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Focal segmental glomerulosclerosis is induced by microRNA-193a and its downregulation of WT1

Nature Medicine volume 19, pages 481–487 (2013)Cite this article

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Abstract

Focal segmental glomerulosclerosis (FSGS) is a frequent and severe glomerular disease characterized by destabilization of podocyte foot processes. We report that transgenic expression of the microRNA miR-193a in mice rapidly induces FSGS with extensive podocyte foot process effacement. Mechanistically, miR-193a inhibits the expression of the Wilms' tumor protein (WT1), a transcription factor and master regulator of podocyte differentiation and homeostasis. Decreased expression levels of WT1 lead to downregulation of its target genes PODXL (podocalyxin) and NPHS1 (nephrin), as well as several other genes crucial for the architecture of podocytes, initiating a catastrophic collapse of the entire podocyte-stabilizing system. We found upregulation of miR-193a in isolated glomeruli from individuals with FSGS compared to normal kidneys or individuals with other glomerular diseases. Thus, upregulation of miR-193a provides a new pathogenic mechanism for FSGS and is a potential therapeutic target.

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Figure 1: Doxycycline-induced miR-193a transgenic mice develop a renal phenotype.
Figure 2: Development of glomerular lesions induced by overexpression of miR-193a after 2, 4, 6 and 10 weeks.
Figure 3: miR-193a target genes in podocytes.
Figure 4: Conditional knockout of Wt1 induces an FSGS phenotype similar to that caused by overexpression of miR-193a.
Figure 5: miR-193a–induced effects are rescued by Wt1 overexpression.
Figure 6: miR-193a in cultured human podocytes and human glomerular diseases.

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Acknowledgements

This study was supported in part by E-Rare JTC 2011, European Research Projects on Rare Diseases, Project # I 923-B13 to D.K. and M.J.M. and a grant from the Deutsche Forschungsgemeinschaft (EN 280/8-1) to C.E. We thank A. Fogo (Vanderbilt University), J. Reiser (Rush University Medical Center) and C. Alpers (University of Washington) for sending us paraffin blocks of kidneys from animal models of proteinuria. Immortalized mouse podocytes were a kind gift of P. Mundel (MGH Boston). Immortalized human podocytes were a gift of L. Schaefer, University of Frankfurt. We thank K. Priessner, U. Rothermel, D. Kruspe, S. Krieger, H. Schachner, G. Asfour, I. Raab, M. Volz and A. Jäger for expert technical assistance and A. Rees for critical reading of the manuscript. Cell sorting was performed by A. Spittler and G. Hofbauer from the Core Facility Cell Sorting, Medical University of Vienna.

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  1. Javier Martinez and Dontscho Kerjaschki: These authors contributed equally to this work.

Authors and Affiliations

  1. Clinical Institute of Pathology, Medical University of Vienna, Vienna, Austria

    Christoph A Gebeshuber, Christoph Kornauth, Renate Kain & Dontscho Kerjaschki

  2. IMBA Institute of Molecular Biotechnology, Vienna, Austria

    Christoph A Gebeshuber & Javier Martinez

  3. Leibniz-Institut für Altersforschung, Fritz-Lipmann-Institut e.V., Jena, Germany

    Lihua Dong, Ralph Sierig & Christoph Englert

  4. TaconicArtemis GmbH, Cologne, Germany

    Jost Seibler & Martina Reiss

  5. Center for Integrative Bioinformatics, Max F Perutz Laboratories, University of Vienna and Medical University of Vienna, Vienna, Austria

    Stefanie Tauber

  6. Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria

    Martin Bilban

  7. Deutsches Krebsforschungszentrum, Zelluläre und Molekulare Pathologie, Heidelberg, Germany

    Shijun Wang & Hermann-Josef Gröne

  8. Department of Internal Medicine III, Division of Nephrology, Medical University of Vienna, Vienna, Austria

    Georg A Böhmig

  9. Medizinische Klinik II, Nephrologie, Universitätsklinikum der RWTH Aachen, Aachen, Germany

    Marcus J Moeller

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Contributions

D.K., C.A.G. and J.M. conceived the project. C.A.G. and D.K. designed the experiments and wrote the paper. C.A.G. and C.K. performed the experiments related to miR-193a. S.T. and M.B. performed the RNA-Seq analysis. C.K., G.A.B., R.K. and M.J.M. selected the human samples. C.E., H.-J.G., L.D. and R.S. generated and characterized the conditional WT1 knockout mouse. J.S. and M.R. generated the inducible miR-193a transgenic mouse. S.W. and H.-J.G. performed the kidney transplantation.

Corresponding author

Correspondence to Dontscho Kerjaschki.

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The authors declare no competing financial interests.

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Supplementary Figures 1–6 and Supplementary Tables 2–4 (PDF 1046 kb)

Supplementary Table 1

Genes regulated in isolated mouse glomeruli upon miR-193a (XLS 9235 kb)

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Gebeshuber, C., Kornauth, C., Dong, L. et al. Focal segmental glomerulosclerosis is induced by microRNA-193a and its downregulation of WT1. Nat Med 19, 481–487 (2013). https://doi.org/10.1038/nm.3142

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