한빛사 논문
Kamalika Mukherjee1,7, Changkyu Gu1,7, Agnieszka Collins1,7, Marcel Mettlen2, Beata Samelko3, Mehmet M. Altintas3, Yashwanth R. Sudhini3, Xuexiang Wang3, Richard Bouley1, Dennis Brown1, Bradley P. Pedro1, Susan L. Bane4, Vineet Gupta3, Paul T. Brinkkoetter5,6, Henning Hagmann5,6, Jochen Reiser3,* & Sanja Sever1,*
1Department of Medicine, Harvard Medical School and Division of Nephrology, Massachusetts General Hospital, Boston, MA, USA. 2Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX, USA. 3Department of Medicine, Rush University Medical Center, Chicago, IL, USA. 4Department of Chemistry, Binghamton University, State University of New York, Binghamton, NY, USA. 5Department of Internal Medicine-Center for Molecular Medicine Cologne, University of Cologne and Faculty of Medicine-University Hospital Cologne, Cologne, Germany. 6Cologne Cluster of Excellence on Cellular Stress Responses in Ageing-Associated Diseases (CECAD) and Systems Biology of Ageing Cologne (Sybacol), Cologne, Germany. 7These authors contributed equally: Kamalika Mukherjee, Changkyu Gu, Agnieszka Collins.
*Corresponding author.
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.
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