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Abstract

Angiotensin -converting enzyme 2 (ACE2) is a regulator of the renin angiotensin system involved in acute lung failure, cardiovascular functions and severe acute respiratory syndrome (SARS) infections in mammals1,2,3. A gene encoding a homologue to ACE2, termed collectrin (Tmem27), has been identified in immediate proximity to the ace2 locus4. The in vivo function of collectrin was unclear. Here we report that targeted disruption of collectrin in mice results in a severe defect in renal amino acid uptake owing to downregulation of apical amino acid transporters in the kidney. Collectrin associates with multiple apical transporters and defines a novel group of renal amino acid transporters. Expression of collectrin in Xenopus oocytes and Madin–Darby canine kidney (MDCK) cells enhances amino acid transport by the transporter B0AT1. These data identify collectrin as a key regulator of renal amino acid uptake.

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References

  1. 1.

    et al. Angiotensin-converting enzyme 2 protects from severe acute lung failure. Nature 436, 112–116 (2005)

  2. 2.

    et al. Angiotensin-converting enzyme 2 is an essential regulator of heart function. Nature 417, 822–828 (2002)

  3. 3.

    et al. A crucial role of angiotensin converting enzyme 2 (ACE2) in SARS coronavirus-induced lung injury. Nature Med. 11, 875–879 (2005)

  4. 4.

    et al. Collectrin, a collecting duct-specific transmembrane glycoprotein, is a novel homolog of ACE2 and is developmentally regulated in embryonic kidneys. J. Biol. Chem. 276, 17132–17139 (2001)

  5. 5.

    et al. The HNF-1 target Collectrin controls insulin exocytosis by SNARE complex formation. Cell Metabol. 2, 373–384 (2005)

  6. 6.

    , , & Tmem27: A cleaved and shed plasma membrane protein that stimulates pancreatic β cell proliferation. Cell Metabol. 2, 385–397 (2005)

  7. 7.

    , & A cre-transgenic mouse strain for the ubiquitous deletion of loxP-flanked gene segments including deletion in germ cells. Nucleic Acids Res. 23, 5080–5081 (1995)

  8. 8.

    , & Hereditary tyrosinemia: an endoplasmic reticulum stress disorder?. Med. Sci. 10, 976–980 (2003)

  9. 9.

    et al. Animal models reveal pathophysiologies of tyrosinemias. J. Nutr. 3, 2063S–2067S (2003)

  10. 10.

    et al. Novel renal amino acid transporters. Annu. Rev. Physiol. 67, 557–572 (2005)

  11. 11.

    & Topology of microvillar membrance hydrolases of kidney and intestine. Physiol. Rev. 62, 91–128 (1982)

  12. 12.

    et al. Luminal kidney and intestine SLC6 amino acid transporters of B0AT-cluster and their tissue distribution in Mus musculus. Am. J. Physiol. Renal Physiol. 290, F376–F383 (2006)

  13. 13.

    et al. Molecular cloning of mouse amino acid transport system B0, a neutral amino acid transporter related to Hartnup disorder. J. Biol. Chem. 279, 24467–24476 (2004)

  14. 14.

    et al. Mutations in SLC6A19, encoding B0AT1, cause Hartnup disorder. Nature Genet. 6, 999–1002 (2004)

  15. 15.

    et al. Hartnup disorder is caused by mutations in the gene encoding the neutral amino acid transporter SLC6A19. Nature Genet. 6, 1003–1007 (2004)

  16. 16.

    , , , & Steady-state kinetic characterization of the mouse BoAT1 sodium-dependent neutral amino acid transporter. Eur. J. Physiol. 451, 338–348 (2005)

  17. 17.

    et al. Molecular cloning of the mouse IMINO system: an Na+- and Cl--dependent proline transporter. Biochem. J. Mar. 15, 417–422 (2005)

  18. 18.

    , & Glutamate transporter EAAC-1-deficient mice develop dicarboxylic aminoaciduria and behavioral abnormalities but no neurodegeneration. EMBO J. 16, 3822–3832 (1997)

  19. 19.

    et al. Slc7a9-deficient mice develop cystinuria non-I and cystine urolithiasis. Hum. Mol. Genet. 12, 2097–2108 (2003)

  20. 20.

    , & Function and structure of heterodimeric amino acid transporters. Am. J. Physiol. Cell Physiol. 81, C1077–C1093 (2001)

  21. 21.

    , , , & A rapid method for the isolation of kidney brush border membranes. Biochim. Biophys. Acta 554, 259–263 (1979)

  22. 22.

    et al. Neutral amino acid transport mediated by ortholog of imino acid transporter SIT1/SLC6A20 in opossum kidney cells. Am. J. Physiol. Renal Physiol. 290, F880–F887 (2006)

  23. 23.

    , , , & Functional cooperation of epithelial heteromeric amino acid transporters expressed in Madin–Darby canine kidney cells. J. Biol. Chem. 278, 1316–1322 (2003)

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Acknowledgements

We thank M. J. Crackower, A. Leibbrandt, Y. Imai, K. Kuba and many others for their contributions. Supported by grants from The National Bank of Austria, The Austrian Ministry of Science and Education, IMBA, an EU Marie Curie Excellence grant, and EUGeneHeart to J.M.P., from the Swiss National Science Foundation to F.V. and EUGINDAT to F.V. and C.A.W.

Author Contributions U.D, R.S., C.R., C.B., G.S., A.R., S.A., J.A.P., D.S., S.M.R.C., V.M., T.R. and C.A.W. performed experiments. U.D., F.V., C.A.W. and J.M.P. planned experiments and wrote the manuscript.

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  1. IMBA, Institute for Molecular Biotechnology of the Austrian Academy of Sciences, Dr. Bohr-Gasse 3, A-1030, Vienna, Austria

    • Ursula Danilczyk
    • , Renu Sarao
    • , J. Andrew Pospisilik
    •  & Josef M. Penninger
  2. Institute of Physiology and Center for Integrative Human Physiology, University of Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland

    • Christine Remy
    • , Chahira Benabbas
    • , Gerti Stange
    • , Dustin Singer
    • , Simone M. R. Camargo
    • , Victoria Makrides
    • , Tamara Ramadan
    • , Francois Verrey
    •  & Carsten A. Wagner
  3. Department of Chemical Ecology and Ecosystem Research, Center of Ecology, University of Vienna, Althanstrasse 14, A-1090 Vienna, Austria

    • Andreas Richter
  4. The Hospital for Sick Children, 555 University Avenue, Toronto, Ontario M5G 1X8, Canada

    • Sudha Arya

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Reprints and permissions information is available at www.nature.com/reprints. The authors declare no competing financial interests.

Corresponding authors

Correspondence to Carsten A. Wagner or Josef M. Penninger.

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https://doi.org/10.1038/nature05475

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