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Pharmacological targeting of actin-dependent dynamin oligomerization ameliorates chronic kidney disease in diverse animal models

Nature Medicine volume 21, pages 601–609 (2015)Cite this article

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Abstract

Dysregulation of the actin cytoskeleton in podocytes represents a common pathway in the pathogenesis of proteinuria across a spectrum of chronic kidney diseases (CKD). The GTPase dynamin has been implicated in the maintenance of cellular architecture in podocytes through its direct interaction with actin. Furthermore, the propensity of dynamin to oligomerize into higher-order structures in an actin-dependent manner and to cross-link actin microfilaments into higher-order structures has been correlated with increased actin polymerization and global organization of the actin cytoskeleton in the cell. We found that use of the small molecule Bis-T-23, which promotes actin-dependent dynamin oligomerization and thus increased actin polymerization in injured podocytes, was sufficient to improve renal health in diverse models of both transient kidney disease and CKD. In particular, administration of Bis-T-23 in these renal disease models restored the normal ultrastructure of podocyte foot processes, lowered proteinuria, lowered collagen IV deposits in the mesangial matrix, diminished mesangial matrix expansion and extended lifespan. These results further establish that alterations in the actin cytoskeleton of kidney podocytes is a common hallmark of CKD, while also underscoring the substantial regenerative potential of injured glomeruli and identifying the oligomerization cycle of dynamin as an attractive potential therapeutic target to treat CKD.

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Figure 1: Dynamin oligomerization is essential for kidney function.
Figure 2: Dynamin oligomerization ameliorates transient proteinuria.
Figure 3: Dynamin oligomerization in podocytes protects against proteinuria.
Figure 4: Dynamin oligomerization targets actin cytoskeleton in podocytes.
Figure 5: Dynamin oligomerization has beneficial effect on kidney morphology in PKCɛKO mice.
Figure 6: Dynamin oligomerization ameliorates proteinuria due to diabetic nephropathy.

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Acknowledgements

This work was supported by the National Institutes of Health (R01 DK093773 and DK087985 to S.S.), the NephCure Foundation (S.S.), and Deutsche Forschungsgemeinschaft (SCHI587/3, 4, 6 to M.S. and REBIRTH 2 to D.H.-K. and S.E.). N.H. is the recipient of the New Investigator Award from Mount Desert Island Biological Laboratory. The DNA encoding genes for PKCɛ and mutant with impaired kinase activity were gifts from J.-W. Soh, Inha University, Incheon, South Korea. Immortalized podocytes from ACTN4 mice, ACTN4 mice and morpholino to downregulate inf2 were gifts from M. Pollak, Beth Israel Deaconess Medical Center, Boston, MA. Tg (L-FABP:DBP-EGFP) and Tg (l-fabp:DBP-EGFP) zebrafish were gifts from J. Xie and B. Anand-Apte, Cleveland Clinic, Cleveland, OH. PKCɛKO mice were gifts from M. Leitges, University of Oslo, Oslo, Norway. CD2APKO mice were gifts from A. Shaw, Washington University, St. Louis, MO.

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Author notes

  1. Mario Schiffer, Beina Teng and Changkyu Gu: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Nephrology, Hannover Medical School, Hannover, Germany

    Mario Schiffer, Beina Teng, Nils Hanke, Song Rong, Faikah Gueler, Patricia Schroder, Irini Tossidou, Joon-Keun Park, Lynne Staggs & Hermann Haller

  2. Mount Desert Island Biological Laboratory, Salsbury Cove, Maine, USA

    Mario Schiffer, Patricia Schroder, Lynne Staggs & Hermann Haller

  3. Department of Medicine, Harvard Medical School and Division of Nephrology, Massachusetts General Hospital, Charlestown, Massachusetts, USA

    Changkyu Gu, Valentina A Shchedrina, Marina Kasaikina, Vincent A Pham & Sanja Sever

  4. Department of Cardiology, Hannover Medical School, Hannover, Germany

    Sergej Erschow & Denise Hilfiker-Kleiner

  5. Department of Medicine, Rush University Medical Center, Chicago, Illinois, USA

    Changli Wei, Chuang Chen, Nicholas Tardi & Jochen Reiser

  6. Pathology Department, University Medical Center Göttingen, Göttingen, Germany

    Samy Hakroush

  7. Pathology Department, Massachusetts General Hospital, Charlestown, Massachusetts, USA

    Martin K Selig

  8. Department of Biomedical Sciences, NYIT COM, Old Westbury, New York, USA

    Aleksandr Vasilyev

  9. Division of Nephrology and Hypertension, Department of Medicine, Leonard M. Miller School of Medicine, Miami, Florida, USA

    Sandra Merscher

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Contributions

M.S., H.H., J.R. and S.S. designed the research; B.T., C.G., V.A.S., M.K., N.H., P.S., L.S., I.T., J.-K.P., S.E., D.H.-K., C.W., S.M., C.C., N.T., S.H., S.R., M.K.S., A.V. and F.G. performed the research. B.T., C.G., M.K., M.S., and S.S. analyzed the data. M.S., B.T., C.G. and S.S. wrote the manuscript.

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Correspondence to Mario Schiffer or Sanja Sever.

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Competing interests

S.S. and J.R. have pending or issued patents on novel kidney-protective therapies that have been out-licensed to Trisaq Inc. in which they have financial interest. In addition, they stand to gain royalties from their commercialization. The remaining authors report no conflicts.

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Schiffer, M., Teng, B., Gu, C. et al. Pharmacological targeting of actin-dependent dynamin oligomerization ameliorates chronic kidney disease in diverse animal models. Nat Med 21, 601–609 (2015). https://doi.org/10.1038/nm.3843

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