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.

The insect nephrocyte is a podocyte-like cell with a filtration slit diaphragm

Abstract

The nephron is the basic structural and functional unit of the vertebrate kidney. It is composed of a glomerulus, the site of ultrafiltration, and a renal tubule, along which the filtrate is modified. Although widely regarded as a vertebrate adaptation1, ‘nephron-like’ features can be found in the excretory systems of many invertebrates, raising the possibility that components of the vertebrate excretory system were inherited from their invertebrate ancestors2. Here we show that the insect nephrocyte has remarkable anatomical, molecular and functional similarity to the glomerular podocyte, a cell in the vertebrate kidney that forms the main size-selective barrier as blood is ultrafiltered to make urine. In particular, both cell types possess a specialized filtration diaphragm, known as the slit diaphragm in podocytes or the nephrocyte diaphragm in nephrocytes. We find that fly (Drosophila melanogaster) orthologues of the major constituents of the slit diaphragm, including nephrin, NEPH1 (also known as KIRREL), CD2AP, ZO-1 (TJP1) and podocin, are expressed in the nephrocyte and form a complex of interacting proteins that closely mirrors the vertebrate slit diaphragm complex. Furthermore, we find that the nephrocyte diaphragm is completely lost in flies lacking the orthologues of nephrin or NEPH1—a phenotype resembling loss of the slit diaphragm in the absence of either nephrin (as in human congenital nephrotic syndrome of the Finnish type, NPHS1) or NEPH1. These changes markedly impair filtration function in the nephrocyte. The similarities we describe between invertebrate nephrocytes and vertebrate podocytes provide evidence suggesting that the two cell types are evolutionarily related, and establish the nephrocyte as a simple model in which to study podocyte biology and podocyte-associated diseases.

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

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Figure 1: The glomerular and nephrocyte filtration barriers are anatomically similar.
Figure 2: Sns and Duf are expressed in Drosophila nephrocytes.
Figure 3: Sns and Duf are required for nephrocyte diaphragm formation and normal morphology.
Figure 4: Analysis of slit-diaphragm-associated protein orthologues in the fly nephrocyte.
Figure 5: Sns and Duf are required for nephrocyte filtration.

References

  1. Smith, H. W. From Fish to Philosopher (Little, Brown, 1953)

    Google Scholar 

  2. Ruppert, E. E. Evolutionary origin of the vertebrate nephron. Am. Zool. 34, 542–533 (1994)

    Article  Google Scholar 

  3. Rodewald, R. & Karnovsky, M. J. Porous substructure of the glomerular slit diaphragm in the rat and mouse. J. Cell Biol. 60, 423–433 (1974)

    CAS  Article  Google Scholar 

  4. Wartiovaara, J. et al. Nephrin strands contribute to a porous slit diaphragm scaffold as revealed by electron tomography. J. Clin. Invest. 114, 1475–1483 (2004)

    CAS  Article  Google Scholar 

  5. Patrakka, J. et al. Congenital nephrotic syndrome (NPHS1): features resulting from different mutations in Finnish patients. Kidney Int. 58, 972–980 (2000)

    CAS  Article  Google Scholar 

  6. Berridge, M. J. & Oschman, J. L. Transporting Epithelia 11–15 (Academic, 1972)

    Google Scholar 

  7. Crossley, A. C. in Comprehensive Insect Physiology, Biochemistry and Pharmacology (eds Kerkut, G. A. & Gilbert, L. I.) 487–515 (Pergamon, 1985)

    Google Scholar 

  8. Kowalevsky, A. Ein Beitrag zur Kenntnis der Excretions-organe. Biol. Centralbl. 9, 74–79 (1889)

    Google Scholar 

  9. Locke, M. & Russell, V. W. in Microscopic Anatomy of Invertebrates (eds Harrison, F. W. & Locke, M.) 687–709 (Wiley, 1998)

    Google Scholar 

  10. Kestila, M. et al. Positionally cloned gene for a novel glomerular protein—nephrin—is mutated in congenital nephrotic syndrome. Mol. Cell 1, 575–582 (1998)

    CAS  Article  Google Scholar 

  11. Sellin, L. et al. NEPH1 defines a novel family of podocin interacting proteins. FASEB J. 17, 115–117 (2003)

    CAS  Article  Google Scholar 

  12. Ruotsalainen, V. et al. Nephrin is specifically located at the slit diaphragm of glomerular podocytes. Proc. Natl Acad. Sci. USA 96, 7962–7967 (1999)

    ADS  CAS  Article  Google Scholar 

  13. Gerke, P., Huber, T. B., Sellin, L., Benzing, T. & Walz, G. Homodimerization and heterodimerization of the glomerular podocyte proteins nephrin and NEPH1. J. Am. Soc. Nephrol. 14, 918–926 (2003)

    CAS  Article  Google Scholar 

  14. Barletta, G. M., Kovari, I. A., Verma, R. K., Kerjaschki, D. & Holzman, L. B. Nephrin and Neph1 co-localize at the podocyte foot process intercellular junction and form cis hetero-oligomers. J. Biol. Chem. 278, 19266–19271 (2003)

    CAS  Article  Google Scholar 

  15. Khoshnoodi, J. et al. Nephrin promotes cell–cell adhesion through homophilic interactions. Am. J. Pathol. 163, 2337–2346 (2003)

    CAS  Article  Google Scholar 

  16. Liu, G. et al. Neph1 and nephrin interaction in the slit diaphragm is an important determinant of glomerular permeability. J. Clin. Invest. 112, 209–221 (2003)

    CAS  Article  Google Scholar 

  17. Donoviel, D. B. et al. Proteinuria and perinatal lethality in mice lacking NEPH1, a novel protein with homology to NEPHRIN. Mol. Cell. Biol. 21, 4829–4836 (2001)

    CAS  Article  Google Scholar 

  18. Tepass, U. & Hartenstein, V. The development of cellular junctions in the Drosophila embryo. Dev. Biol. 161, 563–596 (1994)

    CAS  Article  Google Scholar 

  19. Rugendorff, A., Younossi-Hartenstein, A. & Hartenstein, V. Embryonic origin and differentiation of the Drosophila heart. Rouxs Arch. Dev. Biol. 203, 266–280 (1994)

    Article  Google Scholar 

  20. Huber, T. B. et al. The carboxyl terminus of Neph family members binds to the PDZ domain protein zonula occludens-1. J. Biol. Chem. 278, 13417–13421 (2003)

    CAS  Article  Google Scholar 

  21. Shih, N. Y. et al. Congenital nephrotic syndrome in mice lacking CD2-associated protein. Science 286, 312–315 (1999)

    CAS  Article  Google Scholar 

  22. Shih, N. Y. et al. CD2AP localizes to the slit diaphragm and binds to nephrin via a novel C-terminal domain. Am. J. Pathol. 159, 2303–2308 (2001)

    CAS  Article  Google Scholar 

  23. Boute, N. et al. NPHS2, encoding the glomerular protein podocin, is mutated in autosomal recessive steroid-resistant nephrotic syndrome. Nature Genet. 24, 349–354 (2000)

    CAS  Article  Google Scholar 

  24. Kim, J. M. et al. CD2-associated protein haploinsufficiency is linked to glomerular disease susceptibility. Science 300, 1298–1300 (2003)

    ADS  CAS  Article  Google Scholar 

  25. Schwarz, K. et al. Podocin, a raft-associated component of the glomerular slit diaphragm, interacts with CD2AP and nephrin. J. Clin. Invest. 108, 1621–1629 (2001)

    CAS  Article  Google Scholar 

  26. Galletta, B. J., Chakravarti, M., Banerjee, R. & Abmayr, S. M. SNS: Adhesive properties, localization requirements and ectodomain dependence in S2 cells and embryonic myoblasts. Mech. Dev. 121, 1455–1468 (2004)

    CAS  Article  Google Scholar 

  27. Kramer-Zucker, A. G., Wiessner, S., Jensen, A. M. & Drummond, I. A. Organization of the pronephric filtration apparatus in zebrafish requires Nephrin, Podocin and the FERM domain protein Mosaic eyes. Dev. Biol. 285, 316–329 (2005)

    CAS  Article  Google Scholar 

  28. Akilesh, S. et al. Podocytes use FcRn to clear IgG from the glomerular basement membrane. Proc. Natl Acad. Sci. USA 105, 967–972 (2008)

    ADS  CAS  Article  Google Scholar 

  29. Das, D., Aradhya, R., Ashoka, D. & Inamdar, M. Post-embryonic pericardial cells of Drosophila are required for overcoming toxic stress but not for cardiac function or adult development. Cell Tissue Res. 331, 565–570 (2008)

    Article  Google Scholar 

  30. Huber, T. B. & Benzing, T. The slit diaphragm: a signaling platform to regulate podocyte function. Curr. Opin. Nephrol. Hypertens. 14, 211–216 (2005)

    Article  Google Scholar 

  31. Nagel, A. C., Maier, D. & Preiss, A. Green fluorescent protein as a convenient and versatile marker for studies on functional genomics in Drosophila . Dev. Genes Evol. 212, 93–98 (2002)

    CAS  Article  Google Scholar 

  32. Strunkelnberg, M. et al. rst and its paralogue kirre act redundantly during embryonic muscle development in Drosophila . Development 128, 4229–4239 (2001)

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank F. Evers, Z. Cseresnyes, M. Guerra and E. Salvador for technical assistance, and S. Abmayr, L. Cooley, C. Doe, M. Affolter, K. Fischbach and K. Tryggvason for reagents. We thank V. Hartenstein, M. Inamdar, A. Woolf, I. Miguel-Aliaga, F. Evers, M. Landgraf and members of the Skaer laboratory for discussions, and E. Knust and W. B. Huttner for their support. This work was supported by Wellcome Trust grants awarded to H.S. (072441 and 079221; H.W., B.D. and H.S.); Deutsche Forschungsgemeinschaft SFB 590 awarded to E. Knust (F.G.) and ARC 1242 (H.W., B.D., H.S. and F.G.); an MEC grant awarded to M.R.-G. (BFU2007-62201; S.P.-S. and M.R.-G.); a Fundación Ramón Areces grant to the CBMSO (M.R.-G.); EC grant LSHG-CT-2004-511978 to MYORES (M.R.-G.); and an FPU fellowship from the MEC awarded to A.G.-L.

Author Contributions B.D., H.S. and M.R.-G. designed and directed the project. B.D., H.W., M.R.-G. and S.P.-S. performed the experiments. F.G. and M.W.-B. provided technical assistance. A.G.-L. and R.A. provided materials. B.D. and H.S. wrote the paper. All authors discussed results and commented on the manuscript.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Helen Skaer.

Supplementary information

Supplementary Information

This file contains Supplementary Figures 1-4 with Legends, Supplementary Table 1 and Supplementary Notes (PDF 7650 kb)

PowerPoint slides

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Weavers, H., Prieto-Sánchez, S., Grawe, F. et al. The insect nephrocyte is a podocyte-like cell with a filtration slit diaphragm. Nature 457, 322–326 (2009). https://doi.org/10.1038/nature07526

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature07526

Further reading

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

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