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Expression of renal and intestinal Na/Pi cotransporters in the absence of GABARAP

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Abstract

We have recently shown that the abundance of the renal sodium (Na)/inorganic phosphate (Pi) cotransporter NaPi-IIa is increased in the absence of the GABAA receptor-associated protein (GABARAP). Accordingly, GABARAP-deficient mice have a reduced urinary excretion of Pi. However, their circulating levels of Pi do not differ from wild-type animals, suggesting the presence of a compensatory mechanism responsible for keeping serum Pi values constant. Here, we aimed first to identify the molecular basis of this compensation by analyzing the expression of Na/Pi cotransporters known to be expressed in the kidney and intestine. We found that, in the kidney, the upregulation of NaPi-IIa is not accompanied by changes on the expression of either NaPi-IIc or PiT2, the other cotransporters known to participate in renal Pi reabsorption. In contrast, the intestinal expression of NaPi-IIb is downregulated in mutant animals, suggesting that a reduced intestinal absorption of Pi could contribute to maintain a normophosphatemic status despite the increased renal retention. The second goal of this work was to study whether the alterations on the expression of NaPi-IIa induced by chronic dietary Pi are impaired in the absence of GABARAP. Our data indicate that, in response to high Pi diets, GABARAP-deficient mice downregulate the expression of NaPi-IIa to levels comparable to those seen in wild-type animals. However, in response to low Pi diets, the upregulation of NaPi-IIa is greater in the mutant mice. Thus, both the basal expression and the dietary-induced upregulation of NaPi-IIa are increased in the absence of GABARAP.

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References

  1. Bai L, Collins JF, Ghishan FK (2000) Cloning and characterization of a type III Na-dependent phosphate cotransporter from mouse intestine. Am J Physiol Cell Physiol 279(4):C1135–C1143

    CAS  PubMed  Google Scholar 

  2. Beck L, Karaplis AC, Amizuka N, Hewson AS, Ozawa H, Tenenhouse HS (1998) Targeted inactivation of Npt2 in mice leads to severe renal phosphate wasting, hypercalciuria, and skeletal abnormalities. Proc Natl Acad Sci U S A 95(9):5372–5377

    Article  CAS  PubMed  Google Scholar 

  3. Bergwitz C, Roslin NM, Tieder M, Loredo-Osti JC, Bastepe M, Abu-Zahra H, Frappier D, Burkett K, Carpenter TO, Anderson D, Garabedian M, Sermet I, Fujiwara TM, Morgan K, Tenenhouse HS, Juppner H (2006) SLC34A3 mutations in patients with hereditary hypophosphatemic rickets with hypercalciuria predict a key role for the sodium–phosphate cotransporter NaPi-IIc in maintaining phosphate homeostasis. Am J Hum Genet 78(2):179–192

    Article  CAS  PubMed  Google Scholar 

  4. Biber J, Stieger B, Stange G, Murer H (2007) Isolation of renal proximal tubular brush-border membranes. Nat Protoc 2(6):1356–1359

    Article  CAS  PubMed  Google Scholar 

  5. Collins JF, Bai L, Ghishan FK (2004) The SLC20 family of proteins: dual functions as sodium–phosphate cotransporters and viral receptors. Pflugers Arch 447(5):647–652

    Article  CAS  PubMed  Google Scholar 

  6. Dawson TP, Gandhi R, Le Hir M, Kaissling B (1989) Ecto-5′-nucleotidase: localization in rat kidney by light microscopic histochemical and immunohistochemical methods. J Histochem Cytochem 37:39–47

    CAS  PubMed  Google Scholar 

  7. Forster IC, Hernando N, Biber J, Murer H (2006) Proximal tubular handling of phosphate: a molecular perspective. Kidney Int 70(9):1548–1559

    Article  CAS  PubMed  Google Scholar 

  8. Gisler SM, Stagljar I, Traebert M, Bacic D, Biber J, Murer H (2001) Interaction of the type IIa Na/Pi cotransporter with PDZ proteins. J Biol Chem 276(12):9206–9213

    Article  CAS  PubMed  Google Scholar 

  9. Gupta A, Tenenhouse HS, Hoag HM, Wang D, Khadeer MA, Namba N, Feng X, Hruska KA (2001) Identification of the type II Na(+)–Pi cotransporter (Npt2) in the osteoclast and the skeletal phenotype of Npt2−/− mice. Bone 29(5):467–476

    Article  CAS  PubMed  Google Scholar 

  10. Hattenhauer O, Traebert M, Murer H, Biber J (1999) Regulation of small intestinal Na–P(i) type IIb cotransporter by dietary phosphate intake. Am J Physiol 277(4 Pt 1):G756–G762

    CAS  PubMed  Google Scholar 

  11. Hernando N, Déliot N, Gisler SM, Lederer E, Weinman EJ, Biber J, Murer H (2002) PDZ-domain interactions and apical expression of type IIa Na/P(i) cotransporters. Proc Natl Acad Sci U S A 99(18):11957–11962

    Article  CAS  PubMed  Google Scholar 

  12. Hilfiker H, Hattenhauer O, Traebert M, Forster I, Murer H, Biber J (1998) Characterization of a murine type II sodium–phosphate cotransporter expressed in mammalian small intestine. Proc Natl Acad Sci U S A 95(24):14564–14569

    Article  CAS  PubMed  Google Scholar 

  13. Ichikawa S, Sorenson AH, Imel EA, Friedman NE, Gertner JM, Econs MJ (2006) Intronic deletions in the SLC34A3 gene cause hereditary hypophosphatemic rickets with hypercalciuria. J Clin Endocrinol Metab 91(10):4022–4027

    Article  CAS  PubMed  Google Scholar 

  14. Levi M, Lötscher M, Sorribas V, Custer M, Arar M, Kaissling B, Murer H, Biber J (1994) Cellular mechanisms of acute and chronic adaptation of rat renal P(i) transporter to alterations in dietary P(i). Am J Physiol 267(5 Pt 2):F900–F908

    CAS  PubMed  Google Scholar 

  15. Liesegang A, Loch L, Bürgi E, Risteli J (2005) Influence of phytase added to a vegetarian diet on bone metabolism in pregnant and lactating sows. J Anim Physiol and Anim Nutr 89(3-6):120–128

    Article  CAS  Google Scholar 

  16. Lorenz-Depiereux B, Benet-Pages A, Eckstein G, Tenenbaum-Rakover Y, Wagenstaller J, Tiosano D, Gershoni-Baruch R, Albers N, Lichtner P, Schnabel D, Hochberg Z, Strom TM (2006) Hereditary hypophosphatemic rickets with hypercalciuria is caused by mutations in the sodium–phosphate cotransporter gene SLC34A3. Am J Hum Genet 78(2):193–201

    Article  CAS  PubMed  Google Scholar 

  17. Lötscher M, Wilson P, Nguyen S, Kaissling B, Biber J, Murer H, Levi M (1996) New aspects of adaptation of rat renal Na–Pi cotransporter to alterations in dietary phosphate. Kidney Int 49(4):1012–1018

    Article  PubMed  Google Scholar 

  18. Lundquist P, Murer H, Biber J (2007) Type II Na+–Pi cotransporters in osteoblast mineral formation: regulation by inorganic phosphate. Cell Physiol Biochem 19(1–4):43–56

    Article  CAS  PubMed  Google Scholar 

  19. Madjdpour C, Bacic D, Kaissling B, Murer H, Biber J (2004) Segment-specific expression of sodium–phosphate cotransporters NaPi-IIa and -IIc and interacting proteins in mouse renal proximal tubules. Pflugers Arch 448(4):402–410

    CAS  PubMed  Google Scholar 

  20. Miller WL, Portale AA (2000) Vitamin D 1α-hydroxylase. Trends Endocrinol Metab 11(8):315–319

    Article  CAS  PubMed  Google Scholar 

  21. Ohkido I, Segawa H, Yanagida R, Nakamura M, Miyamoto K (2003) Cloning, gene structure and dietary regulation of the type-IIc Na/Pi cotransporter in the mouse kidney. Pflugers Arch 446(1):106–115

    CAS  PubMed  Google Scholar 

  22. O’Sullivan GA, Kneussel M, Elazar Z, Betz H (2005) GABARAP is not essential for GABA receptor targeting to the synapse. Eur J NeuroSci 22(10):2644–2648

    Article  PubMed  Google Scholar 

  23. Radanovic T, Wagner CA, Murer H, Biber J (2005) Regulation of intestinal phosphate transport. I. Segmental expression and adaptation to low-P(i) diet of the type IIb Na(+)–P(i) cotransporter in mouse small intestine. Am J Physiol Gastrointest Liver Physiol 288(3):G496–G500

    Article  CAS  PubMed  Google Scholar 

  24. Reining SC, Gisler SM, Fuster D, Moe OW, O’Sullivan GA, Betz H, Biber J, Murer H, Hernando N (2009) GABARAP deficiency modulates expression of NaPi-IIa in renal brush-border membranes. Am J Physiol Renal Physiol 296(5):F1118–F1128

    Article  CAS  PubMed  Google Scholar 

  25. Ritthaler T, Traebert M, Lötscher M, Biber J, Murer H, Kaissling B (1999) Effects of phosphate intake on distribution of type II Na/Pi cotransporter mRNA in rat kidney. Kidney Int 55(3):976–983

    Article  CAS  PubMed  Google Scholar 

  26. Sabbagh Y, O’Brien SP, Song W, Boulanger JH, Stockmann A, Arbeeny C, Schiavi SC (2009) Intestinal Npt2b plays a major role in phosphate absorption and homeostasis. J Am Soc Nephrol 20(11):2348–2358

    Article  CAS  PubMed  Google Scholar 

  27. Segawa H, Kaneko I, Takahashi A, Kuwahata M, Ito M, Ohkido I, Tatsumi S, Miyamoto K (2002) Growth-related renal type II Na/Pi cotransporter. J Biol Chem 277(22):19665–19672

    Article  CAS  PubMed  Google Scholar 

  28. Segawa H, Yamanaka S, Ito M, Kuwahata M, Shono M, Yamamoto T, Miyamoto K (2005) Internalization of renal type IIc Na–Pi cotransporter in response to a high-phosphate diet. Am J Physiol Renal Physiol 288(3):F587–F596

    Article  CAS  PubMed  Google Scholar 

  29. Segawa H, Onitsuka A, Kuwahata M, Hanabusa E, Furutani J, Kaneko I, Tomoe Y, Aranami F, Matsumoto N, Ito M, Matsumoto M, Li M, Amizuka N, Miyamoto K (2009) Type IIc sodium-dependent phosphate transporter regulates calcium metabolism. J Am Soc Nephrol 20(1):104–113

    Article  CAS  PubMed  Google Scholar 

  30. Shenolikar S, Voltz JW, Minkoff CM, Wade JB, Weinman EJ (2002) 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(17):11470–11475

    Article  CAS  PubMed  Google Scholar 

  31. Shibasaki Y, Etoh N, Hayasaka M, Takahashi MO, Kakitani M, Yamashita T, Tomizuka K, Hanaoka K (2009) Targeted deletion of the type IIb Na(+)-dependent Pi-co-transporter, NaPi-IIb, results in early embryonic lethality. Biochem Biophys Res Commun 381(4):482–486

    Article  CAS  PubMed  Google Scholar 

  32. Tenenhouse HS, Gauthier C, Martel J, Hoenderop JG, Hartog A, Meyer MH, Meyer RA Jr, Bindels RJ (2002) Na/P(i) cotransporter (Npt2) gene disruption increases duodenal calcium absorption and expression of epithelial calcium channels 1 and 2. Pflugers Arch 444(5):670–676

    Article  CAS  PubMed  Google Scholar 

  33. Villa-Bellosta R, Ravera S, Sorribas V, Stange G, Levi M, Murer H, Biber J, Forster IC (2009) 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(4):F691–F699

    Article  CAS  PubMed  Google Scholar 

  34. Xu H, Bai L, Collins JF, Ghishan FK (2002) Age-dependent regulation of rat intestinal type IIb sodium–phosphate cotransporter by 1, 25-(OH)(2) vitamin D(3). Am J Physiol Cell Physiol 282(3):C487–C493

    CAS  PubMed  Google Scholar 

  35. Zoidis E, Ghirlanda-Keller C, Gosteli-Peter M, Zapf J, Schmid C (2004) Regulation of phosphate (Pi) transport and NaPi-III transporter (Pit-1) mRNA in rat osteoblasts. J Endocrinol 181(3):531–540

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

We thank Dr. V. Sorribas (Zaragoza, Spain) for kindly providing us with the anti-PiT2 antibody. This work was supported by the Swiss National Science Foundation Grant 44342003 (to HM) and the Sixth European Frame Work EuReGene Project Grant 005085 (to HM). SC Reining was supported by a Ph.D. student fellowship from the University Research Priority Program “Integrative Human Physiology” from the University of Zurich.

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Authors and Affiliations

  1. Institute of Physiology, University of Zurich, Winterthurerstr. 190, 8057, Zurich, Switzerland

    Sonja C. Reining, Jürg Biber, Heini Murer & Nati Hernando

  2. Zurich Center for Integrative Human Physiology (ZIHP), University of Zurich, Winterthurerstr. 190, 8057, Zurich, Switzerland

    Sonja C. Reining, Jürg Biber, Heini Murer & Nati Hernando

  3. Institute of Animal Nutrition, Vetsuisse Faculty, University of Zurich, Winterthurerstr. 260, 8057, Zurich, Switzerland

    Annette Liesegang

  4. Department of Neurochemistry, Max-Planck Institute for Brain Research, Deutschordenstr 46, 60528, Frankfurt am Main, Germany

    Heinrich Betz

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  1. Sonja C. Reining
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Correspondence to Nati Hernando.

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Reining, S.C., Liesegang, A., Betz, H. et al. Expression of renal and intestinal Na/Pi cotransporters in the absence of GABARAP. Pflugers Arch - Eur J Physiol 460, 207–217 (2010). https://doi.org/10.1007/s00424-010-0832-2

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  • DOI: https://doi.org/10.1007/s00424-010-0832-2

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