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Simultaneous stabilization of actin cytoskeleton in multiple nephron-specific cells protects the kidney from diverse injury

Author

Listed:
  • Kamalika Mukherjee

    (Harvard Medical School and Division of Nephrology, Massachusetts General Hospital)

  • Changkyu Gu

    (Harvard Medical School and Division of Nephrology, Massachusetts General Hospital)

  • Agnieszka Collins

    (Harvard Medical School and Division of Nephrology, Massachusetts General Hospital)

  • Marcel Mettlen

    (University of Texas Southwestern Medical Center)

  • Beata Samelko

    (Rush University Medical Center)

  • Mehmet M. Altintas

    (Rush University Medical Center)

  • Yashwanth R. Sudhini

    (Rush University Medical Center)

  • Xuexiang Wang

    (Rush University Medical Center)

  • Richard Bouley

    (Harvard Medical School and Division of Nephrology, Massachusetts General Hospital)

  • Dennis Brown

    (Harvard Medical School and Division of Nephrology, Massachusetts General Hospital)

  • Bradley P. Pedro

    (Harvard Medical School and Division of Nephrology, Massachusetts General Hospital)

  • Susan L. Bane

    (Binghamton University, State University of New York)

  • Vineet Gupta

    (Rush University Medical Center)

  • Paul T. Brinkkoetter

    (University of Cologne and Faculty of Medicine-University Hospital Cologne
    Cologne Cluster of Excellence on Cellular Stress Responses in Ageing-Associated Diseases (CECAD) and Systems Biology of Ageing Cologne (Sybacol))

  • Henning Hagmann

    (University of Cologne and Faculty of Medicine-University Hospital Cologne
    Cologne Cluster of Excellence on Cellular Stress Responses in Ageing-Associated Diseases (CECAD) and Systems Biology of Ageing Cologne (Sybacol))

  • Jochen Reiser

    (Rush University Medical Center)

  • Sanja Sever

    (Harvard Medical School and Division of Nephrology, Massachusetts General Hospital)

Abstract

Chronic kidney diseases and acute kidney injury are mechanistically distinct kidney diseases. While chronic kidney diseases are associated with podocyte injury, acute kidney injury affects renal tubular epithelial cells. Despite these differences, a cardinal feature of both acute and chronic kidney diseases is dysregulated actin cytoskeleton. We have shown that pharmacological activation of GTPase dynamin ameliorates podocyte injury in murine models of chronic kidney diseases by promoting actin polymerization. Here we establish dynamin’s role in modulating stiffness and polarity of renal tubular epithelial cells by crosslinking actin filaments into branched networks. Activation of dynamin’s crosslinking capability by a small molecule agonist stabilizes the actomyosin cortex of the apical membrane against injury, which in turn preserves renal function in various murine models of acute kidney injury. Notably, a dynamin agonist simultaneously attenuates podocyte and tubular injury in the genetic murine model of Alport syndrome. Our study provides evidence for the feasibility and highlights the benefits of novel holistic nephron-protective therapies.

Suggested Citation

  • Kamalika Mukherjee & Changkyu Gu & Agnieszka Collins & Marcel Mettlen & Beata Samelko & Mehmet M. Altintas & Yashwanth R. Sudhini & Xuexiang Wang & Richard Bouley & Dennis Brown & Bradley P. Pedro & S, 2022. "Simultaneous stabilization of actin cytoskeleton in multiple nephron-specific cells protects the kidney from diverse injury," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-30101-4
    DOI: 10.1038/s41467-022-30101-4
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