title: Divergent functions of the Rho GTPases Rac1 and Cdc42 in podocyte injury.
abstract: Podocytes are highly specialized epithelial cells with complex actin cytoskeletal architecture crucial for maintenance of the glomerular filtration barrier. The mammalian Rho GTPases Rac1 and Cdc42 are molecular switches that control many cellular processes, but are best known for their roles in the regulation of actin cytoskeleton dynamics. Here, we employed podocyte-specific Cre-lox technology and found that mice with deletion of Rac1 display normal podocyte morphology without glomerular dysfunction well into adulthood. Using the protamine sulfate model of acute podocyte injury, podocyte-specific deletion of Rac1 prevented foot process effacement. In a long-term model of chronic hypertensive glomerular damage, however, loss of Rac1 led to an exacerbation of albuminuria and glomerulosclerosis. In contrast, mice with podocyte-specific deletion of Cdc42 had severe proteinuria, podocyte foot process effacement, and glomerulosclerosis beginning as early as 10 days of age. In addition, slit diaphragm proteins nephrin and podocin were redistributed, and cofilin was dephosphorylated. Cdc42 is necessary for the maintenance of podocyte structure and function, but Rac1 is entirely dispensable in physiological steady state. However, Rac1 has either beneficial or deleterious effects depending on the context of podocyte impairment. Thus, our study highlights the divergent roles of Rac1 and Cdc42 function in podocyte maintenance and injury.
authors.affiliation: Department of Internal Medicine, Division of Nephrology, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Simone M
authors.initials: SM
authors.lastname: Blattner
authors.forename: Jeffrey B
authors.initials: JB
authors.lastname: Hodgin
authors.forename: Masashi
authors.initials: M
authors.lastname: Nishio
authors.forename: Stephanie A
authors.initials: SA
authors.lastname: Wylie
authors.forename: Jharna
authors.initials: J
authors.lastname: Saha
authors.forename: Abdul A
authors.initials: AA
authors.lastname: Soofi
authors.forename: Courtenay
authors.initials: C
authors.lastname: Vining
authors.forename: Ann
authors.initials: A
authors.lastname: Randolph
authors.forename: Nadja
authors.initials: N
authors.lastname: Herbach
authors.forename: Ruediger
authors.initials: R
authors.lastname: Wanke
authors.forename: Kevin B
authors.initials: KB
authors.lastname: Atkins
authors.forename: Hee
authors.initials: H
authors.lastname: Gyung Kang
authors.forename: Anna
authors.initials: A
authors.lastname: Henger
authors.forename: Cord
authors.initials: C
authors.lastname: Brakebusch
authors.forename: Lawrence B
authors.initials: LB
authors.lastname: Holzman
authors.forename: Matthias
authors.initials: M
authors.lastname: Kretzler
mesh_terms: D051339:Actin Depolymerizing Factors / Q000378:metabolism; D058186:Acute Kidney Injury / Q000139:chemically induced / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D000419:Albuminuria / Q000378:metabolism; D000818:Animals; D048430:Cell Shape; D064791:Desoxycorticosterone Acetate; D004195:Disease Models, Animal; D005838:Genotype; D006973:Hypertension / Q000139:chemically induced / Q000201:enzymology / Q000235:genetics; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009392:Nephrectomy; D009479:Neuropeptides / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D010641:Phenotype; D010766:Phosphorylation; D050199:Podocytes / Q000201:enzymology* / Q000473:pathology; D011479:Protamines; D051437:Renal Insufficiency / Q000201:enzymology* / Q000209:etiology / Q000235:genetics / Q000473:pathology; D015398:Signal Transduction; D013997:Time Factors; D020764:cdc42 GTP-Binding Protein / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D020830:rac1 GTP-Binding Protein / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
chemical_list: D051339:Actin Depolymerizing Factors; C581598:Cdc42 protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; C407223:NPHS2 protein; D009479:Neuropeptides; D011479:Protamines; C484602:Rac1 protein, mouse; C113267:nephrin; D064791:Desoxycorticosterone Acetate; D020764:cdc42 GTP-Binding Protein; D020830:rac1 GTP-Binding Protein