Mukherjee, Kamalika ORCID: 0000-0002-5483-7450, Gu, Changkyu, Collins, Agnieszka, Mettlen, Marcel, Samelko, Beata, Altintas, Mehmet M., Sudhini, Yashwanth R., Wang, Xuexiang, Bouley, Richard, Brown, Dennis, Pedro, Bradley P., Bane, Susan L., Gupta, Vineet, Brinkkoetter, Paul T., Hagmann, Henning, Reiser, Jochen and Sever, Sanja (2022). Simultaneous stabilization of actin cytoskeleton in multiple nephron-specific cells protects the kidney from diverse injury. Nat. Commun., 13 (1). BERLIN: NATURE PORTFOLIO. ISSN 2041-1723

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Abstract

A common cellular manifestation for diverse kidney diseases is dysregulated actin cytoskeleton in distinct cell types that include glomerular podocytes and tubular epithelial cells. Here, authors pharmacologically activate dynamin and this results in polymerization and crosslinking of actin filaments to establish the structural integrity of these cells, thus ameliorating disease phenotypes. 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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Mukherjee, KamalikaUNSPECIFIEDorcid.org/0000-0002-5483-7450UNSPECIFIED
Gu, ChangkyuUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Collins, AgnieszkaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mettlen, MarcelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Samelko, BeataUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Altintas, Mehmet M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sudhini, Yashwanth R.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wang, XuexiangUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bouley, RichardUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Brown, DennisUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pedro, Bradley P.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bane, Susan L.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gupta, VineetUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Brinkkoetter, Paul T.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hagmann, HenningUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Reiser, JochenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sever, SanjaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-690187
DOI: 10.1038/s41467-022-30101-4
Journal or Publication Title: Nat. Commun.
Volume: 13
Number: 1
Date: 2022
Publisher: NATURE PORTFOLIO
Place of Publication: BERLIN
ISSN: 2041-1723
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
SOLUBLE UROKINASE RECEPTOR; DOMINANT ALPORT-SYNDROME; DYNAMIN OLIGOMERIZATION; REDOX REGULATION; MITOCHONDRIA; MEMBRANE; ADHESION; PATHOPHYSIOLOGY; ORGANIZATION; MIGRATIONMultiple languages
Multidisciplinary SciencesMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/69018

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