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

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, Susan L. Bane, Vineet Gupta, Paul T. Brinkkoetter, Henning Hagmann, Jochen Reiser () and Sanja Sever ()
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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
Henning Hagmann: University of Cologne and Faculty of Medicine-University Hospital Cologne
Jochen Reiser: Rush University Medical Center
Sanja Sever: Harvard Medical School and Division of Nephrology, Massachusetts General Hospital

Nature Communications, 2022, vol. 13, issue 1, 1-14

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-30101-4

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