title: Pharmacological targeting of actin-dependent dynamin oligomerization ameliorates chronic kidney disease in diverse animal models.
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 cross-link actin microfilaments into higher-order structures has 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 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 substantial regenerative potential of injured glomeruli and identifying the oligomerization cycle of dynamin as an attractive potential therapeutic target to treat CKD.
authors.affiliation: 1] Department of Nephrology, Hannover Medical School, Hannover, Germany. [2] Mount Desert Island Biological Laboratory, Salsbury Cove, Maine, USA.
authors.forename: Mario
authors.initials: M
authors.lastname: Schiffer
authors.affiliation: Department of Nephrology, Hannover Medical School, Hannover, Germany.
authors.forename: Beina
authors.initials: B
authors.lastname: Teng
authors.affiliation: Department of Medicine, Harvard Medical School and Division of Nephrology, Massachusetts General Hospital, Charlestown, Massachusetts, USA.
authors.forename: Changkyu
authors.initials: C
authors.lastname: Gu
authors.affiliation: Department of Medicine, Harvard Medical School and Division of Nephrology, Massachusetts General Hospital, Charlestown, Massachusetts, USA.
authors.forename: Valentina A
authors.initials: VA
authors.lastname: Shchedrina
authors.affiliation: Department of Medicine, Harvard Medical School and Division of Nephrology, Massachusetts General Hospital, Charlestown, Massachusetts, USA.
authors.forename: Marina
authors.initials: M
authors.lastname: Kasaikina
authors.affiliation: Department of Medicine, Harvard Medical School and Division of Nephrology, Massachusetts General Hospital, Charlestown, Massachusetts, USA.
authors.forename: Vincent A
authors.identifier: 0000000170839360
authors.initials: VA
authors.lastname: Pham
authors.affiliation: Department of Nephrology, Hannover Medical School, Hannover, Germany.
authors.forename: Nils
authors.initials: N
authors.lastname: Hanke
authors.affiliation: Department of Nephrology, Hannover Medical School, Hannover, Germany.
authors.forename: Song
authors.initials: S
authors.lastname: Rong
authors.affiliation: Department of Nephrology, Hannover Medical School, Hannover, Germany.
authors.forename: Faikah
authors.initials: F
authors.lastname: Gueler
authors.affiliation: 1] Department of Nephrology, Hannover Medical School, Hannover, Germany. [2] Mount Desert Island Biological Laboratory, Salsbury Cove, Maine, USA.
authors.forename: Patricia
authors.initials: P
authors.lastname: Schroder
authors.affiliation: Department of Nephrology, Hannover Medical School, Hannover, Germany.
authors.forename: Irini
authors.initials: I
authors.lastname: Tossidou
authors.affiliation: Department of Nephrology, Hannover Medical School, Hannover, Germany.
authors.forename: Joon-Keun
authors.initials: JK
authors.lastname: Park
authors.affiliation: 1] Department of Nephrology, Hannover Medical School, Hannover, Germany. [2] Mount Desert Island Biological Laboratory, Salsbury Cove, Maine, USA.
authors.forename: Lynne
authors.initials: L
authors.lastname: Staggs
authors.affiliation: 1] Department of Nephrology, Hannover Medical School, Hannover, Germany. [2] Mount Desert Island Biological Laboratory, Salsbury Cove, Maine, USA.
authors.forename: Hermann
authors.initials: H
authors.lastname: Haller
authors.affiliation: Department of Cardiology, Hannover Medical School, Hannover, Germany.
authors.forename: Sergej
authors.initials: S
authors.lastname: Erschow
authors.affiliation: Department of Cardiology, Hannover Medical School, Hannover, Germany.
authors.forename: Denise
authors.initials: D
authors.lastname: Hilfiker-Kleiner
authors.affiliation: Department of Medicine, Rush University Medical Center, Chicago, Illinois, USA.
authors.forename: Changli
authors.initials: C
authors.lastname: Wei
authors.affiliation: Department of Medicine, Rush University Medical Center, Chicago, Illinois, USA.
authors.forename: Chuang
authors.initials: C
authors.lastname: Chen
authors.affiliation: Department of Medicine, Rush University Medical Center, Chicago, Illinois, USA.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Tardi
authors.affiliation: Pathology Department, University Medical Center Göttingen, Göttingen, Germany.
authors.forename: Samy
authors.initials: S
authors.lastname: Hakroush
authors.affiliation: Pathology Department, Massachusetts General Hospital, Charlestown, Massachusetts, USA.
authors.forename: Martin K
authors.initials: MK
authors.lastname: Selig
authors.affiliation: Department of Biomedical Sciences, NYIT COM, Old Westbury, New York, USA.
authors.forename: Aleksandr
authors.initials: A
authors.lastname: Vasilyev
authors.affiliation: Division of Nephrology and Hypertension, Department of Medicine, Leonard M. Miller School of Medicine, Miami, Florida, USA.
authors.forename: Sandra
authors.initials: S
authors.lastname: Merscher
authors.affiliation: Department of Medicine, Rush University Medical Center, Chicago, Illinois, USA.
authors.forename: Jochen
authors.initials: J
authors.lastname: Reiser
authors.affiliation: Department of Medicine, Harvard Medical School and Division of Nephrology, Massachusetts General Hospital, Charlestown, Massachusetts, USA.
authors.forename: Sanja
authors.initials: S
authors.lastname: Sever
mesh_terms: D020106:Acrylamide / Q000008:administration & dosage; D008841:Actin Cytoskeleton / Q000187:drug effects; D000818:Animals; D003373:Coumaric Acids / Q000008:administration & dosage*; D003487:Cyanoacrylates / Q000008:administration & dosage*; D034281:Dynamins / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D007678:Kidney Glomerulus / Q000187:drug effects / Q000473:pathology / Q000648:ultrastructure; D051379:Mice; D023421:Models, Animal; D050199:Podocytes / Q000187:drug effects* / Q000473:pathology / Q000648:ultrastructure; D011507:Proteinuria / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051436:Renal Insufficiency, Chronic / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D015027:Zebrafish
chemical_list: C000600733:Bis-T-23 compound; D003373:Coumaric Acids; D003487:Cyanoacrylates; D020106:Acrylamide; D034281:Dynamins