title: Arhgap24 inactivates Rac1 in mouse podocytes, and a mutant form is associated with familial focal segmental glomerulosclerosis.
abstract: The specialized epithelial cell of the kidney, the podocyte, has a complex actin-based cytoskeleton. Dynamic regulation of this cytoskeleton is required for efficient barrier function of the kidney. Podocytes are a useful cell type to study the control of the actin cytoskeleton in vivo, because disruption of components of the cytoskeleton results in podocyte damage, cell loss, and a prototypic injury response called focal segmental glomerulosclerosis (FSGS). Searching for actin regulatory proteins that are expressed in podocytes, we identified a RhoA-activated Rac1 GTPase-activating protein (Rac1-GAP), Arhgap24, that was upregulated in podocytes as they differentiated, both in vitro and in vivo. Increased levels of active Rac1 and Cdc42 were measured in Arhgap24 knockdown experiments, which influenced podocyte cell shape and membrane dynamics. Consistent with a role for Arhgap24 in normal podocyte functioning in vivo, sequencing of the ARHGAP24 gene in patients with FSGS identified a mutation that impaired its Rac1-GAP activity and was associated with disease in a family with FSGS. Thus, Arhgap24 contributes to the careful balancing of RhoA and Rac1 signaling in podocytes, the disruption of which may lead to kidney disease.
authors.affiliation: Department of Pathology, Barnes-Jewish Hospital, St. Louis, Missouri 63110, USA.
authors.forename: Shreeram
authors.initials: S
authors.lastname: Akilesh
authors.forename: Hani
authors.initials: H
authors.lastname: Suleiman
authors.forename: Haiyang
authors.initials: H
authors.lastname: Yu
authors.forename: M Christine
authors.initials: MC
authors.lastname: Stander
authors.forename: Peter
authors.initials: P
authors.lastname: Lavin
authors.forename: Rasheed
authors.initials: R
authors.lastname: Gbadegesin
authors.forename: Corinne
authors.initials: C
authors.lastname: Antignac
authors.forename: Martin
authors.initials: M
authors.lastname: Pollak
authors.forename: Jeffrey B
authors.initials: JB
authors.lastname: Kopp
authors.forename: Michelle P
authors.initials: MP
authors.lastname: Winn
authors.forename: Andrey S
authors.initials: AS
authors.lastname: Shaw
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002454:Cell Differentiation; D002462:Cell Membrane / Q000473:pathology; D048430:Cell Shape; D005260:Female; D020690:GTPase-Activating Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000502:physiology*; D055785:Gene Knockdown Techniques; D005923:Glomerulosclerosis, Focal Segmental / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology*; D006801:Humans; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D050505:Mutant Proteins / Q000235:genetics / Q000502:physiology; D009479:Neuropeptides / Q000037:antagonists & inhibitors* / Q000502:physiology; D010375:Pedigree; D050199:Podocytes / Q000473:pathology / Q000502:physiology*; D017386:Sequence Homology, Amino Acid; D020744:rac GTP-Binding Proteins / Q000037:antagonists & inhibitors* / Q000502:physiology; D020830:rac1 GTP-Binding Protein
chemical_list: C497033:ARHGAP24 protein, human; C497034:ARHGAP24 protein, mouse; D020690:GTPase-Activating Proteins; D050505:Mutant Proteins; D009479:Neuropeptides; C484602:Rac1 protein, mouse; D020744:rac GTP-Binding Proteins; D020830:rac1 GTP-Binding Protein