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

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

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Title: Pharmacological targeting of actin-dependent dynamin oligomerization ameliorates chronic kidney disease in diverse animal models
Author: Schiffer, Mario; Teng, Beina; Gu, Changkyu; Shchedrina, Valentina A.; Kasaikina, Marina; Pham, Vincent A.; Hanke, Nils; Rong, Song; Gueler, Faikah; Schroder, Patricia; Tossidou, Irini; Park, Joon-Keun; Staggs, Lynne; Haller, Hermann; Erschow, Sergej; Hilfiker-Kleiner, Denise; Wei, Changli; Chen, Chuang; Tardi, Nicholas; Hakroush, Samy; Selig, Martin K.; Vasilyev, Aleksandr; Merscher, Sandra; Reiser, Jochen; Sever, Sanja

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Citation: Schiffer, M., B. Teng, C. Gu, V. A. Shchedrina, M. Kasaikina, V. A. Pham, N. Hanke, et al. 2015. “Pharmacological targeting of actin-dependent dynamin oligomerization ameliorates chronic kidney disease in diverse animal models.” Nature medicine 21 (6): 601-609. doi:10.1038/nm.3843. http://dx.doi.org/10.1038/nm.3843.
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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 crosslink actin microfilaments into higher order structures have 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 of 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 significant regenerative potential of injured glomeruli and that targeting the oligomerization cycle of dynamin represents an attractive potential therapeutic target to treat CKD.
Published Version: doi:10.1038/nm.3843
Other Sources: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4458177/pdf/
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Citable link to this page: http://nrs.harvard.edu/urn-3:HUL.InstRepos:23993575
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