolism in the female rat. Am J Clin Nutr 47: 694‐699, 1988.
 15.Avraham KB, Hasson T, Steel KP, Kingsley DM, Russell LB, Mooseker MS, Copeland NG, Jenkins NA. The mouse Snell's waltzer deafness gene encodes an unconventional myosin required for structural integrity of inner ear hair cells. Nat Genet 11: 369‐375, 1995.
 16.Azam N, Zhang MY, Wang X, Tenenhouse HS, Portale AA. Disordered regulation of renal 25‐hydroxyvitamin D‐1alpha‐hydroxylase gene expression by phosphorus in X‐linked hypophosphatemic (hyp) mice. Endocrinol 144: 3463‐3468, 2003.
 17.Bacic D, LeHir M, Biber J, Kaissling B, Murer H, Wagner CA. The renal Na+/phosphate cotransporter NaPi‐IIa is internalized via the receptor‐mediated endocytic route in response to parathyroid hormone. Kidney Int 69: 495‐503, 2006.
 18.Bajwa A, Forster MN, Maiti A, Woolbright BL, Beckman MJ. Specific regulation of CYP27B1 and VDR in proximal versus distal renal cells. Arch Biochem Biophys 477: 33‐42, 2008.
 19.Barker SL, Pastor J, Carranza D, Quiones H, Griffith C, Goetz R, Mohammadi M, Ye JF, Zhang JN, Hu MC, Kuro‐o M, Moe OW, Sidhu SS. The demonstration of alpha Klotho deficiency in human chronic kidney disease with a novel synthetic antibody. Nephrol Dial Transpl 30: 223‐233, 2015.
 20.Barthel TK, Mathern DR, Whitfield GK, Haussler CA, Hopper HAt, Hsieh JC, Slater SA, Hsieh G, Kaczmarska M, Jurutka PW, Kolek OI, Ghishan FK, Haussler MR. 1,25‐Dihydroxyvitamin D3/VDR‐mediated induction of FGF23 as well as transcriptional control of other bone anabolic and catabolic genes that orchestrate the regulation of phosphate and calcium mineral metabolism. J Steroid Biochem Mol Biol 103: 381‐388, 2007.
 21.Bell RR, Draper HH, Tzeng DY, Shin HK, Schmidt GR. Physiological responses of human adults to foods containing phosphate additives. J Nutr 107: 42‐50, 1977.
 22.Ben‐Dov IZ, Galitzer H, Lavi‐Moshayoff V, Goetz R, Kuro‐o M, Mohammadi M, Sirkis R, Naveh‐Many T, Silver J. The parathyroid is a target organ for FGF23 in rats. J Clin Invest 117: 4003‐4008, 2007.
 23.Bergwitz C. Dietary phosphate modifies lifespan in Drosophila. Nephrol Dial Transpl 27: 3399‐3406, 2012.
 24.Bergwitz C, Juppner H. Regulation of phosphate homeostasis by PTH, vitamin D, and FGF23. Annu Rev Med 61: 91‐104, 2010.
 25.Bergwitz C, Rasmussen MD, DeRobertis C, Wee MJ, Sinha S, Chen HH, Huang J, Perrimon N. Roles of major facilitator superfamily transporters in phosphate response in Drosophila. PLoS One 7: e31730, 2012.
 26.Bergwitz C, Wee MJ, Sinha S, Huang J, DeRobertis C, Mensah LB, Cohen J, Friedman A, Kulkarni M, Hu Y, Vinayagam A, Schnall‐Levin M, Berger B, Perkins LA, Mohr SE, Perrimon N. Genetic determinants of phosphate response in Drosophila. PLoS One 8: e56753, 2013.
 27.Berndt T, Thomas LF, Craig TA, Sommer S, Li X, Bergstralh EJ, Kumar R. Evidence for a signaling axis by which intestinal phosphate rapidly modulates renal phosphate reabsorption. Proc Nat Acad Sci U S A 104: 11085‐11090, 2007.
 28.Berndt TJ, Pfeifer JD, Knox FG, Kempson SA, Dousa TP. Nicotinamide restores phosphaturic effect of PTH and calcitonin in phosphate deprivation. Am J Physiol 242: F447‐F452, 1982.
 29.Berner W, Kinne R, Murer H. Phosphate transport into brush‐border membrane vesicles isolated from rat small intestine. Biochem J 160: 467‐474, 1976.
 30.Berryman M, Franck Z, Bretscher A. Ezrin is concentrated in the apical microvilli of a wide variety of epithelial cells whereas moesin is found primarily in endothelial cells. J Cell Sci 105: 1025‐1043, 1993.
 31.Biber J, Hernando N, Forster I. Phosphate transporters and their function. Annu Rev Physiol 75: 535‐550, 2013.
 32.Bleskestad IH, Bergrem H, Hartmann A, Godang K, Goransson LG. Fibroblast growth factor 23 and parathyroid hormone after treatment with active vitamin D and sevelamer carbonate in patients with chronic kidney disease stage 3b, a randomized crossover trial. BMC Nephrol 13, 49: 2012.
 33.Block GA, Hulbert‐Shearon TE, Levin NW, Port FK. Association of serum phosphorus and calcium x phosphate product with mortality risk in chronic hemodialysis patients: A national study. Am J Kid Dis 31: 607‐617, 1998.
 34.Block GA, Rosenbaum DP, Leonsson‐Zachrisson M, Astrand M, Johansson S, Knutsson M, Langkilde AM, Chertow GM. Effect of tenapanor on serum phosphate in patients receiving hemodialysis. J Am Soc Nephrol 28: 1933‐1942, 2017.
 35.Block GA, Wheeler DC, Persky MS, Kestenbaum B, Ketteler M, Spiegel DM, Allison MA, Asplin J, Smits G, Hoofnagle AN, Kooienga L, Thadhani R, Mannstadt M, Wolf M, Chertow GM. Effects of phosphate binders in moderate CKD. J Am Soc Nephrol 23: 1407‐1415, 2012.
 36.Block JP, Scribner RA, DeSalvo KB. Fast food, race/ethnicity, and income: A geographic analysis. Am J Prev Med 27: 211‐217, 2004.
 37.Borowitz SM, Granrud GS. Ontogeny of intestinal phosphate absorption in rabbits. Am J Physiol 262: G847‐G853, 1992.
 38.Bottger P, Hede SE, Grunnet M, Hoyer B, Klaerke DA, Pedersen L. Characterization of transport mechanisms and determinants critical for Na+‐dependent Pi symport of the PiT family paralogs human PiT1 and PiT2. Am J Physiol Cell Physiol 291: C1377‐C1387, 2006.
 39.Bottger P, Pedersen L. The central half of Pit2 is not required for its function as a retroviral receptor. J Virol 78: 9564‐9567, 2004.
 40.Bottger P, Pedersen L. Mapping of the minimal inorganic phosphate transporting unit of human PiT2 suggests a structure universal to PiT‐related proteins from all kingdoms of life. BMC biochemistry 12: 21, 2011.
 41.Bourgeois S, Capuano P, Stange G, Muhlemann R, Murer H, Biber J, Wagner CA. The phosphate transporter NaPi‐IIa determines the rapid renal adaptation to dietary phosphate intake in mouse irrespective of persistently high FGF23 levels. Pflugers Archiv 465: 1557‐1572, 2013.
 42.Brennan FE, Fuller PJ. Rapid upregulation of serum and glucocorticoid‐regulated kinase (sgk) gene expression by corticosteroids in vivo. Mol Cell Endocrinol 166: 129‐136, 2000.
 43.Brenza HL, Kimmel‐Jehan C, Jehan F, Shinki T, Wakino S, Anazawa H, Suda T, DeLuca HF. Parathyroid hormone activation of the 25‐hydroxyvitamin D‐3‐1 alpha‐hydroxylase gene promoter. Proc Natl Acad Sci U S A 95: 1387‐1391, 1998.
 44.Bricker NS, Morrin PA, Kime SW, Jr. The pathologic physiology of chronic Bright's disease. An exposition of the “intact nephron hypothesis.” Am J Med 28: 77‐98, 1960.
 45.Budoff MJ, Rader DJ, Reilly MP, Mohler ER, 3rd, Lash J, Yang W, Rosen L, Glenn M, Teal V, Feldman HI, Investigators CS. Relationship of estimated GFR and coronary artery calcification in the CRIC (Chronic Renal Insufficiency Cohort) Study. Am J Kid Dis 58: 519‐526, 2011.
 46.Busch A, Waldegger S, Herzer T, Biber J, Markovich D, Hayes G, Murer H, Lang F. Electrophysiological analysis of Na+/P‐I cotransport mediated by a transporter cloned from rat‐kidney and expressed in Xenopus‐Oocytes. Proc Natl Acad Sci U S A 91: 8205‐8208, 1994.
 47.Buss F, Kendrick‐Jones J. Multifunctional myosin VI has a multitude of cargoes. Proc Natl Acad Sci U S A 108: 5927‐5928, 2011.
 48.Candeal E, Caldas YA, Guillen N, Levi M, Sorribas V. Intestinal phosphate absorption is mediated by multiple transport systems in rats. Am J Physiol Gastrointest Liver Physiol 312: G355‐G366, 2017.
 49.Candeal E, Caldas YA, Guillen N, Levi M, Sorribas V. Na+‐independent phosphate transport in Caco2BBE cells. Am J Physiol Cell Physiol 307: C1113‐C1122, 2014.
 50.Cannata‐Andia JB, Martin KJ. The challenge of controlling phosphorus in chronic kidney disease. Nephrol Dial Transplant 31: 541‐547, 2016.
 51.Capuano P, Radanovic T, Wagner CA, Bacic D, Kato S, Uchiyama Y, St‐Arnoud R, Murer H, Biber J. Intestinal and renal adaptation to a low‐Pi diet of type II NaPi cotransporters in vitamin D receptor‐ and 1alphaOHase‐deficient mice. Am J Physiol Cell Physiol 288: C429‐C434, 2005.
 52.Carney EF. Dialysis: Efficacy of tenapanor in hyperphosphataemia. Nature Rev Nephrol 13: 194, 2017.
 53.Carrigan A, Klinger A, Choquette SS, Luzuriaga‐McPherson A, Bell EK, Darnell B, Gutierrez OM. Contribution of food additives to sodium and phosphorus content of diets rich in processed foods. J Ren Nutr 24: 13‐19, 19e11, 2014.
 54.Chen TH, Kuro‐o M, Chen CH, Sue YM, Chen YC, Wu HH, Cheng CY. The secreted Klotho protein restores phosphate retention and suppresses accelerated aging in Klotho mutant mice. Eur J Pharmacol 698: 67‐73, 2013.
 55.Cheng JB, Motola DL, Mangelsdorf DJ, Russell DW. De‐orphanization of cytochrome P450 2R1: a microsomal vitamin D 25‐hydroxilase. J Biol Chem 278: 38084‐38093, 2003.
 56.Clinkenbeard EL, Cass TA, Ni P, Hum JM, Bellido T, Allen MR, White KE. Conditional deletion of murine Fgf23: Interruption of the normal skeletal responses to phosphate challenge and rescue of genetic hypophosphatemia. J Bone Miner Res 31: 1247‐1257, 2016.
 57.Cording J, Berg J, Kading N, Bellmann C, Tscheik C, Westphal JK, Milatz S, Gunzel D, Wolburg H, Piontek J, Huber O, Blasig IE. In tight junctions, claudins regulate the interactions between occludin, tricellulin and marvelD3, which, inversely, modulate claudin oligomerization. J Cell Sci 126: 554‐564, 2013.
 58.Corut A, Senyigit A, Ugur SA, Altin S, Ozcelik U, Calisir H, Yildirim Z, Gocmen A, Tolun A. Mutations in SLC34A2 cause pulmonary alveolar microlithiasis and are possibly associated with testicular microlithiasis. Am J Hum Genet 79: 650‐656, 2006.
 59.Crawley SW, Mooseker MS, Tyska MJ. Shaping the intestinal brush border. J Cell Biol 207: 441‐451, 2014.
 60.Cunningham R, Biswas R, Brazie M, Steplock D, Shenolikar S, Weinman EJ. Signaling pathways utilized by PTH and dopamine to inhibit phosphate transport in mouse renal proximal tubule cells. Am J Physiol Renal Physiol 296: F355‐F361, 2009.
 61.D'Haese PC, Spasovski GB, Sikole A, Hutchison A, Freemont TJ, Sulkova S, Swanepoel C, Pejanovic S, Djukanovic L, Balducci A, Coen G, Sulowicz W, Ferreira A, Torres A, Curic S, Popovic M, Dimkovic N, De Broe ME. A multicenter study on the effects of lanthanum carbonate (Fosrenol) and calcium carbonate on renal bone disease in dialysis patients. Kidney Int Supp: S73‐78, 2003.
 62.Danisi G, Bonjour JP, Straub RW. Regulation of Na‐dependent phosphate influx across the mucosal border of duodenum by 1,25‐dihydroxycholecalciferol. Pflugers Archiv 388: 227‐232, 1980.
 63.Danisi G, Murer H, Straub RW. Effect of pH on phosphate transport into intestinal brush‐border membrane vesicles. Am J Physiol 246: G180‐G186, 1984.
 64.Danisi G, Straub RW. Unidirectional influx of phosphate across the mucosal membrane of rabbit small intestine. Pflugers Archiv 385: 117‐122, 1980.
 65.Davis GR, Zerwekh JE, Parker TF, Krejs GJ, Pak CY, Fordtran JS. Absorption of phosphate in the jejunum of patients with chronic renal failure before and after correction of vitamin D deficiency. Gastroenterology 85: 908‐916, 1983.
 66.de Boer IH, Rue TC, Kestenbaum B. Serum phosphorus concentrations in the third National Health and Nutrition Examination Survey (NHANES III). Am J Kid Dis 53: 399‐407, 2009.
 67.Delacour D, Salomon J, Robine S, Louvard D. Plasticity of the brush border—the yin and yang of intestinal homeostasis. Nat Rev Gastro Hepat 13: 161‐174, 2016.
 68.Deliot N, Hernando N, Horst‐Liu Z, Gisler SM, Capuano P, Wagner CA, Bacic D, O'Brien S, Biber J, Murer H. Parathyroid hormone treatment induces dissociation of type IIa Na+‐P(i) cotransporter‐Na+/H+ exchanger regulatory factor‐1 complexes. Am J Physiol Cell Physiol 289: C159‐C167, 2005.
 69.Demay MB, Kiernan MS, DeLuca HF, Kronenberg HM. Sequences in the human parathyroid hormone gene that bind the 1,25‐dihydroxyvitamin D3 receptor and mediate transcriptional repression in response to 1,25‐dihydroxyvitamin D3. Proc Natl Acad Sci U S A 89: 8097‐8101, 1992.
 70.Dhayat NA, Ackermann D, Pruijm M, Ponte B, Ehret G, Guessous I, Leichtle AB, Paccaud F, Mohaupt M, Fiedler GM, Devuyst O, Pechere‐Bertschi A, Burnier M, Martin PY, Bochud M, Vogt B, Fuster DG. Fibroblast growth factor 23 and markers of mineral metabolism in individuals with preserved renal function. Kidney Int 90: 648‐657, 2016.
 71.Dhingra R, Sullivan LM, Fox CS, Wang TJ, D'Agostino RB, Sr., Gaziano JM, Vasan RS. Relations of serum phosphorus and calcium levels to the incidence of cardiovascular disease in the community. Arch Int Med 167: 879‐885, 2007.
 72.Eckberg K, Kramer H, Wolf M, Durazo‐Arvizu R, Tayo B, Luke A, Cooper R. Impact of westernization on fibroblast growth factor 23 levels among individuals of African ancestry. Nephrol Dial Transpl 30: 630‐635, 2015.
 73.Ehnes C, Forster IC, Kohler K, Bacconi A, Stange G, Biber J, Murer H. Structure‐function relations of the first and fourth predicted extracellular linkers of the type IIa Na+/Pi cotransporter: I. Cysteine scanning mutagenesis. J Gen Physiol 124: 475‐488, 2004.
 74.El Marjou F, Janssen KP, Chang BHJ, Li M, Hindie V, Chan L, Louvard D, Chambon P, Metzger D, Robine S. Tissue‐specific and inducible Cre‐mediated recombination in the gut epithelium. Genesis 39: 186‐193, 2004.
 75.Elder GJ, Center J. The role of calcium and non calcium‐based phosphate binders in chronic kidney disease. Nephrology 22(Suppl 2): 42‐46, 2017.
 76.Eto N, Miyata Y, Ohno H, Yamashita T. Nicotinamide prevents the development of hyperphosphataemia by suppressing intestinal sodium‐dependent phosphate transporter in rats with adenine‐induced renal failure. Nephrol Dial Transpl 20: 1378‐1384, 2005.
 77.Farrell KB, Tusnady GE, Eiden MV. New structural arrangement of the extracellular regions of the phosphate transporter SLC20A1, the receptor for Gibbon Ape leukemia virus. J Biol Chem 284: 29979‐29987, 2009.
 78.Farrow EG, Davis SI, Summers LJ, White KE. Initial FGF23‐mediated signaling occurs in the distal convoluted tubule. J Am Soc Nephrol 20: 955‐960, 2009.
 79.Fass R, Do S, Hixson LJ. Fatal hyperphosphatemia following Fleet Phospo‐Soda in a patient with colonic ileus. Am J Gastro 88: 929‐932, 1993.
 80.Fenollar‐Ferrer C, Patti M, Knopfel T, Werner A, Forster IC, Forrest LR. Structural fold and binding sites of the human Na(+)‐phosphate cotransporter NaPi‐II. Biophys J 106: 1268‐1279, 2014.
 81.Fine A, Patterson J. Severe hyperphosphatemia following phosphate administration for bowel preparation in patients with renal failure: Two cases and a review of the literature. Am J Kid Dis 29: 103‐105, 1997.
 82.Floege J. Phosphate binders in chronic kidney disease: A systematic review of recent data. J Nephrol 29: 329‐340, 2016.
 83.Foley RN, Collins AJ, Herzog CA, Ishani A, Kalra PA. Serum phosphorus levels associate with coronary atherosclerosis in young adults. J Am Soc Nephrol 20: 397‐404, 2009.
 84.Forster IC, Hernando N, Biber J, Murer H. Phosphate transporters of the SLC20 and SLC34 families. Mol Aspects Med 34: 386‐395, 2013.
 85.Forster IC, Loo DD, Eskandari S. Stoichiometry and Na+ binding cooperativity of rat and flounder renal type II Na+‐Pi cotransporters. Am J Physiol 276: F644‐F649, 1999.
 86.Forster IC, Virkki L, Bossi E, Murer H, Biber J. Electrogenic kinetics of a mammalian intestinal type IIb Na(+)/P(i) cotransporter. J Membr Biol 212: 177‐190, 2006.
 87.France MM, Turner JR. The mucosal barrier at a glance. J Cell Sci 130: 307‐314, 2017.
 88.Fujita H, Chiba H, Yokozaki H, Sakai N, Sugimoto K, Wada T, Kojima T, Yamashita T, Sawada N. Differential expression and subcellular localization of claudin‐7,‐8,‐12,‐13, and‐15 along the mouse intestine. J Histochem Cytochem 54: 933‐944, 2006.
 89.Fukuda N, Tanaka H, Tominaga Y, Fukagawa M, Kurokawa K, Seino Y. Decreased 1,25‐dihydroxyvitamin‐D(3) receptor density is associated with a more severe form of parathyroid hyperplasia in chronic uremic patients. J Clin Invest 92: 1436‐1443, 1993.
 90.Furuse M, Fujita K, Hiiragi T, Fujimoto K, Tsukita S. Claudin‐1 and ‐2: Novel integral membrane proteins localizing at tight junctions with no sequence similarity to occludin. J Cell Biol 141: 1539‐1550, 1998.
 91.Furuse M, Hirase T, Itoh M, Nagafuchi A, Yonemura S, Tsukita S, Tsukita S. Occludin—a novel integral membrane‐protein localizing at tight junctions. J Cell Biol 123: 1777‐1788, 1993.
 92.Galitzer H, Ben‐Dov IZ, Silver J, Naveh‐Many T. Parathyroid cell resistance to fibroblast growth factor 23 in secondary hyperparathyroidism of chronic kidney disease. Kidney Int 77: 211‐218, 2010.
 93.Gattineni J, Alphonse P, Zhang Q, Mathews N, Bates CM, Baum M. Regulation of renal phosphate transport by FGF23 is mediated by FGFR1 and FGFR4. Am J Physiol Renal Physiol 306: F351‐F358, 2014.
 94.Gattineni J, Bates C, Twombley K, Dwarakanath V, Robinson ML, Goetz R, Mohammadi M, Baum M. 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: F282‐F291, 2009.
 95.Ghezzi C, Meinild AK, Murer H, Forster IC. Voltage‐ and substrate‐dependent interactions between sites in putative re‐entrant domains of a Na(+)‐coupled phosphate cotransporter. Pflugers Archiv 461: 645‐663, 2011.
 96.Ghezzi C, Murer H, Forster IC. Substrate interactions of the electroneutral Na+‐coupled inorganic phosphate cotransporter (NaPi‐IIc). J Physiol 587: 4293‐4307, 2009.
 97.Giral H, Caldas Y, Sutherland E, Wilson P, Breusegem S, Barry N, Blaine J, Jiang T, Wang XX, Levi M. Regulation of rat intestinal Na‐dependent phosphate transporters by dietary phosphate. Am J Physiol Renal Physiol 297: F1466‐F1475, 2009.
 98.Giral H, Cranston D, Lanzano L, Caldas Y, Sutherland E, Rachelson J, Dobrinskikh E, Weinman EJ, Doctor RB, Gratton E, Levi M. NHE3 regulatory factor 1 (NHERF1) modulates intestinal sodium‐dependent phosphate transporter (NaPi‐2b) expression in apical microvilli. J Biol Chem 287: 35047‐35056, 2012.
 99.Gisler SM, Stagljar I, Traebert M, Bacic D, Biber J, Murer H. Interaction of the type IIa Na/Pi cotransporter with PDZ proteins. J Biol Chem 276: 9206‐9213, 2001.
 100.Gong Y, Renigunta V, Himmerkus N, Zhang J, Renigunta A, Bleich M, Hou J. Claudin‐14 regulates renal Ca(+)(+) transport in response to CaSR signalling via a novel microRNA pathway. EMBO J 31: 1999‐2012, 2012.
 101.Goodman WG, Goldin J, Kuizon BD, Yoon C, Gales B, Sider D, Wang Y, Chung J, Emerick A, Greaser L, Elashoff RM, Salusky IB. Coronary‐artery calcification in young adults with end‐stage renal disease who are undergoing dialysis. New Engl J Med 342: 1478‐1483, 2000.
 102.Gray RW, Napoli JL. Dietary phosphate deprivation increases 1,25‐dihydroxyvitamin‐D3 synthesis in rat‐kidney in vitro. J Biol Chem 258: 1152‐1155, 1983.
 103.Guerreiro PM, Bataille AM, Parker SL, Renfro JL. Active removal of inorganic phosphate from cerebrospinal fluid by the choroid plexus. Am J Physiol Renal Physiol 306: F1275‐F1284, 2014.
 104.Gunzel D. Claudins: vital partners in transcellular and paracellular transport coupling. Pflugers Archiv 469: 35‐44, 2017.
 105.Gunzel D, Stuiver M, Kausalya PJ, Haisch L, Krug SM, Rosenthal R, Meij IC, Hunziker W, Fromm M, Muller D. Claudin‐10 exists in six alternatively spliced isoforms that exhibit distinct localization and function. J Cell Sci 122: 1507‐1517, 2009.
 106.Gutierrez OM, Anderson C, Isakova T, Scialla J, Negrea L, Anderson AH, Bellovich K, Chen J, Robinson N, Ojo A, Lash J, Feldman HI, Wolf M, Group CS. Low socioeconomic status associates with higher serum phosphate irrespective of race. J Am Soc Nephrol 21: 1953‐1960, 2010.
 107.Gutierrez OM, Isakova T, Enfield G, Wolf M. Impact of poverty on serum phosphate concentrations in the Third National Health and Nutrition Examination Survey. J Ren Nutr 21: 140‐148, 2011.
 108.Han X, Yang J, Li L, Huang J, King G, Quarles LD. Conditional deletion of Fgfr1 in the proximal and distal tubule identifies distinct roles in phosphate and calcium transport. PLoS One 11: e0147845, 2016.
 109.Harrison HE, Harrison HC. Intestinal transport of phosphate: Action of vitamin D, calcium, and potassium. Am J Physiol 201: 1007‐1012, 1961.
 110.Hatano R, Fujii E, Segawa H, Mukaisho K, Matsubara M, Miyamoto K, Hattori T, Sugihara H, Asano S. Ezrin, a membrane cytoskeletal cross‐linker, is essential for the regulation of phosphate and calcium homeostasis. Kidney Int 83: 41‐49, 2013.
 111.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: G756‐G762, 1999.
 112.Haussler MR. Vitamin D receptors: Nature and function. Annu Rev Nutr 6: 527‐562, 1986.
 113.Haut LL, Alfrey AC, Guggenheim S, Buddington B, Schrier N. Renal toxicity of phosphate in rats. Kidney Int 17: 722‐731, 1980.
 114.Hayes G, Busch A, Lotscher M, Waldegger S, Lang F, Verrey F, Biber J, Murer H. Role of N‐linked glycosylation in rat renal Na/Pi‐cotransport. J Biol Chem 269: 24143‐24149, 1994.
 115.Hegan PS, Giral H, Levi M, Mooseker MS. Myosin VI is required for maintenance of brush border structure, composition, and membrane trafficking functions in the intestinal epithelial cell. Cytoskeleton 69: 235‐251, 2012.
 116.Helander HF, Fandriks L. Surface area of the digestive tract—revisited. Scand J Gastro 49: 681‐689, 2014.
 117.Henning SJ. Plasma concentrations of total and free corticosterone during development in the rat. Am J Physiol 235: E451‐F456, 1978.
 118.Henry HL. The 25(OH)D(3)/1alpha,25(OH)(2)D(3)‐24R‐hydroxylase: A catabolic or biosynthetic enzyme? Steroids 66: 391‐398, 2001.
 119.Hernando N, Deliot N, Gisler SM, Lederer E, Weinman EJ, Biber J, Murer H. PDZ‐domain interactions and apical expression of type IIa Na/P(i) cotransporters. Proc Natl Acad Sci U S A 99: 11957‐11962, 2002.
 120.Hernando N, Myakala K, Simona F, Knopfel T, Thomas L, Murer H, Wagner CA, Biber J. Intestinal depletion of NaPi‐IIb/Slc34a2 in mice: Renal and hormonal adaptation. J Bone Miner Res 30: 1925‐1937, 2015.
 121.Hildmann B, Storelli C, Danisi G, Murer H. Regulation of Na+‐Pi cotransport by 1,25‐dihydroxyvitamin D3 in rabbit duodenal brush‐border membrane. Am J Physiol 242: G533‐G539, 1982.
 122.Hilfiker H, Hattenhauer O, Traebert M, Forster I, Murer H, Biber J. Characterization of a murine type II sodium‐phosphate cotransporter expressed in mammalian small intestine. Proc Natl Acad Sci U S A 95: 14564‐14569, 1998.
 123.Holmes JL, Van Itallie CM, Rasmussen JE, Anderson JM. Claudin profiling in the mouse during postnatal intestinal development and along the gastrointestinal tract reveals complex expression patterns. Gene Expr Patterns 6: 581‐588, 2006.
 124.Honegger KJ, Capuano P, Winter C, Bacic D, Stange G, Wagner CA, Biber J, Murer H, Hernando N. Regulation of sodium‐proton exchanger isoform 3 (NHE3) by PKA and exchange protein directly activated by cAMP (EPAC). Proc Natl Acad Sci U S A 103: 803‐808, 2006.
 125.Hori M, Kinoshita Y, Taguchi M, Fukumoto S. Phosphate enhances Fgf23 expression through reactive oxygen species in UMR‐106 cells. J Bone Miner Metab 34: 132‐139, 2016.
 126.Hou JH, Renigunta A, Yang J, Waldegger S. Claudin‐4 forms paracellular chloride channel in the kidney and requires claudin‐8 for tight junction localization. Proc Natl Acad Sci U S A 107: 18010‐18015, 2010.
 127.Hsieh YJ, Wanner BL. Global regulation by the seven‐component Pi signaling system. Curr Opin Microbiol 13: 198‐203, 2010.
 128.Hu MC, Shi M, Gillings N, Flores B, Takahashi M, Kuro OM, Moe OW. Recombinant alpha‐Klotho may be prophylactic and therapeutic for acute to chronic kidney disease progression and uremic cardiomyopathy. Kidney Intl 91: 1104‐1114, 2017.
 129.Hu MC, Shi M, Zhang J, Pastor J, Nakatani T, Lanske B, Razzaque MS, Rosenblatt KP, Baum MG, Kuro‐o M, Moe OW. Klotho: A novel phosphaturic substance acting as an autocrine enzyme in the renal proximal tubule. FASEB J 24: 3438‐3450, 2010.
 130.Hu MC, Shi MJ, Zhang JN, Quinones H, Kuro‐o M, Moe OW. Klotho deficiency is an early biomarker of renal ischemia‐reperfusion injury and its replacement is protective. Kidney Int 78: 1240‐1251, 2010.
 131.Hu MC, Shiizaki K, Kuro‐o M, Moe OW. Fibroblast growth factor 23 and Klotho: Physiology and pathophysiology of an endocrine network of mineral metabolism. Annu Rev Physiol 75: 503‐533, 2013.
 132.Hu MS, Kayne LH, Jamgotchian N, Ward HJ, Lee DB. Paracellular phosphate absorption in rat colon: A mechanism for enema‐induced hyperphosphatemia. Miner Electrolyte Metab 23: 7‐12, 1997.
 133.Hughes MR, Brumbaugh PF, Haussler MR, Wergedal JE, Baylink DJ. Regulation of serum 1‐alpha,25‐dihydroxyvitamin‐D3 by calcium and phosphate in rat. Science 190: 578‐580, 1975.
 134.Ichikawa S, Guigonis V, Imel EA, Courouble M, Heissat S, Henley JD, Sorenson AH, Petit B, Lienhardt A, Econs MJ. Novel GALNT3 mutations causing hyperostosis‐hyperphosphatemia syndrome result in low intact fibroblast growth factor 23 concentrations. J Clin Endocrinol Metab 92: 1943‐1947, 2007.
 135.Imura A, Iwano A, Tohyama O, Tsuji Y, Nozaki K, Hashimoto N, Fujimori T, Nabeshima Y. Secreted Klotho protein in sera and CSF: Implication for post‐translational cleavage in release of Klotho protein from cell membrane. FEBS Lett 565: 143‐147, 2004.
 136.Inden M, Iriyama M, Zennami M, Sekine S, Hara A, Yamada M, Hozumi I. The type III transporters (PiT‐1 and PiT‐2) are the major sodium‐dependent phosphate transporters in the mice and human brains. Brain Res 1637: 128‐136, 2016.
 137.Iqbal TH, Lewis KO, Cooper BT. Phytase activity in the human and rat small intestine. Gut 35: 1233‐1236, 1994.
 138.Isakova T, Wahl P, Vargas GS, Gutierrez OM, Scialla J, Xie HL, Appleby D, Nessel L, Bellovich K, Chen J, Hamm L, Gadegbeku C, Horwitz E, Townsend RR, Anderson CAM, Lash JP, Hsu CY, Leonard MB, Wolf M, Grp CS. Fibroblast growth factor 23 is elevated before parathyroid hormone and phosphate in chronic kidney disease. Kidney Int 79: 1370‐1378, 2011.
 139.Ishimura E, Okuno S, Yamakawa T, Inaba M, Nishizawa Y. Serum magnesium concentration is a significant predictor of mortality in maintenance hemodialysis patients. Magnesium Res 20: 237‐244, 2007.
 140.Ito N, Findlay DM, Anderson PH, Bonewald LF, Atkins GJ. Extracellular phosphate modulates the effect of 1alpha,25‐dihydroxy vitamin D3 (1,25D) on osteocyte like cells. J Steroid Biochem Mol Biol 136: 183‐186, 2013.
 141.Jamal SA, Vandermeer B, Raggi P, Mendelssohn DC, Chatterley T, Dorgan M, Lok CE, Fitchett D, Tsuyuki RT. Effect of calcium‐based versus non‐calcium‐based phosphate binders on mortality in patients with chronic kidney disease: An updated systematic review and meta‐analysis. Lancet 382: 1268‐1277, 2013.
 142.Jensen N, Autzen JK, Pedersen L. Slc20a2 is critical for maintaining a physiologic inorganic phosphate level in cerebrospinal fluid. Neurogenetics 17: 125‐130, 2016.
 143.Jensen N, Schroder HD, Hejbol EK, Fuchtbauer EM, de Oliveira JR, Pedersen L. Loss of function of Slc20a2 associated with familial idiopathic Basal Ganglia calcification in humans causes brain calcifications in mice. J Mol Neurosci 51: 994‐999, 2013.
 144.Jin C, Zoidis E, Ghirlanda C, Schmid C. Dexamethasone and cyclic AMP regulate sodium phosphate cotransporter (NaPi‐IIb and Pit‐1) mRNA and phosphate uptake in rat alveolar type II epithelial cells. Lung 188: 51‐61, 2010.
 145.Juan D, Liptak P, Gray TK. Absorption of inorganic phosphate in the human jejunum and its inhibition by salmon calcitonin. J Clin Endocrinol Metab 43: 517‐522, 1976.
 146.Kaffman A, Herskowitz I, Tjian R, O'Shea EK. Phosphorylation of the transcription factor PHO4 by a cyclin‐CDK complex, PHO80‐PHO85. Science 263: 1153‐1156, 1994.
 147.Karim‐Jimenez Z, Hernando N, Biber J, Murer H. A dibasic motif involved in parathyroid hormone‐induced down‐regulation of the type IIa NaPi cotransporter. Proc Natl Acad Sci U S A 97: 12896‐12901, 2000.
 148.Katai K, Miyamoto K, Kishida S, Segawa H, Nii T, Tanaka H, Tani Y, Arai H, Tatsumi S, Morita K, Taketani Y, Takeda E. Regulation of intestinal Na+‐dependent phosphate co‐transporters by a low‐phosphate diet and 1,25‐dihydroxyvitamin D3. Biochem J 343(Pt 3): 705‐712, 1999.
 149.Katai K, Tanaka H, Tatsumi S, Fukunaga Y, Genjida K, Morita K, Kuboyama N, Suzuki T, Akiba T, Miyamoto K, Takeda E. Nicotinamide inhibits sodium‐dependent phosphate cotransport activity in rat small intestine. Nephrol DIal Transpl 14: 1195‐1201, 1999.
 150.Kavanaugh MP, Miller DG, Zhang W, Law W, Kozak SL, Kabat D, Miller AD. Cell‐surface receptors for gibbon ape leukemia virus and amphotropic murine retrovirus are inducible sodium‐dependent phosphate symporters. Proc Natl Acad Sci 91: 7071‐7075, 1994.
 151.Kayne LH, Dargenio DZ, Meyer JH, Hu MS, Jamgotchian N, Lee DBN. Analysis of segmental phosphate absorption in intact rats—a compartmental analysis approach. J Clin Invest 91: 915‐922, 1993.
 152.Kestenbaum B, Sampson JN, Rudser KD, Patterson DJ, Seliger SL, Young B, Sherrard DJ, Andress DL. Serum phosphate levels and mortality risk among people with chronic kidney disease. J Am Soc Nephrol 16: 520‐528, 2005.
 153.Ketteler M, Liangos O, Biggar PH. Treating hyperphosphatemia—current and advancing drugs. Expert Opin Pharmacother 17: 1873‐1879, 2016.
 154.Keusch I, Traebert M, Lotscher M, Kaissling B, Murer H, Biber J. Parathyroid hormone and dietary phosphate provoke a lysosomal routing of the proximal tubular Na/Pi‐cotransporter type II. Kidney Int 54: 1224‐1232, 1998.
 155.Khundmiri SJ, Murray RD, Lederer E. PTH and vitamin D. Compr Physiol 6: 561‐601, 2016.
 156.Kidney Disease: Improving Global Outcomes (KDIGO) CKD‐MBD Work Group. KDIGO clinical practice guideline for the diagnosis, evaluation, prevention, and treatment of Chronic Kidney Disease‐Mineral and Bone Disorder (CKD‐MBD). Kidney Int Suppl: S1‐S130, 2009.
 157.Kim HR, Nam BY, Kim DW, Kang MW, Han JH, Lee MJ, Shin DH, Doh FM, Koo HM, Ko KI, Kim CH, Oh HJ, Yoo TH, Kang SW, Han DS, Han SH. Circulating alpha‐klotho levels in CKD and relationship to progression. Am J Kid Dis 61: 899‐909, 2013.
 158.Knopfel T, Pastor‐Arroyo EM, Schnitzbauer U, Kratschmar DV, Odermatt A, Pellegrini G, Hernando N, Wagner CA. The intestinal phosphate transporter NaPi‐IIb (Slc34a2) is required to protect bone during dietary phosphate restriction. Sci Rep 7: 11018, 2017.
 159.Kohler K, Forster IC, Stange G, Biber J, Murer H. Essential cysteine residues of the type IIa Na+/Pi cotransporter. Pflugers Archiv 446: 203‐210, 2003.
 160.Kohler K, Forster IC, Stange G, Biber J, Murer H. Identification of functionally important sites in the first intracellular loop of the NaPi‐IIa cotransporter. Am J Physiol Renal Physiol 282: F687‐F696, 2002.
 161.Kohler K, Forster IC, Stange G, Biber J, Murer H. Transport function of the renal type IIa Na+/P(i) cotransporter is codetermined by residues in two opposing linker regions. J Gen Physiol 120: 693‐705, 2002.
 162.Koiwa F, Kazama JJ, Tokumoto A, Onoda N, Kato H, Okada T, Nii‐Kono T, Fukagawa M, Shigematsu T, Group RODCR. Sevelamer hydrochloride and calcium bicarbonate reduce serum fibroblast growth factor 23 levels in dialysis patients. Ther Apher Dial 9: 336‐339, 2005.
 163.Kojima T, Ninomiya T, Konno T, Kohno T, Taniguchi M, Sawada N. Expression of tricellulin in epithelial cells and non‐epithelial cells. Histol Histopathol 28: 1383‐1392, 2013.
 164.Kolek OI, Hines ER, Jones MD, LeSueur LK, Lipko MA, Kiela PR, Collins JF, Haussler MR, Ghishan FK. 1alpha,25‐Dihydroxyvitamin D3 upregulates FGF23 gene expression in bone: the final link in a renal‐gastrointestinal‐skeletal axis that controls phosphate transport. Am J Physiol Gastrointest Liver Physiol 289: G1036‐G1042, 2005.
 165.Krajisnik T, Bjorklund P, Marsell R, Ljunggren O, Akerstrom G, Jonsson KB, Westin G, Larsson TE. Fibroblast growth factor‐23 regulates parathyroid hormone and 1alpha‐hydroxylase expression in cultured bovine parathyroid cells. J Endocrinol 195: 125‐131, 2007.
 166.Krajisnik T, Olauson H, Mirza MA, Hellman P, Akerstrom G, Westin G, Larsson TE, Bjorklund P. Parathyroid Klotho and FGF‐receptor 1 expression decline with renal function in hyperparathyroid patients with chronic kidney disease and kidney transplant recipients. Kidney Int 78: 1024‐1032, 2010.
 167.Krug SM, Gunzel D, Conrad MP, Rosenthal R, Fromm A, Amasheh S, Schulzke JD, Fromm M. Claudin‐17 forms tight junction channels with distinct anion selectivity. Cell Mol Life Sci 69: 2765‐2778, 2012.
 168.Kumar R, Thompson EB. The structure of the nuclear hormone receptors. Steroids 64: 310‐319, 1999.
 169.Kuro‐o M, Matsumura Y, Aizawa H, Kawaguchi H, Suga T, Utsugi T, Ohyama Y, Kurabayashi M, Kaname T, Kume E, Iwasaki H, Iida A, Shiraki‐Iida T, Nishikawa S, Nagai R, Nabeshima YI. Mutation of the mouse klotho gene leads to a syndrome resembling ageing. Nature 390: 45‐51, 1997.
 170.Kuro OM, Moe OW. FGF23‐alphaKlotho as a paradigm for a kidney‐bone network. Bone 100: 4‐18, 2016.
 171.Labonte ED, Carreras CW, Leadbetter MR, Kozuka K, Kohler J, Koo‐McCoy S, He LM, Dy E, Black D, Zhong ZY, Langsetmo I, Spencer AG, Bell N, Deshpande D, Navre M, Lewis JG, Jacobs JW, Charmot D. Gastrointestinal inhibition of sodium‐hydrogen exchanger 3 reduces phosphorus absorption and protects against vascular calcification in CKD. J Am Soc Nephrol 26: 1138‐1149, 2015.
 172.Lamarche MG, Wanner BL, Crepin S, Harel J. The phosphate regulon and bacterial virulence: A regulatory network connecting phosphate homeostasis and pathogenesis. FEMS Microbiol Rev 32: 461‐473, 2008.
 173.Lambert G, Forster IC, Biber J, Murer H. Cysteine residues and the structure of the rat renal proximal tubular type II sodium phosphate cotransporter (rat NaPi IIa). J Membr Biol 176: 133‐141, 2000.
 174.Lameris AL, Huybers S, Kaukinen K, Makela TH, Bindels RJ, Hoenderop JG, Nevalainen PI. Expression profiling of claudins in the human gastrointestinal tract in health and during inflammatory bowel disease. Scand J Gastro 48: 58‐69, 2013.
 175.Lau WL, Festing MH, Giachelli CM. Phosphate and vascular calcification: Emerging role of the sodium‐dependent phosphate co‐transporter PiT‐1. Thromb Haemost 104: 464‐470, 2010.
 176.Lee DB, Walling MW, Gafter U, Silis V, Coburn JW. Calcium and inorganic phosphate transport in rat colon: Dissociated response to 1,25‐dihydroxyvitamin D3. J Clin Invest 65: 1326‐1331, 1980.
 177.Lee GJ, Mossa‐Al Hashimi L, Debnam ES, Unwin RJ, Marks J. Postprandial adjustments in renal phosphate excretion do not involve a gut‐derived phosphaturic factor. Exp Physiol102: 462‐474, 2017.
 178.Lenglet A, Liabeuf S, El Esper N, Brisset S, Mansour J, Lemaire‐Hurtel AS, Mary A, Brazier M, Kamel S, Mentaverri R, Choukroun G, Fournier A, Massy ZA. Efficacy and safety of nicotinamide in haemodialysis patients: The NICOREN study. Nephrol Dial Transpl 32: 870‐879, 2016.
 179.Lenglet A, Liabeuf S, Guffroy P, Fournier A, Brazier M, Massy ZA. Use of nicotinamide to treat hyperphosphatemia in dialysis patients. Drugs in R&D 13: 165‐173, 2013.
 180.Leon JB, Sullivan CM, Sehgal AR. The prevalence of phosphorus‐containing food additives in top‐selling foods in grocery stores. J Ren Nutr 23: 265‐270 e262, 2013.
 181.Levey AS, Atkins R, Coresh J, Cohen EP, Collins AJ, Eckardt KU, Nahas ME, Jaber BL, Jadoul M, Levin A, Powe NR, Rossert J, Wheeler DC, Lameire N, Eknoyan G. Chronic kidney disease as a global public health problem: Approaches and initiatives—a position statement from Kidney Disease Improving Global Outcomes. Kidney Int 72: 247‐259, 2007.
 182.Lin HH, Liou HH, Wu MS, Lin CY, Huang CC. Long‐term sevelamer treatment lowers serum fibroblast growth factor 23 accompanied with increasing serum Klotho levels in chronic haemodialysis patients. Nephrol 19: 672‐678, 2014.
 183.Loh TP, Metz MP. Trends and physiology of common serum biochemistries in children aged 0‐18 years. Pathology 47: 452‐461, 2015.
 184.Maher ER, Young G, Smyth‐Walsh B, Pugh S, Curtis JR. Aortic and mitral valve calcification in patients with end‐stage renal disease. Lancet 2: 875‐877, 1987.
 185.Markiewicz LH, Honke J, Haros M, Swiatecka D, Wroblewska B. Diet shapes the ability of human intestinal microbiota to degrade phytate–‐in vitro studies. J Appl Microbiol 115: 247‐259, 2013.
 186.Markov AG, Veshnyakova A, Fromm M, Amasheh M, Amasheh S. Segmental expression of claudin proteins correlates with tight junction barrier properties in rat intestine. J Comp Physiol B 180: 591‐598, 2010.
 187.Marks J, Lee GJ, Nadaraja SP, Debnam ES, Unwin RJ. Experimental and regional variations in Na+‐dependent and Na+‐independent phosphate transport along the rat small intestine and colon. Physiol Rep 3: e12281, 2015.
 188.Marks J, Srai SK, Biber J, Murer H, Unwin RJ, Debnam ES. Intestinal phosphate absorption and the effect of vitamin D: A comparison of rats with mice. Exp Physiol 91: 531‐537, 2006.
 189.Martin RR, Lisehora GR, Braxton M, Jr., Barcia PJ. Fatal poisoning from sodium phosphate enema. Case report and experimental study. JAMA 257: 2190‐2192, 1987.
 190.Masuyama R, Stockmans I, Torrekens S, Van Looveren R, Maes C, Carmeliet P, Bouillon R, Carmeliet G. Vitamin D receptor in chondrocytes promotes osteoclastogenesis and regulates FGF23 production in osteoblasts. J Clin Invest 116: 3150‐3159, 2006.
 191.Matsumura Y, Aizawa H, Shiraki‐Iida T, Nagai R, Kuro‐o M, Nabeshima Y. Identification of the human klotho gene and its two transcripts encoding membrane and secreted klotho protein. Biochem Biophys Res Commun 242: 626‐630, 1998.
 192.McHardy GJ, Parsons DS. The absorption of water and salt from the small intestine of the rat. Q J Exp Physiol Cogn Med Sci 42: 33‐48, 1957.
 193.McHaffie GS, Graham C, Kohl B, Strunck‐Warnecke U, Werner A. The role of an intracellular cysteine stretch in the sorting of the type II Na/phosphate cotransporter. Biochim Biophys Acta 1768: 2099‐2106, 2007.
 194.McPherson K, Healy MJ, Flynn FV, Piper KA, Garcia‐Webb P. The effect of age, sex and other factors on blood chemistry in health. Clin Chim Acta 84: 373‐397, 1978.
 195.Meir T, Durlacher K, Pan Z, Amir G, Richards WG, Silver J, Naveh‐Many T. Parathyroid hormone activates the orphan nuclear receptor Nurr1 to induce FGF23 transcription. Kidney Int 86: 1106‐1115, 2014.
 196.Miller DG, Edwards RH, Miller AD. Cloning of the cellular receptor for amphotropic murine retroviruses reveals homology to that for gibbon ape leukemia virus. Proc Natl Acad Sci USA 91: 78‐82, 1994.
 197.Miyamoto K, Ito M, Kuwahata M, Kato S, Segawa H. Inhibition of intestinal sodium‐dependent inorganic phosphate transport by fibroblast growth factor 23. Ther Apher Dial 9: 331‐335, 2005.
 198.Mizuno M, Mitchell JH, Crawford S, Huang CL, Maalouf N, Hu MC, Moe OW, Smith SA, Vongpatanasin W. High dietary phosphate intake induces hypertension and augments exercise pressor reflex function in rats. Am J Physiol Regul Integr Comp Physiol 311: R39‐R48, 2016.
 199.Morishita K, Shirai A, Kubota M, Katakura Y, Nabeshima Y, Takeshige K, Kamiya T. The progression of aging in Klotho mutant mice can be modified by dietary phosphorus and zinc. J Nutr 131: 3182‐3188, 2001.
 200.Mouillon JM, Persson BL. New aspects on phosphate sensing and signalling in Saccharomyces cerevisiae. FEMS Yeast Res 6: 171‐176, 2006.
 201.Mulroney SE, Woda CB, Halaihel N, Louie B, McDonnell K, Schulkin J, Haramati A, Levi M. Central control of renal sodium‐phosphate (NaPi‐2) transporters. Am J Physiol Renal Physiol 286: F647‐F652, 2004.
 202.National Kidney F. K/DOQI clinical practice guidelines for chronic kidney disease: Evaluation, classification, and stratification. Am J Kid Dis 39: S1‐S266, 2002.
 203.Nishimura M, Naito S. Tissue‐specific mRNA expression profiles of human solute carrier transporter superfamilies. Drug Metab Pharmacokinet 23: 22‐44, 2008.
 204.O'Hara B, Johann SV, Klinger HP, Blair DG, Rubinson H, Dunn KJ, Sass P, Vitek SM, Robins T. Characterization of a human gene conferring sensitivity to infection by gibbon ape leukemia virus. Cell Growth Differ 1: 119‐127, 1990.
 205.Ohnishi M, Razzaque MS. Dietary and genetic evidence for phosphate toxicity accelerating mammalian aging. FASEB J 24: 3562‐3571, 2010.
 206.Olah Z, Lehel C, Anderson WB, Eiden MV, Wilson CA. The cellular receptor for Gibbon Ape leukemia virus is a novel high‐affinity sodium‐dependent phosphate transporter. J Biol Chem 269: 25426‐25431, 1994.
 207.Oliveira RB, Cancela AL, Graciolli FG, Dos Reis LM, Draibe SA, Cuppari L, Carvalho AB, Jorgetti V, Canziani ME, Moyses RM. Early control of PTH and FGF23 in normophosphatemic CKD patients: A new target in CKD‐MBD therapy? Clin J Am Soc Nephrol 5: 286‐291, 2010.
 208.Ori Y, Rozen‐Zvi B, Chagnac A, Herman M, Zingerman B, Atar E, Gafter U, Korzets A. Fatalities and severe metabolic disorders associated with the use of sodium phosphate enemas: A single center's experience. Arch Int Med 172: 263‐265, 2012.
 209.Palmada M, Dieter M, Speil A, Bohmer C, Mack AF, Wagner HJ, Klingel K, Kandolf R, Murer H, Biber J, Closs EI, Lang F. Regulation of intestinal phosphate cotransporter NaPi IIb by ubiquitin ligase Nedd4‐2 and by serum‐ and glucocorticoid‐dependent kinase 1. Am J Physiol Gastrointest Liver Physiol 287: G143‐G150, 2004.
 210.Palmer SC, Gardner S, Tonelli M, Mavridis D, Johnson DW, Craig JC, French R, Ruospo M, Strippoli GF. Phosphate‐binding agents in adults with CKD: A network meta‐analysis of randomized trials. Am J Kid Dis 68: 691‐702, 2016.
 211.Patel L, Bernard LM, Elder GJ. Sevelamer versus calcium‐based binders for treatment of hyperphosphatemia in CKD: A meta‐analysis of randomized controlled trials. Clin J Am Soc Nephrol 11: 232‐244, 2016.
 212.Patti M, Fenollar‐Ferrer C, Werner A, Forrest LR, Forster IC. Cation interactions and membrane potential induce conformational changes in NaPi‐IIb. Biophys J 111: 973‐988, 2016.
 213.Pavik I, Jaeger P, Ebner L, Wagner CA, Petzold K, Spichtig D, Poster D, Wuthrich RP, Russmann S, Serra AL. Secreted Klotho and FGF23 in chronic kidney disease Stage 1 to 5: A sequence suggested from a cross‐sectional study. Nephrol Dial Transpl 28: 352‐359, 2013.
 214.Perwad F, Azam N, Zhang MY, Yamashita T, Tenenhouse HS, Portale AA. Dietary and serum phosphorus regulate fibroblast growth factor 23 expression and 1,25‐dihydroxyvitamin D metabolism in mice. Endocrinology 146: 5358‐5364, 2005.
 215.Perwad F, Zhang MY, Tenenhouse HS, Portale AA. Fibroblast growth factor 23 impairs phosphorus and vitamin D metabolism in vivo and suppresses 25‐hydroxyvitamin D‐1alpha‐hydroxylase expression in vitro. Am J Physiol Renal Physiol 293: F1577‐F1583, 2007.
 216.Peter WLS, Wazny LD, Weinhandl E, Cardone KE, Hudson JQ. A review of phosphate binders in chronic kidney disease: Incremental progress or just higher costs? Drugs 77: 1155‐1186, 2017.
 217.Pfister MF, Forgo J, Ziegler U, Biber J, Murer H. cAMP‐dependent and ‐independent downregulation of type II Na‐Pi cotransporters by PTH. Am J Physiol 276: F720‐F725, 1999.
 218.Pfister MF, Hilfiker H, Forgo J, Lederer E, Biber J, Murer H. Cellular mechanisms involved in the acute adaptation of OK cell Na/Pi‐cotransport to high‐ or low‐Pi medium. Pflugers Archiv 435: 713‐719, 1998.
 219.Pfister MF, Ruf I, Stange G, Ziegler U, Lederer E, Biber J, Murer H. Parathyroid hormone leads to the lysosomal degradation of the renal type II Na/Pi cotransporter. Proc Natl Acad Sci U S A 95: 1909‐1914, 1998.
 220.Picard N, Capuano P, Stange G, Mihailova M, Kaissling B, Murer H, Biber J, Wagner CA. Acute parathyroid hormone differentially regulates renal brush border membrane phosphate cotransporters. Pflugers Archiv 460: 677‐687, 2010.
 221.Portale AA, Booth BE, Halloran BP, Morris RC. Effect of dietary phosphorus on circulating concentrations of 1,25‐dihydroxyvitamin‐D and immunoreactive parathyroid‐hormone in children with moderate renal‐insufficiency. J Clin Invest 73: 1580‐1589, 1984.
 222.Quamme G, Pfeilschifter J, Murer H. Parathyroid hormone inhibition of Na+/phosphate cotransport in OK cells: intracellular [Ca2+] as a second messenger. Biochim Biophys Acta 1013: 166‐172, 1989.
 223.Radanovic T, Murer H, Biber J. Expression of the Na/P(i)‐cotransporter type IIb in Sf9 cells: Functional characterization and purification. J Membr Biol 194: 91‐96, 2003.
 224.Radanovic T, Wagner CA, 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: G496‐G500, 2005.
 225.Raggi P, Boulay A, Chasan‐Taber S, Amin N, Dillon M, Burke SK, Chertow GM. Cardiac calcification in adult hemodialysis patients. A link between end‐stage renal disease and cardiovascular disease? J Am Coll Cardiol 39: 695‐701, 2002.
 226.Ravera S, Virkki LV, Murer H, Forster IC. Deciphering PiT transport kinetics and substrate specificity using electrophysiology and flux measurements. Am J Physiol Cell Physiol 293: C606‐C620, 2007.
 227.Reczek D, Berryman M, Bretscher A. Identification of EBP50: A PDZ‐containing phosphoprotein that associates with members of the ezrin‐radixin‐moesin family. J Cell Biol 139: 169‐179, 1997.
 228.Reining SC, Gisler SM, Fuster D, Moe OW, O'Sullivan GA, Betz H, Biber J, Murer H, Hernando N. GABARAP deficiency modulates expression of NaPi‐IIa in renal brush‐border membranes. Am J Physiol Renal Physiol 296: F1118‐F1128, 2009.
 229.Reining SC, Liesegang A, Betz H, Biber J, Murer H, Hernando N. Expression of renal and intestinal Na/Pi cotransporters in the absence of GABARAP. Pflugers Archiv 460: 207‐217, 2010.
 230.Rhee Y, Bivi N, Farrow E, Lezcano V, Plotkin LI, White KE, Bellido T. Parathyroid hormone receptor signaling in osteocytes increases the expression of fibroblast growth factor‐23 in vitro and in vivo. Bone 49: 636‐643, 2011.
 231.Ritter CS, Armbrecht HJ, Slatopolsky E, Brown AJ. 25‐Hydroxyvitamin D‐3 suppresses PTH synthesis and secretion by bovine parathyroid cells. Kidney Int 70: 654‐659, 2006.
 232.Ritter CS, Slatopolsky E. Phosphate toxicity in CKD: The killer among us. Clin J Am Soc Nephrol 11: 1088‐1100, 2016.
 233.Ritz E, Hahn K, Ketteler M, Kuhlmann MK, Mann J. Phosphate additives in food–‐a health risk. Dtsch Arztebl Int 109: 49‐55, 2012.
 234.Rodriguez‐Ortiz ME, Lopez I, Munoz‐Castaneda JR, Martinez‐Moreno JM, Ramirez AP, Pineda C, Canalejo A, Jaeger P, Aguilera‐Tejero E, Rodriguez M, Felsenfeld A, Almaden Y. Calcium deficiency reduces circulating levels of FGF23. J Am Soc Nephrol 23: 1190‐1197, 2012.
 235.Sabbagh Y, O'Brien SP, Song W, Boulanger JH, Stockmann A, Arbeeny C, Schiavi SC. Intestinal npt2b plays a major role in phosphate absorption and homeostasis. J Am Soc Nephrol 20: 2348‐2358, 2009.
 236.Saito A, Nikolaidis NM, Amlal H, Uehara Y, Gardner JC, LaSance K, Pitstick LB, Bridges JP, Wikenheiser‐Brokamp KA, McGraw DW, Woods JC, Sabbagh Y, Schiavi SC, Altinisik G, Jakopovic M, Inoue Y, McCormack FX. Modeling pulmonary alveolar microlithiasis by epithelial deletion of the Npt2b sodium phosphate cotransporter reveals putative biomarkers and strategies for treatment. Sci Transl Med 7: 313ra181, 2015.
 237.Saito H, Kusano K, Kinosaki M, Ito H, Hirata M, Segawa H, Miyamoto K, Fukushima N. Human fibroblast growth factor‐23 mutants suppress Na+‐dependent phosphate co‐transport activity and 1 alpha,25‐dihydroxyvitamin D‐3 production. J Biol Chem 278: 2206‐2211, 2003.
 238.Saito H, Maeda A, Ohtomo S, Hirata M, Kusano K, Kato S, Ogata E, Segawa H, Miyamoto K, Fukushima N. Circulating FGF‐23 is regulated by 1alpha,25‐dihydroxyvitamin D3 and phosphorus in vivo. J Biol Chem 280: 2543‐2549, 2005.
 239.Salaun C, Rodrigues P, Heard JM. Transmembrane topology of PiT‐2, a phosphate transporter‐retrovirus receptor. J Virol 75: 5584‐5592, 2001.
 240.Saotome I, Curto M, McClatchey AI. Ezrin is essential for epithelial organization and villus morphogenesis in the developing intestine. Dev Cell 6: 855‐864, 2004.
 241.Scanni R, vonRotz M, Jehle S, Hulter HN, Krapf R. The human response to acute enteral and parenteral phosphate loads. J Am Soc Nephrol 25: 2730‐2739, 2014.
 242.Schiavi SC, Tang W, Bracken C, O'Brien SP, Song W, Boulanger J, Ryan S, Phillips L, Liu S, Arbeeny C, Ledbetter S, Sabbagh Y. Npt2b deletion attenuates hyperphosphatemia associated with CKD. J Am Soc Nephrol 23: 1691‐1700, 2012.
 243.Schlemmer U, Frolich W, Prieto RM, Grases F. Phytate in foods and significance for humans: Food sources, intake, processing, bioavailability, protective role and analysis. Mol Nutr Food Res 53(Suppl 2): S330‐375, 2009.
 244.Segawa H, Kaneko I, Yamanaka S, Ito M, Kuwahata M, Inoue Y, Kato S, Miyamoto K. Intestinal Na‐P(i) cotransporter adaptation to dietary P(i) content in vitamin D receptor null mice. Am J Physiol Renal Physiol 287: F39‐F47, 2004.
 245.Segawa H, Kawakami E, Kaneko I, Kuwahata M, Ito M, Kusano K, Saito H, Fukushima N, Miyamoto K. Effect of hydrolysis‐resistant FGF23‐R179Q on dietary phosphate regulation of the renal type‐II Na/Pi transporter. Pflugers Archiv 446: 585‐592, 2003.
 246.Segawa H, Yamanaka S, Ito M, Kuwahata M, Shono M, Yamamoto T, Miyamoto K. Internalization of renal type IIc Na‐Pi cotransporter in response to a high‐phosphate diet. Am J Physiol Renal Physiol 288: F587‐F596, 2005.
 247.Segawa H, Yamanaka S, Onitsuka A, Tomoe Y, Kuwahata M, Ito M, Taketani Y, Miyamoto K. Parathyroid hormone‐dependent endocytosis of renal type IIc Na‐Pi cotransporter. Am J Physiol Renal Physiol 292: F395‐F403, 2007.
 248.Selamet U, Tighiouart H, Sarnak MJ, Beck G, Levey AS, Block G, Ix JH. Relationship of dietary phosphate intake with risk of end‐stage renal disease and mortality in chronic kidney disease stages 3‐5: The Modification of Diet in Renal Disease Study. Kidney Int 89: 176‐184, 2016.
 249.Shalhoub V, Shatzen EM, Ward SC, Davis J, Stevens J, Bi V, Renshaw L, Hawkins N, Wang W, Chen C, Tsai MM, Cattley RC, Wronski TJ, Xia XC, Li XD, Henley C, Eschenberg M, Richards WG. FGF23 neutralization improves chronic kidney disease‐associated hyperparathyroidism yet increases mortality. J Clin Invest 122: 2543‐2553, 2012.
 250.Shen L, Weber CR, Raleigh DR, Yu D, Turner JR. Tight junction pore and leak pathways: A dynamic duo. Annu Rev Physiol 73: 283‐309, 2011.
 251.Shenolikar S, Voltz JW, Cunningham R, Weinman EJ. Regulation of ion transport by the NHERF family of PDZ proteins. Physiology 19: 362‐369, 2004.
 252.Shenolikar S, Voltz JW, Minkoff CM, Wade JB, Weinman EJ. Targeted disruption of the mouse NHERF‐1 gene promotes internalization of proximal tubule sodium‐phosphate cotransporter type IIa and renal phosphate wasting. Proc Natl Acad Sci U S A 99: 11470‐11475, 2002.
 253.Sherman RA, Mehta O. Phosphorus and potassium content of enhanced meat and poultry products: Implications for patients who receive dialysis. Clin J Am Soc Nephrol 4: 1370‐1373, 2009.
 254.Shibasaki Y, Etoh N, Hayasaka M, Takahashi MO, Kakitani M, Yamashita T, Tomizuka K, Hanaoka K. Targeted deletion of the tybe IIb Na(+)‐dependent Pi‐co‐transporter, NaPi‐IIb, results in early embryonic lethality. Biochem Biophys Res Commun 381: 482‐486, 2009.
 255.Shigematsu T, Horiuchi N, Ogura Y, Miyahara T, Suda T. Human parathyroid‐hormone inhibits renal 24‐hydroxylase activity of 25‐hydroxyvitamin‐D3 by a mechanism involving adenosine‐3',5'‐monophosphate in rats. Endocrinology 118: 1583‐1589, 1986.
 256.Shigematsu T, Kono T, Satoh K, Yokoyama K, Yoshida T, Hosoya T, Shirai K. Phosphate overload accelerates vascular calcium deposition in end‐stage renal disease patients. Nephrol Dial Transpl 18(Suppl 3): iii86‐89, 2003.
 257.Shimada T, Kakitani M, Yamazaki Y, Hasegawa H, Takeuchi Y, Fujita T, Fukumoto S, Tomizuka K, Yamashita T. Targeted ablation of Fgf23 demonstrates an essential physiological role of FGF23 in phosphate and vitamin D metabolism. J Clin Invest 113: 561‐568, 2004.
 258.Shimada T, Mizutani S, Muto T, Yoneya T, Hino R, Takeda S, Takeuchi Y, Fujita T, Fukumoto S, Yamashita T. Cloning and characterization of FGF23 as a causative factor of tumor‐induced osteomalacia. Proc Natl Acad Sci U S A 98: 6500‐6505, 2001.
 259.Shimada T, Muto T, Urakawa I, Yoneya T, Yamazaki Y, Okawa K, Takeuchi Y, Fujita T, Fukumoto S, Yamashita T. Mutant FGF‐23 responsible for autosomal dominant hypophosphatemic, rickets is resistant to proteolytic cleavage and causes hypophosphatemia in vivo. Endocrinology 143: 3179‐3182, 2002.
 260.Shimamura Y, Hamada K, Inoue K, Ogata K, Ishihara M, Kagawa T, Inoue M, Fujimoto S, Ikebe M, Yuasa K, Yamanaka S, Sugiura T, Terada Y. Serum levels of soluble secreted alpha‐Klotho are decreased in the early stages of chronic kidney disease, making it a probable novel biomarker for early diagnosis. Clin Exp Nephrol16: 722‐729, 2012.
 261.Silver J, Russell J, Sherwood LM. Regulation by vitamin‐D metabolites of messenger ribonucleic‐acid for preproparathyroid hormone in isolated bovine parathyroid cells. Proc Natl Acad Sci U S A 82: 4270‐4273, 1985.
 262.Slatopolsky E, Caglar S, Pennell JP, Taggart DD, Canterbury JM, Reiss E, Bricker NS. On the pathogenesis of hyperparathyroidism in chronic experimental renal insufficiency in the dog. J Clin Invest 50: 492‐499, 1971.
 263.Slatopolsky E, Finch J, Denda M, Ritter C, Zhong M, Dusso A, MacDonald PN, Brown AJ. Phosphorus restriction prevents parathyroid gland growth. High phosphorus directly stimulates PTH secretion in vitro. J Clin Invest 97: 2534‐2540, 1996.
 264.Slatopolsky E, Robson AM, Elkan I, Bricker NS. Control of phosphate excretion in uremic man. J Clin Invest 47: 1865‐1874, 1968.
 265.Slominska EM, Kowalik K, Smolenski RT, Szolkiewicz M, Rutkowski P, Rutkowski B, Swierczynski J. Accumulation of poly(ADP‐ribose) polymerase inhibitors in children with chronic renal failure. Ped Nephrol 21: 800‐806, 2006.
 266.Sneddon WB, Ruiz GW, Gallo LI, Xiao K, Zhang Q, Rbaibi Y, Weisz OA, Apodaca GL, Friedman PA. Convergent signaling pathways regulate parathyroid hormone and fibroblast growth factor‐23 action on NPT2A‐mediated phosphate transport. J Biol Chem 291: 18632‐18642, 2016.
 267.Spudich G, Chibalina MV, Au JS, Arden SD, Buss F, Kendrick‐Jones J. Myosin VI targeting to clathrin‐coated structures and dimerization is mediated by binding to Disabled‐2 and PtdIns(4,5)P2. Nat Cell Biol 9: 176‐183, 2007.
 268.St‐Arnaud R, Messerlian S, Moir JM, Omdahl JL, Glorieux FH. The 25‐hydroxyvitamin D 1‐alpha‐hydroxylase gene maps to the pseudovitamin D‐deficiency rickets (PDDR) disease locus. J Bone Miner Res 12: 1552‐1559, 1997.
 269.Stauber A, Radanovic T, Stange G, Murer H, Wagner CA, Biber J. Regulation of intestinal phosphate transport. II. Metabolic acidosis stimulates Na(+)‐dependent phosphate absorption and expression of the Na(+)‐P(i) cotransporter NaPi‐IIb in small intestine. Am J Physiol Gastrointest Liver Physiol 288: G501‐G506, 2005.
 270.Stubbs JR, Liu S, Tang W, Zhou J, Wang Y, Yao X, Quarles LD. Role of hyperphosphatemia and 1,25‐dihydroxyvitamin D in vascular calcification and mortality in fibroblastic growth factor 23 null mice. J Am Soc Nephrol 18: 2116‐2124, 2007.
 271.Sugiura H, Yoshida T, Tsuchiya K, Mitobe M, Nishimura S, Shirota S, Akiba T, Nihei H. Klotho reduces apoptosis in experimental ischaemic acute renal failure. Nephrol Dial Transpl 20: 2636‐2645, 2005.
 272.Suzuki A, Ammann P, Nishiwaki‐Yasuda K, Sekiguchi S, Asano S, Nagao S, Kaneko R, Hirabayashi M, Oiso Y, Itoh M, Caverzasio J. Effects of transgenic Pit‐1 overexpression on calcium phosphate and bone metabolism. J Bone Miner Metab 28: 139‐148, 2010.
 273.Takahashi Y, Tanaka A, Nakamura T, Fukuwatari T, Shibata K, Shimada N, Ebihara I, Koide H. Nicotinamide suppresses hyperphosphatemia in hemodialysis patients. Kidney Int 65: 1099‐1104, 2004.
 274.Takasugi S, Akutsu M, Nagata M. Oral phosphorus supplementation secondarily increases circulating fibroblast growth factor 23 levels at least partially via stimulation of parathyroid hormone secretion. J Nutr Sci Vitaminol 60: 140‐144, 2014.
 275.Takenaka T, Inoue T, Miyazaki T, Hayashi M, Suzuki H. Xeno‐klotho inhibits parathyroid hormone signaling. J Bone Miner Res 31: 455‐462, 2016.
 276.Takeyama K, Kitanaka S, Sato T, Kobori M, Yanagisawa J, Kato S. 25‐Hydroxyvitamin D3 1alpha‐hydroxylase and vitamin D synthesis. Science 277: 1827‐1830, 1997.
 277.Tamura A, Hayashi H, Imasato M, Yamazaki Y, Hagiwara A, Wada M, Noda T, Watanabe M, Suzuki Y, Tsukita S. Loss of claudin‐15, but not claudin‐2, causes Na+ deficiency and glucose malabsorption in mouse small intestine. Gastroenterology 140: 913‐923, 2011.
 278.Tanaka H, Yamamoto Y, Kashihara H, Yamazaki Y, Tani K, Fujiyoshi Y, Mineta K, Takeuchi K, Tamura A, Tsukita S. Claudin‐21 has a paracellular channel role at tight junctions. Mol Cell Biol 36: 954‐964, 2016.
 279.Taylor AN. In vitro phosphate transport in chick ileum: Effect of cholecalciferol, calcium, sodium and metabolic inhibitors. J Nutr 104: 489‐494, 1974.
 280.Thomas L, Bettoni C, Knopfel T, Hernando N, Biber J, Wagner CA. Acute adaption to oral or intravenous phosphate requires parathyroid hormone. J Am Soc Nephrol 28: 903‐914, 2017.
 281.Thomas L, Wagner CA, Biber J, Hernando N. Adaptation of opossum kidney cells to luminal phosphate: Effects of phosphonoformic acid and kinase inhibitors. Kidney Blood Press Res 41: 298‐310, 2016.
 282.Tomoe Y, Segawa H, Shiozawa K, Kaneko I, Tominaga R, Hanabusa E, Aranami F, Furutani J, Kuwahara S, Tatsumi S, Matsumoto M, Ito M, Miyamoto K. Phosphaturic action of fibroblast growth factor 23 in Npt2 null mice. Am J Physiol Renal Physiol 298: F1341‐F1350, 2010.
 283.Tonelli M, Sacks F, Pfeffer M, Gao Z, Curhan G, Cholesterol, Recurrent Events Trial I. Relation between serum phosphate level and cardiovascular event rate in people with coronary disease. Circulation 112: 2627‐2633, 2005.
 284.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: L868‐L873, 1999.
 285.Traebert M, Volkl H, Biber J, Murer H, Kaissling B. Luminal and contraluminal action of 1‐34 and 3‐34 PTH peptides on renal type IIa Na‐P(i) cotransporter. Am J Physiol Renal Physiol 278: F792‐F798, 2000.
 286.Tuttle KR, Short RA. Longitudinal relationships among coronary artery calcification, serum phosphorus, and kidney function. Clin J Am Soc Nephrol 4: 1968‐1973, 2009.
 287.Urakawa I, Yamazaki Y, Shimada T, Iijima K, Hasegawa H, Okawa K, Fujita T, Fukumoto S, Yamashita T. Klotho converts canonical FGF receptor into a specific receptor for FGF23. Nature 444: 770‐774, 2006.
 288.Uribarri J. Phosphorus homeostasis in normal health and in chronic kidney disease patients with special emphasis on dietary phosphorus intake. Semin Dial 20: 295‐301, 2007.
 289.Van Itallie C, Rahner C, Anderson JM. Regulated expression of claudin‐4 decreases paracellular conductance through a selective decrease in sodium permeability. J Clin Invest 107: 1319‐1327, 2001.
 290.Van Itallie CM, Rogan S, Yu A, Vidal LS, Holmes J, Anderson JM. Two splice variants of claudin‐10 in the kidney create paracellular pores with different ion selectivities. Am J Physio,Renal Physiol 291: F1288‐F1299, 2006.
 291.van Zuijdewijn CLMD, Grooteman MPC, Bots ML, Blankestijn PJ, Steppan S, Buechel J, Groenwold RHH, Brandenburg V, van den Dorpel MA, ter Wee PM, Nube MJ, Vervloet MG. Serum magnesium and sudden death in European hemodialysis patients. Plos One 10: e0143104, 2015.
 292.Vervloet MC, Sezer S, Massy ZA, Johansson L, Cozzolino M, Fouque D, Kidne E‐EWGC, Grp ERNW. The role of phosphate in kidney disease. Nat Rev Nephrol 13: 27‐38, 2017.
 293.Villa‐Bellosta R, Ravera S, Sorribas V, Stange G, Levi M, Murer H, Biber J, Forster IC. The Na+‐Pi cotransporter PiT‐2 (SLC20A2) is expressed in the apical membrane of rat renal proximal tubules and regulated by dietary Pi. Am J Physiol Renal Physiol 296: F691‐F699, 2009.
 294.Virkki LV, Murer H, Forster IC. Voltage clamp fluorometric measurements on a type II Na+‐coupled Pi cotransporter: Shedding light on substrate binding order. J Gen Physiol 127: 539‐555, 2006.
 295.Wagner CA, Hernando N, Forster IC, Biber J. The SLC34 family of sodium‐dependent phosphate transporters. Pflugers Archiv 466: 139‐153, 2014.
 296.Waldegger S, Klingel K, Barth P, Sauter M, Lanzendorfer M, Kandolf R, Lang F. h‐sgk serine‐threonine protein kinase gene as transcriptional target of transforming growth factor beta in human intestine. Gastroenterology 116: 1081‐1088, 1999.
 297.Walling MW. Intestinal Ca and phosphate transport: Differential responses to vitamin D3 metabolites. Am J Physiol 233: E488‐E494, 1977.
 298.Wallingford MC, Chia JJ, Leaf EM, Borgeia S, Chavkin NW, Sawangmake C, Marro K, Cox TC, Speer MY, Giachelli CM. SLC20A2 deficiency in mice leads to elevated phosphate levels in cerbrospinal fluid and glymphatic pathway‐associated arteriolar calcification, and recapitulates human idiopathic basal ganglia calcification. Brain Pathol 27: 64‐76, 2017.
 299.Walton J, Gray TK. Absorption of inorganic phosphate in the human small intestine. Clin Sci 56: 407‐412, 1979.
 300.Wang C, Li Y, Shi L, Ren J, Patti M, Wang T, de Oliveira JR, Sobrido MJ, Quintans B, Baquero M, Cui X, Zhang XY, Wang L, Xu H, Wang J, Yao J, Dai X, Liu J, Zhang L, Ma H, Gao Y, Ma X, Feng S, Liu M, Wang QK, Forster IC, Zhang X, Liu JY. Mutations in SLC20A2 link familial idiopathic basal ganglia calcification with phosphate homeostasis. Nat Genet 44: 254‐256, 2012.
 301.Weinman EJ, Biswas RS, Peng G, Shen L, Turner CL, E X, Steplock D, Shenolikar S, Cunningham R. Parathyroid hormone inhibits renal phosphate transport by phosphorylation of serine 77 of sodium‐hydrogen exchanger regulatory factor‐1. J Clin Invest 117: 3412‐3420, 2007.
 302.Weinman EJ, Steplock D, Shenolikar S, Biswas R. Fibroblast growth factor‐23‐mediated inhibition of renal phosphate transport in mice requires sodium‐hydrogen exchanger regulatory factor‐1 (NHERF‐1) and synergizes with parathyroid hormone. J Biol Chem 286: 37216‐37221, 2011.
 303.Weinman EJ, Steplock D, Wang YP, Shenolikar S. Characterization of a protein cofactor that mediates protein kinase‐–a regulation of the renal brush‐border membrane Na+‐H+ exchanger. J Clin Invest 95: 2143‐2149, 1995.
 304.Weinman EJ, Steplock D, Zhang YH, Biswas R, Bloch RJ, Shenolikar S. Cooperativity between the phosphorylation of Thr(95) and Ser(77) of NHERF‐1 in the hormonal regulation of renal phosphate transport. J Biol Chem 285: 25134‐25138, 2010.
 305.Wickham E. Phosphorus content in commonly consumed beverages. J Renal Nutr 24: E1‐E4, 2014.
 306.Williams AF, Barclay AN. The immunoglobulin superfamily‐–domains for cell surface recognition. Annu Rev Immunol 6: 381‐405, 1988.
 307.Xie J, Cha SK, An SW, Kuro‐o M, Birnbaumer L, Huang CL. Cardioprotection by Klotho through downregulation of TRPC6 channels in the mouse heart. Nat Commun 3: 1238, 2012.
 308.Xie J, Yoon J, An SW, Kuro‐o M, Huang CL. Soluble klotho protects against uremic cardiomyopathy independently of fibroblast growth factor 23 and phosphate. J Am Soc Nephrol 26: 1150‐1160, 2015.
 309.Xu H, Bai L, Collins JF, Ghishan FK. 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: C487‐C493, 2002.
 310.Xu H, Collins JF, Bai LQ, Kiela PR, Ghishan FK. Regulation of the human sodium‐phosphate cotransporter NaPi‐IIb gene promoter by epidermal growth factor. Am J Physiol Cell Physiol 280: C628‐C636, 2001.
 311.Xu H, Inouye M, Hines ER, Collins JF, Ghishan FK. Transcriptional regulation of the human NaPi‐IIb cotransporter by EGF in Caco‐2 cells involves c‐myb. Am J Physiol Cell Physiol 284: C1262‐C1271, 2003.
 312.Xu H, Inouye M, Missey T, Collins JF, Ghishan FK. Functional characterization of the human intestinal NaPi‐IIb cotransporter in hamster fibroblasts and Xenopus oocytes. Biochim Biophys Acta 1567: 97‐105, 2002.
 313.Xu H, Uno JK, Inouye M, Xu L, Drees JB, Collins JF, Ghishan FK. Regulation of intestinal NaPi‐IIb cotransporter gene expression by estrogen. Am J Physiol gastrointest Liver Physiol 285: G1317‐G1324, 2003.
 314.Yadav MC, Bottini M, Cory E, Bhattacharya K, Kuss P, Narisawa S, Sah RL, Beck L, Fadeel B, Farquharson C, Millan JL. Skeletal mineralization deficits and impaired biogenesis and function of chondrocyte‐derived matrix vesicles in phospho1(‐/‐) and phospho1/Pi t1 double‐knockout mice. J Bone Miner Res 31: 1275‐1286, 2016.
 315.Yamamoto R, Minamizaki T, Yoshiko Y, Yoshioka H, Tanne K, Aubin JE, Maeda N. 1 alpha,25‐dihydroxyvitamin D‐3 acts predominately in mature osteoblasts under conditions of high extracellular phosphate to increase fibroblast growth factor 23 production in vitro. J Endocrinol 206: 279‐286, 2010.
 316.Yu X, Sabbagh Y, Davis SI, Demay MB, White KE. Genetic dissection of phosphate‐ and vitamin D‐mediated regulation of circulating Fgf23 concentrations. Bone 36: 971‐977, 2005.
 317.Yuan B, Feng JQ, Bowman S, Liu Y, Blank RD, Lindberg I, Drezner MK. Hexa‐D‐arginine treatment increases 7B2*PC2 activity in hyp‐mouse osteoblasts and rescues the HYP phenotype. J Bone Miner Res 28: 56‐72, 2013.
 318.Zhang HT, Berezov A, Wang Q, Zhang G, Drebin J, Murali R, Greene MI. ErbB receptors: From oncogenes to targeted cancer therapies. J Clin Invest 117: 2051‐2058, 2007.
 319.Zhang MY, Wang X, Wang JT, Compagnone NA, Mellon SH, Olson JL, Tenenhouse HS, Miller WL, Portale AA. Dietary phosphorus transcriptionally regulates 25‐hydroxyvitamin D‐1alpha‐hydroxylase gene expression in the proximal renal tubule. Endocrinology 143: 587‐595, 2002.
 320.Zhang S, Gillihan R, He N, Fields T, Liu S, Green T, Stubbs JR. Dietary phosphate restriction suppresses phosphaturia but does not prevent FGF23 elevation in a mouse model of chronic kidney disease. Kidney Int 84: 713‐721, 2013.
 321.Zierk J, Arzideh F, Rechenauer T, Haeckel R, Rascher W, Metzler M, Rauh M. Age‐ and sex‐specific dynamics in 22 hematologic and biochemical analytes from birth to adolescence. Clin Chem 61: 964‐973, 2015.

 

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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Article Title: Mechanisms and Regulation of Intestinal Phosphate Absorption
 

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