title: Mechanisms of the proteinuria induced by Rho GTPases.
abstract: Podocytes are highly differentiated cells that play an important role in maintaining glomerular filtration barrier integrity; a function regulated by small GTPase proteins of the Rho family. To investigate the role of Rho A in podocyte biology, we created transgenic mice expressing doxycycline-inducible constitutively active (V14 Rho) or dominant-negative Rho A (N19 Rho) in podocytes. Specific induction of either Rho A construct in podocytes caused albuminuria and foot process effacement along with disruption of the actin cytoskeleton as evidenced by decreased expression of the actin-associated protein synaptopodin. The mechanisms of these adverse effects, however, appeared to be different. Active V14 Rho enhanced actin polymerization, caused a reduction in nephrin mRNA and protein levels, promoted podocyte apoptosis, and decreased endogenous Rho A levels. In contrast, the dominant-negative N19 Rho caused a loss of podocyte stress fibers, did not alter the expression of either nephrin or Rho A, and did not cause podocyte apoptosis. Thus, our findings suggest that Rho A plays an important role in maintaining the integrity of the glomerular filtration barrier under basal conditions, but enhancement of Rho A activity above basal levels promotes podocyte injury.
authors.affiliation: Division of Nephrology, Department of Medicine, Duke University and Durham VA Medical Centers, Durham, North Carolina 27710, USA.
authors.forename: Liming
authors.initials: L
authors.lastname: Wang
authors.forename: Mathew J
authors.initials: MJ
authors.lastname: Ellis
authors.forename: Jose A
authors.initials: JA
authors.lastname: Gomez
authors.forename: William
authors.initials: W
authors.lastname: Eisner
authors.forename: Walter
authors.initials: W
authors.lastname: Fennell
authors.forename: David N
authors.initials: DN
authors.lastname: Howell
authors.forename: Phillip
authors.initials: P
authors.lastname: Ruiz
authors.forename: Timothy A
authors.initials: TA
authors.lastname: Fields
authors.forename: Robert F
authors.initials: RF
authors.lastname: Spurney
mesh_terms: D008841:Actin Cytoskeleton / Q000201:enzymology; D000419:Albuminuria / Q000201:enzymology / Q000209:etiology* / Q000235:genetics / Q000473:pathology; D000818:Animals; D017209:Apoptosis; D005786:Gene Expression Regulation; D005838:Genotype; D060730:Glomerular Filtration Barrier / Q000201:enzymology* / Q000473:pathology; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D008840:Microfilament Proteins / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D010641:Phenotype; D050199:Podocytes / Q000201:enzymology* / Q000473:pathology; D012333:RNA, Messenger / Q000378:metabolism; D022502:Stress Fibers / Q000201:enzymology; D013997:Time Factors; D020742:rhoA GTP-Binding Protein / Q000235:genetics / Q000378:metabolism*
chemical_list: D008565:Membrane Proteins; D008840:Microfilament Proteins; D012333:RNA, Messenger; C503968:Synpo protein, mouse; C113267:nephrin; D020742:rhoA GTP-Binding Protein