Growth-related Renal Type II Na/Pi Cotransporter

Growth is critically dependent on the retention of a variety of nutrients. The kidney contributes to this positive external balance. In the present study, we isolated a cDNA from the human and rat kidney that encodes a growth-related Na+-dependent inorganic phosphate (Pi) cotransporter (type IIc). Microinjection of type IIc cRNA into Xenopus oocytes demonstrated sodium-dependent Pi cotransport activity. Affinity for Pi was 0.07 mm in 100 mm Na+. The transport activity was dependent on extracellular pH. In electrophysiological studies, type IIc Na/Pi cotransport was electroneutral, whereas type IIa was highly electrogenic. In Northern blotting analysis, the type IIc transcript was only expressed in the kidney and highly in weaning animals. In immunohistochemical analysis, the type IIc protein was shown to be localized at the apical membrane of the proximal tubular cells in superficial and midcortical nephrons of weaning rat kidney. Hybrid depletion experiments suggested that type IIc could function as a Na/Pi cotransporter in weaning animals, but its role is reduced in adults. The finding of the present study suggest that the type IIc is a growth-related renal Na/Pi cotransporter, which has a high affinity for Pi and is electroneutral. Growth is critically dependent on the retention of a variety of nutrients. The kidney contributes to this positive external balance. In the present study, we isolated a cDNA from the human and rat kidney that encodes a growth-related Na+-dependent inorganic phosphate (Pi) cotransporter (type IIc). Microinjection of type IIc cRNA into Xenopus oocytes demonstrated sodium-dependent Pi cotransport activity. Affinity for Pi was 0.07 mm in 100 mm Na+. The transport activity was dependent on extracellular pH. In electrophysiological studies, type IIc Na/Pi cotransport was electroneutral, whereas type IIa was highly electrogenic. In Northern blotting analysis, the type IIc transcript was only expressed in the kidney and highly in weaning animals. In immunohistochemical analysis, the type IIc protein was shown to be localized at the apical membrane of the proximal tubular cells in superficial and midcortical nephrons of weaning rat kidney. Hybrid depletion experiments suggested that type IIc could function as a Na/Pi cotransporter in weaning animals, but its role is reduced in adults. The finding of the present study suggest that the type IIc is a growth-related renal Na/Pi cotransporter, which has a high affinity for Pi and is electroneutral. Inorganic phosphate (Pi) is of critical importance to body functions, particularly during periods of growth. The kidneys contribute to the maintenance of the positive Pi balance required for growth by reabsorbing a high fraction of the filtered Pi (1Spitzer A. Barac-Nieto M. Pediatr. Nephrol. 2001; 16: 763-771Crossref PubMed Scopus (36) Google Scholar). The capacity for Na+-dependent phosphate cotransport across the luminal brush border membrane of renal proximal tubular cells is higher in juveniles than in adults (2Caverzasio J. Muer H. Fleish H. Bonjour J.P. Pflugers Arch. Eur. J. Physiol. 1982; 394: 217-221Crossref PubMed Scopus (32) Google Scholar, 3Neiberger R.E. Barac-Nieto M. Spitzer A. Am. J. Physiol. 1989; 257: F268-F274PubMed Google Scholar). Several mammalian renal Na+-dependent Pi cotransporters have recently been isolated and characterized (4Muer H. Hernando N. Foster I. Biber J. Physiol. Rev. 2000; 80: 1373-1409Crossref PubMed Scopus (439) Google Scholar). The cDNAs of these transporters can be divided into three types (types I–III) in the kidney cortex (4Muer H. Hernando N. Foster I. Biber J. Physiol. Rev. 2000; 80: 1373-1409Crossref PubMed Scopus (439) Google Scholar). Type II Na/Pi cotransporters belong to a unique class of Na+-coupled cotransport proteins. They can be further subdivided into two subgroups, type IIa and type IIb (4Muer H. Hernando N. Foster I. Biber J. Physiol. Rev. 2000; 80: 1373-1409Crossref PubMed Scopus (439) Google Scholar). Type IIa cotransporters are expressed in the proximal tubule of the kidney, whereas type IIb are expressed in several tissues such as the lung and small intestine (4Muer H. Hernando N. Foster I. Biber J. Physiol. Rev. 2000; 80: 1373-1409Crossref PubMed Scopus (439) Google Scholar). Functional characteristics, proximal tubular localization of the mRNAs, and apical expression of type IIa Na/Pi cotransporters suggest that this protein represents the most likely pathway of proximal tubular apical Na+-dependent entry of Pi (4Muer H. Hernando N. Foster I. Biber J. Physiol. Rev. 2000; 80: 1373-1409Crossref PubMed Scopus (439) Google Scholar). Age dependence was observed at the level of the type IIa Na/Pi cotransporter protein expression (5Sorribas V. Lotscher M. Loffing J. Biber J. Kaislling B. Muer H. Levi M. Kidney Int. 1996; 50: 855-863Abstract Full Text PDF PubMed Scopus (37) Google Scholar, 6Silverstein D.M. Barac-Nieto M. Spitzer A. Kidney Int. 1996; 49: 1023-1026Abstract Full Text PDF PubMed Scopus (20) Google Scholar). In addition, a specific type IIa-related Na/Pi cotransporter protein was postulated to account for high Pi transport rates in weaning animals (7Silverstein D.M. Barac-Nieto M. Muer H. Spitzer A. Am. J. Physiol. 1997; 273: R928-R933Crossref PubMed Google Scholar). Evidence for this was obtained by antisense experiments and transport expression in Xenopus oocytes (1Spitzer A. Barac-Nieto M. Pediatr. Nephrol. 2001; 16: 763-771Crossref PubMed Scopus (36) Google Scholar,7Silverstein D.M. Barac-Nieto M. Muer H. Spitzer A. Am. J. Physiol. 1997; 273: R928-R933Crossref PubMed Google Scholar). When mRNA isolated from the kidney cortex of rapidly growing rats was treated with type IIa transporter antisense oligonucleotides or was depleted of type IIa-specific mRNA by a subtractive hybridization procedure, Na+-dependent Pi uptake was still detected in injected oocytes (1Spitzer A. Barac-Nieto M. Pediatr. Nephrol. 2001; 16: 763-771Crossref PubMed Scopus (36) Google Scholar, 7Silverstein D.M. Barac-Nieto M. Muer H. Spitzer A. Am. J. Physiol. 1997; 273: R928-R933Crossref PubMed Google Scholar). The type IIa transporter-depleted mRNA contained a mRNA species that showed some sequence homology to the type IIa transporter encoding message. This conclusion is compatible with the observation that young type IIa (Npt2) knock-out mice lacking type IIa mRNA and protein retain the capacity to reabsorb Pi at a rate that cannot be explained by the presence of type I and III Na/Pitransporter (8Beck L. Karaplis A.S. Amizuka N. Hewson S. Ozawa H. Tenenhouse H.S. Proc. Natl. Acad. Sci. U. S. A. 1998; 95: 5372-5377Crossref PubMed Scopus (502) Google Scholar, 9Hoag H.H. Martel T. Gauthier C. Tenenhouse H.S. J. Clin. Invest. 1999; 104: 679-686Crossref PubMed Scopus (81) Google Scholar). In the present study, we isolated a growth-related type II Na/Pi cotransporter in human and rat kidneys. Male Wister rats (3 weeks after birth) were purchased from Shizuoka Laboratory Animal Center (Shizuoka, Japan). They were housed in plastic cages and fed standard rat chow diet (Oriental, Osaka, Japan) ad libitum for the first week. After that period, they received a diet containing 1.2% calcium and 0.6% phosphorus for 5 days. On the 6th day, the following three groups of six rats each were established: the control Pi group, rats that were chronically fed a diet containing 0.6% Pi; the low Pi group, rats that received a diet containing a low percentage (0.02%) of Pi; and the high Pigroup, in which the rats received a high percentage (1.2%) Pi diet. After 7 days of the given diet, all of the rats were anesthetized with intraperitoneal pentobarbital, and their kidneys were removed rapidly. cDNAs for human expressed sequence tags (EST) (GenBankTM/EBI/DDBJ accession no. AI792826), which we found in the course of EST database searches to show nucleotide sequence similarity to human type IIa Na/Picotransporter, were obtained using IMAGE (integrated and molecular analysis of genomes and their expression). The ∼0.8-kb SacI fragment was excised from human cDNA (IMAGE cDNA clone 1535299) and labeled with 32P using the Megaprime DNA labeling system, dCTP (Amersham Biosciences) for use as a probe to screen a human kidney 5′-Stretch Plus cDNA library (CLONTECH). Screening of the cDNA library and isolation of positive plaques were performed as described previously (10Miyamoto K. Tatsumi S. Sonoda T. Yamamoto H. Minami H. Taketani Y. Takeda E. Biochem. J. 1995; 305: 81-85Crossref PubMed Scopus (66) Google Scholar, 11Tatsumi S. Miyamoto K. Kouda T. Motonaga K. Katai K. Ohkido I. Morita K. Segawa H. Tani Y. Yamamoto H. Taketani Y. Takeda E. J. Biol. Chem. 1998; 273: 28568-28575Abstract Full Text Full Text PDF PubMed Scopus (24) Google Scholar). The human type IIc Na/Pi cotransporter fragment (corresponding to nucleotides 89–600 of the nucleotide sequence) was used to isolate a rat cDNA for type IIc Na/Picotransporter. The oligo(dT)-primed cDNA library was prepared from rat kidney poly(A)+ RNA using the Superscript Choice system (Invitrogen) (12Segawa H. Fukasawa Y. Miyamoto K. Takeda E. Endou H. Kanai Y. J. Biol. Chem. 1999; 274: 19745-19751Abstract Full Text Full Text PDF PubMed Scopus (424) Google Scholar). The synthesized cDNA was ligated to λZIPLOX EcoRI arms (Invitrogen). Screening of the cDNA library and isolation of the positive plaques were performed as described previously (12Segawa H. Fukasawa Y. Miyamoto K. Takeda E. Endou H. Kanai Y. J. Biol. Chem. 1999; 274: 19745-19751Abstract Full Text Full Text PDF PubMed Scopus (424) Google Scholar). cRNAs obtained by in vitro transcription using T7 RNA polymerase for the human type IIc cDNA (hNPIIc) and rat type IIa (NaPi-2) in plasmid pBluescript SK− (Stratagene) were linearized with XbaI as described previously (12Segawa H. Fukasawa Y. Miyamoto K. Takeda E. Endou H. Kanai Y. J. Biol. Chem. 1999; 274: 19745-19751Abstract Full Text Full Text PDF PubMed Scopus (424) Google Scholar). Xenopus oocyte expression studies and uptake measurements were performed as described previously (11Tatsumi S. Miyamoto K. Kouda T. Motonaga K. Katai K. Ohkido I. Morita K. Segawa H. Tani Y. Yamamoto H. Taketani Y. Takeda E. J. Biol. Chem. 1998; 273: 28568-28575Abstract Full Text Full Text PDF PubMed Scopus (24) Google Scholar,12Segawa H. Fukasawa Y. Miyamoto K. Takeda E. Endou H. Kanai Y. J. Biol. Chem. 1999; 274: 19745-19751Abstract Full Text Full Text PDF PubMed Scopus (424) Google Scholar). The uptake rates of [32P]phosphorus were measured 2–3 days after injection of cRNA. For expression experiments, 25 ng of cRNA was injected into each oocyte. Xenopus oocyte expression was performed as described previously (11Tatsumi S. Miyamoto K. Kouda T. Motonaga K. Katai K. Ohkido I. Morita K. Segawa H. Tani Y. Yamamoto H. Taketani Y. Takeda E. J. Biol. Chem. 1998; 273: 28568-28575Abstract Full Text Full Text PDF PubMed Scopus (24) Google Scholar, 12Segawa H. Fukasawa Y. Miyamoto K. Takeda E. Endou H. Kanai Y. J. Biol. Chem. 1999; 274: 19745-19751Abstract Full Text Full Text PDF PubMed Scopus (424) Google Scholar). Groups of six to eight oocytes were incubated in 500 μl of standard uptake solution (100 mm NaCl, 2 mm KCl, 1 mmCaCl2, 1 mm MgCl2 10 mmHEPES, and 5 mm Tris, pH 7.4) or Na+-free uptake solution in which NaCl in standard uptake solution was replaced by choline chloride containing 0.1 μCi of radiolabeled compounds (10Miyamoto K. Tatsumi S. Sonoda T. Yamamoto H. Minami H. Taketani Y. Takeda E. Biochem. J. 1995; 305: 81-85Crossref PubMed Scopus (66) Google Scholar,11Tatsumi S. Miyamoto K. Kouda T. Motonaga K. Katai K. Ohkido I. Morita K. Segawa H. Tani Y. Yamamoto H. Taketani Y. Takeda E. J. Biol. Chem. 1998; 273: 28568-28575Abstract Full Text Full Text PDF PubMed Scopus (24) Google Scholar). Electrophysiological measurements were performed at room temperature using oocytes 3 days after cRNA injection. The oocytes were impaled with two 3 mKCl-filled electrodes with resistances of 0.5–2 MΩ. The electrodes were connected to a commercial two-electrode voltage clamp amplifier (CEZ 1250, Nihon Koden, Tokyo Japan) via Ag-AgCl pellet electrodes and referenced to an Ag-AgCl pellet that was connected to the bath via a 3 m KCl-agar bridge. The voltage clamp was controlled by an analog-to-digital-to-analog interface board (Digidata 1200, Axon Instruments, Foster City, CA) using pCLAMP 6 software (Axon Instruments). The voltage clamp was for 2 at to membrane The external control solution contained NaCl, 2 KCl, 1 and 5 pH was to this solution at the The were to pH The rate of the was and of the bath solution was 10 For depletion experiments, rat kidney poly(A)+ RNA was at for 5 in solution mm NaCl and a of a to rat type II phosphate and further incubated at for S. J. A. Biber J. M. H. J. Biol. Chem. Full Text PDF PubMed Google Scholar). The of type IIa nucleotides antisense type IIa nucleotides type IIc nucleotides and antisense type IIc nucleotides are to the rat type IIa and type IIc mRNA sequence (7Silverstein D.M. Barac-Nieto M. Muer H. Spitzer A. Am. J. Physiol. 1997; 273: R928-R933Crossref PubMed Google Scholar). The of poly(A)+ RNA was injected into the and uptake measurements were performed as described previously (10Miyamoto K. Tatsumi S. Sonoda T. Yamamoto H. Minami H. Taketani Y. Takeda E. Biochem. J. 1995; 305: 81-85Crossref PubMed Scopus (66) Google Scholar, 11Tatsumi S. Miyamoto K. Kouda T. Motonaga K. Katai K. Ohkido I. Morita K. Segawa H. Tani Y. Yamamoto H. Taketani Y. Takeda E. J. Biol. Chem. 1998; 273: 28568-28575Abstract Full Text Full Text PDF PubMed Scopus (24) Google Scholar). membrane used border membrane were prepared from rat kidney by the as described previously K. Segawa H. H. Morita K. H. Tatsumi S. Taketani Y. Miyamoto K. S. Y. Takeda E. J. Biochem. 1997; PubMed Scopus Google Scholar). The of and were measured to the of the were at for 5 in in the presence or of and to The were on (Amersham The were treated with IIa K. Segawa H. H. Morita K. H. Tatsumi S. Taketani Y. Miyamoto K. S. Y. Takeda E. J. Biochem. 1997; PubMed Scopus Google or type IIc Na/Pi cotransporter and with as the The were detected using the Plus system (Amersham Biosciences) A. Segawa H. Miyamoto K. H. Y. K. H. Takeda E. Endou H. Kanai Y. J. Biol. Chem. 1999; 274: Full Text Full Text PDF PubMed Scopus Google Scholar). brush border membrane analysis of the rat kidney was performed as described previously with A. Segawa H. Miyamoto K. H. Y. K. H. Takeda E. Endou H. Kanai Y. J. Biol. Chem. 1999; 274: Full Text Full Text PDF PubMed Scopus Google Scholar). For were incubated with IIa or type IIc Na/Pi cotransporter at they were treated with for the were treated with to of rat type IIc Na/Pi cotransporter was The were for with were as described previously K. Segawa H. H. Morita K. H. Tatsumi S. Taketani Y. Miyamoto K. S. Y. Takeda E. J. Biochem. 1997; PubMed Scopus Google Scholar). are expressed as the groups were by analysis of and of were as a The human type IIc cDNA was with an of encoding analysis of the sequence the presence of eight The extracellular of human type IIc cotransporter contained for protein was detected at and in the were the three that the protein was to Na/Pi cotransporters in human type IIa and type IIb S. V. V. Biber J. Muer H. Proc. Natl. Acad. Sci. PubMed Scopus Google Scholar, L. Biochem. 1999; PubMed Scopus Google Scholar). homology to types I and III Na/Pi cotransporters was (10Miyamoto K. Tatsumi S. Sonoda T. Yamamoto H. Minami H. Taketani Y. Takeda E. Biochem. J. 1995; 305: 81-85Crossref PubMed Scopus (66) Google Scholar, B. H. T. Growth Google Scholar). The of homology were detected in that have been suggested to be the The most in the protein with the type II Na/Pi cotransporters was found in the containing of of was present in the type IIb of human and kidney. The expression of type IIc mRNA was by Northern blotting using human Northern and poly(A)+ RNA from rat tissues and the type IIc cDNA as a a was observed only in the kidney. were detected in the or In addition, the expression of the type IIc mRNA was higher in weaning animals days with in adults days The of type IIc mRNA were in animals. The of human type IIc Na/Pi cotransporter were in Xenopus shown in the of Xenopus oocytes with human type IIc Na/Pi cotransporter in a to the level in oocytes uptake by human type IIc was dependent on but and in a in the presence of The uptake was and the for Type Na/Pi uptake was by a a of proximal tubular Na/Pi cotransport The and for was mm and 3 of at a membrane of during the of of oocytes the type IIa Na/Pi cotransporter with Pi that on the presence of external Na+. were observed the was to or oocytes of Pi was by a to the from to during with 1 mm Pi in type IIa Na/Pi suggest that the by 1 mm that the observation that the Na/Pi cotransport by the type IIa cotransporter was I. Hernando N. Biber J. Muer H. J. Physiol. 1998; PubMed Scopus Google Scholar). In a of oocytes the type IIc cotransporter with the suggested type by the type IIc Na/Pi cotransporter is electroneutral. The molecular of type IIc Na/Pi cotransporter protein was by blotting analysis In isolated from the rat kidney days the specific with a of measured by the presence of in the experiments, the In addition, type IIc Na/Pi cotransporter in cells was observed as and using The type IIc with the protein In addition, we the type IIc with type IIa Na/Pi cotransporter The type IIc with in the 7 cells the type IIa or type IIb we in rat renal type IIc protein blotting demonstrated that the of type IIc protein in the was in weaning in and in In isolated from the kidney of a rat days fed a diet low in Pi for 7 days were prepared and used for The of type IIc transporter protein were for the with in rats fed the control diet. In the high Pi diet the level of type IIc transporter of type IIc Na/Pi cotransporter protein was performed with the kidneys of weaning rats days In and expression of type IIc cotransporter protein was detected in the superficial and The control The expression was observed in proximal higher was that type IIc was localized in the brush border of proximal tubular cells and was in the membrane was in superficial nephrons than in In in weaning type IIa-related was detected only in nephrons and but in the superficial and midcortical Type IIa-related was observed in a which likely to the in weaning rat kidney In the kidney and type was detected only in nephrons and in the superficial and midcortical Type IIa-related was observed in midcortical and nephrons in Evidence for the type IIc was obtained by antisense described RNA isolated from the kidney of rats was treated with type IIa transporter antisense oligonucleotides of type IIa-specific Na+-dependent Pi uptake was in injected oocytes In poly(A)+ RNA isolated from the kidney of weaning rats was treated with type IIa antisense Pi uptake was still detected in injected oocytes In type IIc antisense oligonucleotides Pi uptake in oocytes poly(A)+ RNA from weaning rat kidney Pi uptake in oocytes poly(A)+ RNA from rat kidney Pi during as has been by balance studies, studies, and studies with isolated (1Spitzer A. Barac-Nieto M. Pediatr. Nephrol. 2001; 16: 763-771Crossref PubMed Scopus (36) Google Scholar, J. Muer H. Fleish H. Bonjour J.P. Pflugers Arch. Eur. J. Physiol. 1982; 394: 217-221Crossref PubMed Scopus (32) Google Scholar, 3Neiberger R.E. Barac-Nieto M. Spitzer A. Am. J. Physiol. 1989; 257: F268-F274PubMed Google Scholar). This is to a in the a in the for Pi of the brush border membrane Na/Pi and pH dependence of type Na/Pi cotransport this protein as a for a Na/Pi cotransporter in a high Pi transport activity in weaning animals (4Muer H. Hernando N. Foster I. Biber J. Physiol. Rev. 2000; 80: 1373-1409Crossref PubMed Scopus (439) Google Scholar). In addition, of the of the type IIc transporter with in the studies J. Am. J. Physiol. Google Scholar, N. M. Pflugers Arch. Eur. J. Physiol. PubMed Google Scholar). for the renal type IIa Na/Picotransporter, of oocytes the type IIa Na/Pi cotransporter with Pi an that was dependent on the presence of and the I. Hernando N. Biber J. Muer H. J. Physiol. 1998; PubMed Scopus Google Scholar). type IIc Na/Pi cotransport was electroneutral. The and for were obtained using the human type and A. S. T. Biber J. H. Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus Google characterized the by the type IIa (NaPi-2) from rat kidney in Xenopus They showed that in the presence of extracellular Pi an for membrane in the of with the from the of on the extracellular and membrane in to the to Na/Pi at pH from studies L. B. J. Biol. Chem. Full Text PDF PubMed Google Scholar, N. M. Pflugers Arch. Eur. J. Physiol. PubMed Scopus Google of a to 3 for the at Pi suggested a for type IIa Na/Pi cotransport at In the present suggest that type IIc has the to Na/Pi at pH as from studies L. B. J. Biol. Chem. Full Text PDF PubMed Google Scholar, N. M. Pflugers Arch. Eur. J. Physiol. PubMed Scopus Google Scholar). The of an during growth is transporter transport Pi across the apical membrane of the proximal as the for be the entry of Pi from the tubular into the the and the high Pi The Pi measured in isolated kidneys using was in growing animals than in adults M. Spitzer A. Am. J. Physiol. Google Scholar). This a for an Na/Pi cotransporter in growing animals. further studies are to the role of the Na/Pi cotransporter in The type IIc transporter protein is detected in the apical membrane of renal proximal tubular in analysis that type IIc Na/Pi cotransporter is present in the from rat kidneys. in the depletion type IIc antisense the Pi uptake in oocytes by of renal poly(A)+ RNA from suggest that of type IIc is for the observed in the the of type IIc mRNA and of type Age dependence was observed at the level of type IIa Na/Pi cotransporter protein expression (1Spitzer A. Barac-Nieto M. Pediatr. Nephrol. 2001; 16: 763-771Crossref PubMed Scopus (36) Google Scholar, A. Am. J. Physiol. 1997; Google Scholar, M. I. Levi M. Am. J. Physiol. 1999; Google Scholar, M. Lotscher M. T. Biber J. H. B. J. Am. Nephrol. 1999; Google Scholar). In the kidneys of expression of the type IIa was observed in and nephrons only and was in the cortex M. Lotscher M. T. Biber J. H. B. J. Am. Nephrol. 1999; Google Scholar). After of during expression of the transporter was high in the membrane of all In the expression that in type IIa in the membrane of superficial and midcortical nephrons M. Lotscher M. T. Biber J. H. B. J. Am. Nephrol. 1999; Google Scholar). M. Lotscher M. T. Biber J. H. B. J. Am. Nephrol. 1999; Google that the of type IIa protein in the of rats was to of that in In renal type IIc protein was detected in and and was in the superficial and midcortical of the kidney in weaning animals. The type IIc protein in was and was detected in the nephrons in the kidney. The present suggest that the high expression of type IIc Na/Pi cotransporter in the kidney of weaning rats high Pi transport activity in weaning animals during of the type IIa Na/Picotransporter. is that the of type IIc protein in superficial nephrons in the weaning rats only be to the but be by the Pi of the M. Lotscher M. T. Biber J. H. B. J. Am. Nephrol. 1999; Google Scholar). The rats were fed with rat and from the rats were fed the standard diet with a Pi of 0.6% J. J. PubMed Scopus Google Scholar). the Pi the type IIc protein in the weaning kidney. the of the of type IIc The of the present study suggest that a high Pi diet the expression of type IIc whereas a low Pi diet the of type IIc protein in is suggested that the of Pi are in the of type IIc protein in weaning the of weaning contribute to the observed in type IIa and type IIc in the H.H. Martel T. Gauthier C. Tenenhouse H.S. J. Clin. Invest. 1999; 104: 679-686Crossref PubMed Scopus (81) Google the knock-out on and expression of Na/Pi cotransporter and H.H. Martel T. Gauthier C. Tenenhouse H.S. J. Clin. Invest. 1999; 104: 679-686Crossref PubMed Scopus (81) Google Scholar). all Na/Pi cotransport in mice is of that in They that mice cannot be for by the in renal expression of type I and type III transporters (8Beck L. Karaplis A.S. Amizuka N. Hewson S. Ozawa H. Tenenhouse H.S. Proc. Natl. Acad. Sci. U. S. A. 1998; 95: 5372-5377Crossref PubMed Scopus (502) Google Scholar, 9Hoag H.H. Martel T. Gauthier C. Tenenhouse H.S. J. Clin. Invest. 1999; 104: 679-686Crossref PubMed Scopus (81) Google Scholar). They that in the protein could account for the in Na/Pi cotransport in renal proximal (8Beck L. Karaplis A.S. Amizuka N. Hewson S. Ozawa H. Tenenhouse H.S. Proc. Natl. Acad. Sci. U. S. A. 1998; 95: 5372-5377Crossref PubMed Scopus (502) Google Scholar, 9Hoag H.H. Martel T. Gauthier C. Tenenhouse H.S. J. Clin. Invest. 1999; 104: 679-686Crossref PubMed Scopus (81) Google Scholar). the present suggest that type IIc is highly expressed in the renal cortex in weaning animals and a of high Pi low Pi transport activity in the from mice kidney be to the low expression of the type IIc Na/Pi studies are to the of type IIc Na/Pi cotransporter in the the by which the weaning kidney the high rates of required for the maintenance of a positive external balance. In this study, the type IIc was a growth-related renal Na/Pi cotransporter, which is highly expressed in the weaning kidney. K. K. and N.