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Vol. 31, No. 6, 2008
Issue release date: February 2009
Section title: Original Paper
Free Access
Kidney Blood Press Res 2008;31:421–432
(DOI:10.1159/000190788)

A Mutation in the Mouse Chd2 Chromatin Remodeling Enzyme Results in a Complex Renal Phenotype

Marfella C.G.A.a · Henninger N.b · LeBlanc S.E.a · Krishnan N.c · Garlick D.S.d · Holzman L.B.e · Imbalzano A.N.a
Departments of aCell Biology and bNeurology, cRenal Division, Department of Internal Medicine, and dDepartment of Cancer Biology, University of Massachusetts Medical School, Worcester, Mass., and eDivision of Nephrology, University of Michigan Medical School, Ann Arbor, Mich., USA
email Corresponding Author

Abstract

Background and Aims: Glomerular diseases are the third leading cause of kidney failure worldwide, behind only diabetes and hypertension. The molecular mechanisms underlying the cause of glomerular diseases are still largely unknown. The identification and characterization of new molecules associated with glomerular function should provide new insights into understanding the diverse group of glomerular diseases. The Chd2 protein belongs to a family of enzymes involved in ATP-dependent chromatin remodeling, suggesting that it likely functions as an epigenetic regulator of gene expression via the modification of chromatin structure. Methods: In this study, we present a detailed histomorphologic characterization of mice containing a mutation in the chromodomain helicase DNA-binding protein 2 (Chd2). Results: We show that Chd2-mutant mice present with glomerulopathy, proteinuria, and significantly impaired kidney function. Additionally, serum analysis revealed decreased hemoglobin and hematocrit levels in Chd2-mutant mice, suggesting that the glomerulopathy observed in these mice is associated with anemia. Conclusion: Collectively, the data suggest a role for the Chd2 protein in the maintenance of kidney function.

© 2009 S. Karger AG, Basel


  

Key Words

  • Chd2
  • Chromatin remodeling enzyme
  • Glomerular disease
  • Proteinuria
  • Anemia

References

  1. El Nahas M: The global challenge of chronic kidney disease. Kidney Int 2005;68:2918–2929.
  2. US Renal Data System, USRDS 2006 Annual Data Report: Atlas of End-Stage Renal Disease in the United States. Bethesda, National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, 2006.
  3. Miniño AM, Heron MP, Smith BL: Deaths: preliminary data for 2004. Natl Vital Stat Rep 2006;54:1–49.

    External Resources

  4. Lysaght MJ: Maintenance dialysis population dynamics: current trends and long-term implications. J Am Soc Nephrol 2002;13 (suppl 1):S37–S40.

    External Resources

  5. Xue JL, Ma JZ, Louis TA, Collins AJ: Forecast of the number of patients with end-stage renal disease in the United States to the year 2010. J Am Soc Nephrol 2001;12:2753–2758.
  6. Pavenstadt H, Kriz W, Kretzler M: Cell biology of the glomerular podocyte. Physiol Rev 2003;83:253–307.
  7. Kriz W, LeHir M: Pathways to nephron loss starting from glomerular diseases-insights from animal models. Kidney Int 2005;67:404–419.
  8. Saleem MA: Biology of the human podocyte. Nephron Exp Nephrol 2003;95:e87–e92.
  9. Shankland SJ: The podocyte’s response to injury: role in proteinuria and glomerulosclerosis. Kidney Int 2006;69:2131–2147.
  10. Levidiotis V, Power DA: New insights into the molecular biology of the glomerular filtration barrier and associated disease. Nephrology (Carlton) 2005;10:157–166.
  11. Boute N, Gribouval O, Roselli S, Benessy F, Lee H, Fuchshuber A, Dahan K, Gubler MC, Niaudet P, Antignac C: NPHS2, encoding the glomerular protein podocin, is mutated in autosomal recessive steroid-resistant nephrotic syndrome. Nat Genet 2000;24:349–354.
  12. Kestila M, Lenkkeri U, Mannikko M, Lamerdin J, McCready P, Putaala H, Ruotsalainen V, Morita T, Nissinen M, Herva R, Kashtan CE, Peltonen L, Holmberg C, Olsen A, Tryggvason K: Positionally cloned gene for a novel glomerular protein – nephrin – is mutated in congenital nephrotic syndrome. Mol Cell 1998;1:575–582.
  13. Asanuma K, Mundel P: The role of podocytes in glomerular pathobiology. Clin Exp Nephrol 2003;7:255–259.
  14. Meyrier A: Mechanisms of disease: focal segmental glomerulosclerosis. Nat Clin Pract Nephrol 2005;1:44–54.
  15. Roselli S, Gribouval O, Boute N, Sich M, Benessy F, Attie T, Gubler MC, Antignac C: Podocin localizes in the kidney to the slit diaphragm area. Am J Pathol 2002;160:131–139.
  16. Ruotsalainen V, Ljungberg P, Wartiovaara J, Lenkkeri U, Kestila M, Jalanko H, Holmberg C, Tryggvason K: Nephrin is specifically located at the slit diaphragm of glomerular podocytes. Proc Natl Acad Sci USA 1999;96:7962–7967.
  17. Kreidberg JA: Podocyte differentiation and glomerulogenesis. J Am Soc Nephrol 2003;14:806–814.
  18. Bates CM: Kidney development: regulatory molecules crucial to both mice and men. Mol Genet Metab 2000;71:391–396.
  19. Burrow CR: Regulatory molecules in kidney development. Pediatr Nephrol 2000;14:240–253.
  20. Marfella CG, Ohkawa Y, Coles AH, Garlick DS, Jones SN, Imbalzano AN: Mutation of the SNF2 family member Chd2 affects mouse development and survival. J Cell Physiol 2006;209:162–171.
  21. de la Serna IL, Ohkawa Y, Imbalzano AN: Chromatin remodelling in mammalian differentiation: lessons from ATP-dependent remodellers. Nat Rev Genet 2006;7:461–473.
  22. Marfella CG, Imbalzano AN: The Chd family of chromatin remodelers. Mutat Res 2007;618:30–40.
  23. Delmas V, Stokes DG, Perry RP: A mammalian DNA-binding protein that contains a chromodomain and an SNF2/SWI2-like helicase domain. Proc Natl Acad Sci USA 1993;90:2414–2418.
  24. Woodage T, Basrai MA, Baxevanis AD, Hieter P, Collins FS: Characterization of the CHD family of proteins. Proc Natl Acad Sci USA 1997;94:11472–11477.
  25. Marfella CG, Ohkawa Y, Coles AH, Garlick DS, Jones SN, Imbalzano AN: Mutation of the SNF2 family member Chd2 affects mouse development and survival (erratum). J Cell Physiol 2007;212:562.
  26. Stokes DG, Perry RP: DNA-binding and chromatin localization properties of CHD1. Mol Cell Biol 1995;15:2745–2753.
  27. Ge Q, Nilasena DS, O’Brien CA, Frank MB, Targoff IN: Molecular analysis of a major antigenic region of the 240-kD protein of Mi-2 autoantigen. J Clin Invest 1995;96:1730–1737.
  28. Seelig HP, Moosbrugger I, Ehrfeld H, Fink T, Renz M, Genth E: The major dermatomyositis-specific Mi-2 autoantigen is a presumed helicase involved in transcriptional activation. Arthritis Rheum 1995;38:1389–1399.
  29. Seelig HP, Renz M, Targoff IN, Ge Q, Frank MB: Two forms of the major antigenic protein of the dermatomyositis-specific Mi-2 autoantigen. Arthritis Rheum 1996;39:1769–1771.
  30. Kulkarni S, Nagarajan P, Wall J, Donovan DJ, Donell RL, Ligon AH, Venkatachalam S, Quade BJ: Disruption of chromodomain helicase DNA binding protein 2 (CHD2) causes scoliosis. Am J Med Genet A 2008;146A: 1117–1127.
  31. Roselli S, Heidet L, Sich M, Henger A, Kretzler M, Gubler MC, Antignac C: Early glomerular filtration defect and severe renal disease in podocin-deficient mice. Mol Cell Biol 2004;24:550–560.
  32. Ruggenenti P, Schieppati A, Remuzzi G: Progression, remission, regression of chronic renal diseases. Lancet 2001;357:1601–1608.
  33. Rostand SG, Brunzell JD, Cannon RO 3rd, Victor RG: Cardiovascular complications in renal failure. J Am Soc Nephrol 1991;2:1053–1062.
  34. Giunti S, Barit D, Cooper ME: Mechanisms of diabetic nephropathy: role of hypertension. Hypertension 2006;48:519–526.
  35. Rossert J, Froissart M: Role of anemia in progression of chronic kidney disease. Semin Nephrol 2006;26:283–289.
  36. Krantz SB: Erythropoietin. Blood 1991;77:419–434.
  37. Ratcliffe PJ: Molecular biology of erythropoietin. Kidney Int 1993;44:887–904.
  38. Thompson PM, Gotoh T, Kok M, White PS, Brodeur GM: CHD5, a new member of the chromodomain gene family, is preferentially expressed in the nervous system. Oncogene 2003;22:1002–1011.
  39. White PS, Thompson PM, Gotoh T, Okawa ER, Igarashi J, Kok M, Winter C, Gregory SG, Hogarty MD, Maris JM, Brodeur GM: Definition and characterization of a region of 1p36.3 consistently deleted in neuroblastoma. Oncogene 2005;24:2684–2694.
  40. Vissers LE, van Ravenswaaij CM, Admiraal R, Hurst JA, de Vries BB, Janssen IM, van der Vliet WA, Huys EH, de Jong PJ, Hamel BC, Schoenmakers EF, Brunner HG, Veltman JA, van Kessel AG: Mutations in a new member of the chromodomain gene family cause CHARGE syndrome. Nat Genet 2004;36:955–957.
  41. Pisoni RL, Bragg-Gresham JL, Young EW, Akizawa T, Asano Y, Locatelli F, Bommer J, Cruz JM, Kerr PG, Mendelssohn DC, Held PJ, Port FK: Anemia management and outcomes from 12 countries in the Dialysis Outcomes and Practice Patterns Study (DOPPS). Am J Kidney Dis 2004;44:94–111.
  42. Ware JE Jr, Sherbourne CD: The MOS 36-item short-form health survey (SF-36). I. Conceptual framework and item selection. Med Care 1992;30:473–483.

  

Author Contacts

Anthony N. Imbalzano
Department of Cell Biology, University of Massachusetts Medical School
55 Lake Avenue North, Worcester, MA 01655 (USA)
Tel. +1 508 856 1029, Fax +1 508 856 5612
E-Mail anthony.imbalzano@umassmed.edu

  

Article Information

Received: September 30, 2008
Accepted: November 17, 2008
Published online: January 14, 2009
Number of Print Pages : 12
Number of Figures : 5, Number of Tables : 2, Number of References : 42

  

Publication Details

Kidney and Blood Pressure Research

Vol. 31, No. 6, Year 2008 (Cover Date: February 2009)

Journal Editor: Wanner C. (Würzburg)
ISSN: 1420-4096 (Print), eISSN: 1423-0143 (Online)

For additional information: http://www.karger.com/KBR


Copyright / Drug Dosage / Disclaimer

Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in goverment regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

Abstract

Background and Aims: Glomerular diseases are the third leading cause of kidney failure worldwide, behind only diabetes and hypertension. The molecular mechanisms underlying the cause of glomerular diseases are still largely unknown. The identification and characterization of new molecules associated with glomerular function should provide new insights into understanding the diverse group of glomerular diseases. The Chd2 protein belongs to a family of enzymes involved in ATP-dependent chromatin remodeling, suggesting that it likely functions as an epigenetic regulator of gene expression via the modification of chromatin structure. Methods: In this study, we present a detailed histomorphologic characterization of mice containing a mutation in the chromodomain helicase DNA-binding protein 2 (Chd2). Results: We show that Chd2-mutant mice present with glomerulopathy, proteinuria, and significantly impaired kidney function. Additionally, serum analysis revealed decreased hemoglobin and hematocrit levels in Chd2-mutant mice, suggesting that the glomerulopathy observed in these mice is associated with anemia. Conclusion: Collectively, the data suggest a role for the Chd2 protein in the maintenance of kidney function.

© 2009 S. Karger AG, Basel


  

Author Contacts

Anthony N. Imbalzano
Department of Cell Biology, University of Massachusetts Medical School
55 Lake Avenue North, Worcester, MA 01655 (USA)
Tel. +1 508 856 1029, Fax +1 508 856 5612
E-Mail anthony.imbalzano@umassmed.edu

  

Article Information

Received: September 30, 2008
Accepted: November 17, 2008
Published online: January 14, 2009
Number of Print Pages : 12
Number of Figures : 5, Number of Tables : 2, Number of References : 42

  

Publication Details

Kidney and Blood Pressure Research

Vol. 31, No. 6, Year 2008 (Cover Date: February 2009)

Journal Editor: Wanner C. (Würzburg)
ISSN: 1420-4096 (Print), eISSN: 1423-0143 (Online)

For additional information: http://www.karger.com/KBR


Article / Publication Details

First-Page Preview
Abstract of Original Paper

Received: 9/30/2008
Accepted: 11/17/2008
Published online: 1/14/2009
Issue release date: February 2009

Number of Print Pages: 12
Number of Figures: 5
Number of Tables: 2

ISSN: 1420-4096 (Print)
eISSN: 1423-0143 (Online)

For additional information: http://www.karger.com/KBR


Copyright / Drug Dosage

Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in goverment regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

References

  1. El Nahas M: The global challenge of chronic kidney disease. Kidney Int 2005;68:2918–2929.
  2. US Renal Data System, USRDS 2006 Annual Data Report: Atlas of End-Stage Renal Disease in the United States. Bethesda, National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, 2006.
  3. Miniño AM, Heron MP, Smith BL: Deaths: preliminary data for 2004. Natl Vital Stat Rep 2006;54:1–49.

    External Resources

  4. Lysaght MJ: Maintenance dialysis population dynamics: current trends and long-term implications. J Am Soc Nephrol 2002;13 (suppl 1):S37–S40.

    External Resources

  5. Xue JL, Ma JZ, Louis TA, Collins AJ: Forecast of the number of patients with end-stage renal disease in the United States to the year 2010. J Am Soc Nephrol 2001;12:2753–2758.
  6. Pavenstadt H, Kriz W, Kretzler M: Cell biology of the glomerular podocyte. Physiol Rev 2003;83:253–307.
  7. Kriz W, LeHir M: Pathways to nephron loss starting from glomerular diseases-insights from animal models. Kidney Int 2005;67:404–419.
  8. Saleem MA: Biology of the human podocyte. Nephron Exp Nephrol 2003;95:e87–e92.
  9. Shankland SJ: The podocyte’s response to injury: role in proteinuria and glomerulosclerosis. Kidney Int 2006;69:2131–2147.
  10. Levidiotis V, Power DA: New insights into the molecular biology of the glomerular filtration barrier and associated disease. Nephrology (Carlton) 2005;10:157–166.
  11. Boute N, Gribouval O, Roselli S, Benessy F, Lee H, Fuchshuber A, Dahan K, Gubler MC, Niaudet P, Antignac C: NPHS2, encoding the glomerular protein podocin, is mutated in autosomal recessive steroid-resistant nephrotic syndrome. Nat Genet 2000;24:349–354.
  12. Kestila M, Lenkkeri U, Mannikko M, Lamerdin J, McCready P, Putaala H, Ruotsalainen V, Morita T, Nissinen M, Herva R, Kashtan CE, Peltonen L, Holmberg C, Olsen A, Tryggvason K: Positionally cloned gene for a novel glomerular protein – nephrin – is mutated in congenital nephrotic syndrome. Mol Cell 1998;1:575–582.
  13. Asanuma K, Mundel P: The role of podocytes in glomerular pathobiology. Clin Exp Nephrol 2003;7:255–259.
  14. Meyrier A: Mechanisms of disease: focal segmental glomerulosclerosis. Nat Clin Pract Nephrol 2005;1:44–54.
  15. Roselli S, Gribouval O, Boute N, Sich M, Benessy F, Attie T, Gubler MC, Antignac C: Podocin localizes in the kidney to the slit diaphragm area. Am J Pathol 2002;160:131–139.
  16. Ruotsalainen V, Ljungberg P, Wartiovaara J, Lenkkeri U, Kestila M, Jalanko H, Holmberg C, Tryggvason K: Nephrin is specifically located at the slit diaphragm of glomerular podocytes. Proc Natl Acad Sci USA 1999;96:7962–7967.
  17. Kreidberg JA: Podocyte differentiation and glomerulogenesis. J Am Soc Nephrol 2003;14:806–814.
  18. Bates CM: Kidney development: regulatory molecules crucial to both mice and men. Mol Genet Metab 2000;71:391–396.
  19. Burrow CR: Regulatory molecules in kidney development. Pediatr Nephrol 2000;14:240–253.
  20. Marfella CG, Ohkawa Y, Coles AH, Garlick DS, Jones SN, Imbalzano AN: Mutation of the SNF2 family member Chd2 affects mouse development and survival. J Cell Physiol 2006;209:162–171.
  21. de la Serna IL, Ohkawa Y, Imbalzano AN: Chromatin remodelling in mammalian differentiation: lessons from ATP-dependent remodellers. Nat Rev Genet 2006;7:461–473.
  22. Marfella CG, Imbalzano AN: The Chd family of chromatin remodelers. Mutat Res 2007;618:30–40.
  23. Delmas V, Stokes DG, Perry RP: A mammalian DNA-binding protein that contains a chromodomain and an SNF2/SWI2-like helicase domain. Proc Natl Acad Sci USA 1993;90:2414–2418.
  24. Woodage T, Basrai MA, Baxevanis AD, Hieter P, Collins FS: Characterization of the CHD family of proteins. Proc Natl Acad Sci USA 1997;94:11472–11477.
  25. Marfella CG, Ohkawa Y, Coles AH, Garlick DS, Jones SN, Imbalzano AN: Mutation of the SNF2 family member Chd2 affects mouse development and survival (erratum). J Cell Physiol 2007;212:562.
  26. Stokes DG, Perry RP: DNA-binding and chromatin localization properties of CHD1. Mol Cell Biol 1995;15:2745–2753.
  27. Ge Q, Nilasena DS, O’Brien CA, Frank MB, Targoff IN: Molecular analysis of a major antigenic region of the 240-kD protein of Mi-2 autoantigen. J Clin Invest 1995;96:1730–1737.
  28. Seelig HP, Moosbrugger I, Ehrfeld H, Fink T, Renz M, Genth E: The major dermatomyositis-specific Mi-2 autoantigen is a presumed helicase involved in transcriptional activation. Arthritis Rheum 1995;38:1389–1399.
  29. Seelig HP, Renz M, Targoff IN, Ge Q, Frank MB: Two forms of the major antigenic protein of the dermatomyositis-specific Mi-2 autoantigen. Arthritis Rheum 1996;39:1769–1771.
  30. Kulkarni S, Nagarajan P, Wall J, Donovan DJ, Donell RL, Ligon AH, Venkatachalam S, Quade BJ: Disruption of chromodomain helicase DNA binding protein 2 (CHD2) causes scoliosis. Am J Med Genet A 2008;146A: 1117–1127.
  31. Roselli S, Heidet L, Sich M, Henger A, Kretzler M, Gubler MC, Antignac C: Early glomerular filtration defect and severe renal disease in podocin-deficient mice. Mol Cell Biol 2004;24:550–560.
  32. Ruggenenti P, Schieppati A, Remuzzi G: Progression, remission, regression of chronic renal diseases. Lancet 2001;357:1601–1608.
  33. Rostand SG, Brunzell JD, Cannon RO 3rd, Victor RG: Cardiovascular complications in renal failure. J Am Soc Nephrol 1991;2:1053–1062.
  34. Giunti S, Barit D, Cooper ME: Mechanisms of diabetic nephropathy: role of hypertension. Hypertension 2006;48:519–526.
  35. Rossert J, Froissart M: Role of anemia in progression of chronic kidney disease. Semin Nephrol 2006;26:283–289.
  36. Krantz SB: Erythropoietin. Blood 1991;77:419–434.
  37. Ratcliffe PJ: Molecular biology of erythropoietin. Kidney Int 1993;44:887–904.
  38. Thompson PM, Gotoh T, Kok M, White PS, Brodeur GM: CHD5, a new member of the chromodomain gene family, is preferentially expressed in the nervous system. Oncogene 2003;22:1002–1011.
  39. White PS, Thompson PM, Gotoh T, Okawa ER, Igarashi J, Kok M, Winter C, Gregory SG, Hogarty MD, Maris JM, Brodeur GM: Definition and characterization of a region of 1p36.3 consistently deleted in neuroblastoma. Oncogene 2005;24:2684–2694.
  40. Vissers LE, van Ravenswaaij CM, Admiraal R, Hurst JA, de Vries BB, Janssen IM, van der Vliet WA, Huys EH, de Jong PJ, Hamel BC, Schoenmakers EF, Brunner HG, Veltman JA, van Kessel AG: Mutations in a new member of the chromodomain gene family cause CHARGE syndrome. Nat Genet 2004;36:955–957.
  41. Pisoni RL, Bragg-Gresham JL, Young EW, Akizawa T, Asano Y, Locatelli F, Bommer J, Cruz JM, Kerr PG, Mendelssohn DC, Held PJ, Port FK: Anemia management and outcomes from 12 countries in the Dialysis Outcomes and Practice Patterns Study (DOPPS). Am J Kidney Dis 2004;44:94–111.
  42. Ware JE Jr, Sherbourne CD: The MOS 36-item short-form health survey (SF-36). I. Conceptual framework and item selection. Med Care 1992;30:473–483.