Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

Common variation in GPC5 is associated with acquired nephrotic syndrome

Nature Genetics volume 43, pages 459–463 (2011)Cite this article

Subjects

Abstract

Severe proteinuria is a defining factor of nephrotic syndrome irrespective of the etiology. Investigation of congenital nephrotic syndrome has shown that dysfunction of glomerular epithelial cells (podocytes) plays a crucial role in this disease1. Acquired nephrotic syndrome is also assumed to be associated with podocyte injury. Here we identify an association between variants in GPC5, encoding glypican-5, and acquired nephrotic syndrome through a genome-wide association study and replication analysis (P value under a recessive model (Prec) = 6.0 × 10−11, odds ratio = 2.54). We show that GPC5 is expressed in podocytes and that the risk genotype is associated with higher expression. We further show that podocyte-specific knockdown and systemic short interfering RNA injection confers resistance to podocyte injury in mouse models of nephrosis. This study identifies GPC5 as a new susceptibility gene for nephrotic syndrome and implicates GPC5 as a promising therapeutic target for reducing podocyte vulnerability in glomerular disease.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Association P value plot of the GPC5 region in nephrotic syndrome and LD construction.
Figure 2: Association between rs16946160 genotype and GPC5 mRNA expression and localization of expression in human kidney.
Figure 3: In vitro functional analysis of GPC5.
Figure 4: PAN-FGF2–induced nephrotic syndrome in wild-type sibling (sib) mice is attenuated by Gpc5 conditional knockdown.
Figure 5: siRNA against Gpc5 ameliorates PAN-FGF2–induced nephrotic syndrome and Adriamycin-induced albuminuria.

Similar content being viewed by others

References

  1. Somlo, S. & Mundel, P. Getting a foothold in nephrotic syndrome. Nat. Genet. 24, 333–335 (2000).

    Article  CAS  Google Scholar 

  2. Reiser, J. et al. Induction of B7–1 in podocytes is associated with nephrotic syndrome. J. Clin. Invest. 113, 1390–1397 (2004).

    Article  CAS  Google Scholar 

  3. Mathieson, P.W. Update on the podocyte. Curr. Opin. Nephrol. Hypertens. 18, 206–211 (2009).

    Article  Google Scholar 

  4. Johnstone, D.B. & Holzman, L.B. Clinical impact of research on the podocyte slit diaphragm. Nat. Clin. Pract. Nephrol. 2, 271–282 (2006).

    Article  CAS  Google Scholar 

  5. Kawachi, H. et al. Slit diaphragm dysfunction in proteinuric states: identification of novel therapeutic targets for nephrotic syndrome. Clin. Exp. Nephrol. 13, 275–280 (2009).

    Article  CAS  Google Scholar 

  6. Doi, K., Okamoto, K., Tokunaga, K., Fujita, T. & Noiri, E. Genome study of kidney disease in the age of post genome-sequencing. Endocr. Metab. Immune Disord. Drug Targets 8, 173–183 (2008).

    Article  CAS  Google Scholar 

  7. Kopp, J.B. et al. MYH9 is a major-effect risk gene for focal segmental glomerulosclerosis. Nat. Genet. 40, 1175–1184 (2008).

    Article  CAS  Google Scholar 

  8. Freedman, B.I. et al. The apolipoprotein L1 (APOL1) gene and nondiabetic nephropathy in African Americans. J. Am. Soc. Nephrol. 21, 1422–1426 (2010).

    Article  CAS  Google Scholar 

  9. Genovese, G. et al. Association of trypanolytic ApoL1 variants with kidney disease in African Americans. Science 329, 841–845 (2010).

    Article  CAS  Google Scholar 

  10. Unoki, H. et al. SNPs in KCNQ1 are associated with susceptibility to type 2 diabetes in East Asian and European populations. Nat. Genet. 40, 1098–1102 (2008).

    Article  CAS  Google Scholar 

  11. Veugelers, M. et al. Characterization of glypican-5 and chromosomal localization of human GPC5, a new member of the glypican gene family. Genomics 40, 24–30 (1997).

    Article  CAS  Google Scholar 

  12. Hara, M., Yanagihara, T., Itoh, M., Matsuno, M. & Kihara, I. Immunohistochemical and urinary markers of podocyte injury. Pediatr. Nephrol. 12, 43–48 (1998).

    Article  CAS  Google Scholar 

  13. Hara, M. et al. Apical cell membranes are shed into urine from injured podocytes: a novel phenomenon of podocyte injury. J. Am. Soc. Nephrol. 16, 408–416 (2005).

    Article  CAS  Google Scholar 

  14. Nakamura, T. et al. Urinary excretion of podocytes in patients with diabetic nephropathy. Nephrol. Dial. Transplant. 15, 1379–1383 (2000).

    Article  CAS  Google Scholar 

  15. Wong, W. et al. Chronic humoral rejection of human kidney allografts is associated with MMP-2 accumulation in podocytes and its release in the urine. Am. J. Transplant. 10, 2463–2471 (2010).

    Article  CAS  Google Scholar 

  16. Shmueli, O. et al. GeneNote: whole genome expression profiles in normal human tissues. C. R. Biol. 326, 1067–1072 (2003).

    Article  CAS  Google Scholar 

  17. Bernfield, M. et al. Functions of cell surface heparan sulfate proteoglycans. Annu. Rev. Biochem. 68, 729–777 (1999).

    Article  CAS  Google Scholar 

  18. Steinfeld, R., Van Den Berghe, H. & David, G. Stimulation of fibroblast growth factor receptor-1 occupancy and signaling by cell surface-associated syndecans and glypican. J. Cell Biol. 133, 405–416 (1996).

    Article  CAS  Google Scholar 

  19. Schlessinger, J., Lax, I. & Lemmon, M. Regulation of growth factor activation by proteoglycans: what is the role of the low affinity receptors? Cell 83, 357–360 (1995).

    Article  CAS  Google Scholar 

  20. De Cat, B. & David, G. Developmental roles of the glypicans. Semin. Cell Dev. Biol. 12, 117–125 (2001).

    Article  CAS  Google Scholar 

  21. Williamson, D. et al. Role for amplification and expression of glypican-5 in rhabdomyosarcoma. Cancer Res. 67, 57–65 (2007).

    Article  CAS  Google Scholar 

  22. Song, H.H., Shi, W. & Filmus, J. OCI-5/rat glypican-3 binds to fibroblast growth factor-2 but not to insulin-like growth factor-2. J. Biol. Chem. 272, 7574–7577 (1997).

    Article  CAS  Google Scholar 

  23. Filmus, J., Capurro, M. & Rast, J. Glypicans. Genome Biol. 9, 224 (2008).

    Article  Google Scholar 

  24. Kim, B.S., Chen, J., Weinstein, T., Noiri, E. & Goligorsky, M.S. VEGF expression in hypoxia and hyperglycemia: reciprocal effect on branching angiogenesis in epithelial-endothelial co-cultures. J. Am. Soc. Nephrol. 13, 2027–2036 (2002).

    Article  CAS  Google Scholar 

  25. Chen, J. et al. VEGF-induced mobilization of caveolae and increase in permeability of endothelial cells. Am. J. Physiol. Cell Physiol. 282, C1053–C1063 (2002).

    Article  CAS  Google Scholar 

  26. Rico, M. et al. WT1-interacting protein and ZO-1 translocate into podocyte nuclei after puromycin aminonucleoside treatment. Am. J. Physiol. Renal Physiol. 289, F431–F441 (2005).

    Article  CAS  Google Scholar 

  27. Ray, P.E., Liu, X.H., Xu, L. & Rakusan, T. Basic fibroblast growth factor in HIV-associated hemolytic uremic syndrome. Pediatr. Nephrol. 13, 586–593 (1999).

    Article  CAS  Google Scholar 

  28. Ogata, S., Yorioka, N. & Kohno, N. Glucose and prednisolone alter basic fibroblast growth factor expression in peritoneal mesothelial cells and fibroblasts. J. Am. Soc. Nephrol. 12, 2787–2796 (2001).

    CAS  PubMed  Google Scholar 

  29. Floege, J. et al. Basic fibroblast growth factor augments podocyte injury and induces glomerulosclerosis in rats with experimental membranous nephropathy. J. Clin. Invest. 96, 2809–2819 (1995).

    Article  CAS  Google Scholar 

  30. Kriz, W., Hahnel, B., Rosener, S. & Elger, M. Long-term treatment of rats with FGF-2 results in focal segmental glomerulosclerosis. Kidney Int. 48, 1435–1450 (1995).

    Article  CAS  Google Scholar 

  31. Ohnishi, Y. et al. A high-throughput SNP typing system for genome-wide association studies. J. Hum. Genet. 46, 471–477 (2001).

    Article  CAS  Google Scholar 

  32. Okamoto, K. et al. Identification of KCNJ15 as a susceptibility gene in Asian patients with type 2 diabetes mellitus. Am. J. Hum. Genet. 86, 54–64 (2010).

    Article  CAS  Google Scholar 

  33. Nishida, N., Tanabe, T., Takasu, M., Suyama, A. & Tokunaga, K. Further development of multiplex single nucleotide polymorphism typing method, the DigiTag2 assay. Anal. Biochem. 364, 78–85 (2007).

    Article  CAS  Google Scholar 

  34. Li, Y., Willer, C., Sanna, S. & Abecasis, G. Genotype imputation. Annu. Rev. Genomics Hum. Genet. 10, 387–406 (2009).

    Article  CAS  Google Scholar 

  35. Kawachi, H., Koike, H., Kurihara, H., Sakai, T. & Shimizu, F. Cloning of rat homologue of podocin: expression in proteinuric states and in developing glomeruli. J. Am. Soc. Nephrol. 14, 46–56 (2003).

    Article  CAS  Google Scholar 

  36. Nosaka, K. et al. Permeable type I collagen membrane promotes glomerular epithelial cell growth in culture. Kidney Int. 43, 470–478 (1993).

    Article  CAS  Google Scholar 

  37. Lai, J.P. et al. Sulfatase 2 up-regulates glypican 3, promotes fibroblast growth factor signaling, and decreases survival in hepatocellular carcinoma. Hepatology 47, 1211–1222 (2008).

    Article  CAS  Google Scholar 

  38. Bradley, S.P. et al. Gene silencing in the endocrine pancreas mediated by short-interfering RNA. Pancreas 31, 373–379 (2005).

    Article  CAS  Google Scholar 

  39. Larson, S.D., Jackson, L.N., Chen, L.A., Rychahou, P.G. & Evers, B.M. Effectiveness of siRNA uptake in target tissues by various delivery methods. Surgery 142, 262–269 (2007).

    Article  Google Scholar 

  40. Saito, T., Sumithran, E., Glasgow, E.F. & Atkins, R.C. The enhancement of aminonucleoside nephrosis by the co-administration of protamine. Kidney Int. 32, 691–699 (1987).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank all participating doctors and staff from collaborating institutes for providing DNA samples. We also thank the technical staff of the Laboratory for Endocrinology and Metabolism at the RIKEN Center for Genomic Medicine for providing technical assistance. This study was partially supported by the BioBank Japan Project on the Implementation of Personalized Medicine, Ministry of Education, Culture, Sports, Science and Technology (MEXT), Japan, to E.N. (#3023168). This study was also supported by a Grant-in-Aid for Scientific research on Priority Area 'Comprehensive Genomics' from MEXT, Japan to K.T. (#17020003).

Author information

Authors and Affiliations

  1. Department of Nephrology and Endocrinology, Department of Hemodialysis and Apheresis, University Hospital, The University of Tokyo, Tokyo, Japan

    Koji Okamoto, Kent Doi, Toshiro Fujita & Eisei Noiri

  2. Department of Human Genetics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan

    Koji Okamoto, Katsushi Tokunaga, Nao Nishida & Akihiko Mabuchi

  3. Department of Nephrology, Hypertension, Diabetology, Endocrinology and Metabolism, Fukushima Medical University School of Medicine, Fukushima, Japan

    Hodaka Suzuki, Tetsuo Katoh & Tsuyoshi Watanabe

  4. Laboratory for Statistical Analysis, Center for Genomic Medicine, RIKEN, Yokohama, Japan

    Atsushi Takahashi

  5. Laboratory for Genotyping Development, Center for Genomic Medicine, RIKEN, Yokohama, Japan

    Michiaki Kubo

  6. Laboratory for Endocrinology and Metabolism, Center for Genomic Medicine, RIKEN, Yokohama, Japan

    Shiro Maeda

  7. Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan

    Yusuke Nakamura

  8. Science and Technology Research Partnership for Sustainable Development (SATREPS), Japan Science Technology (JST), Tokyo, Japan

    Eisei Noiri

Authors
  1. Koji Okamoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Katsushi Tokunaga
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Kent Doi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Toshiro Fujita
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Hodaka Suzuki
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Tetsuo Katoh
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Tsuyoshi Watanabe
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Nao Nishida
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Akihiko Mabuchi
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Atsushi Takahashi
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Michiaki Kubo
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Shiro Maeda
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Yusuke Nakamura
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Eisei Noiri
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

K.O. performed all experimental work and data analysis and wrote the first draft of the manuscript. A.T. and M.K. obtained raw GWAS data. N.N. supported the variation screening. Y.N. planned and designed the BioBank project. K.O., S.M., K.T. and E.N. designed the experiments. T.F., S.M., A.M., K.T. and E.N. supervised the project. K.D., H.S., T.K. and T.W. collected the case data and clinical data. The manuscript was finalized by K.O. with the assistance of all authors.

Corresponding author

Correspondence to Eisei Noiri.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Note, Supplementary Tables 1–6 and Supplementary Figures 1–10. (PDF 1388 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Okamoto, K., Tokunaga, K., Doi, K. et al. Common variation in GPC5 is associated with acquired nephrotic syndrome. Nat Genet 43, 459–463 (2011). https://doi.org/10.1038/ng.792

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ng.792

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing