title: Cdc42 deficiency induces podocyte apoptosis by inhibiting the Nwasp/stress fibers/YAP pathway.
abstract: Podocyte apoptosis is a major mechanism that leads to proteinuria in many chronic kidney diseases. However, the concert mechanisms that cause podocyte apoptosis in these kidney diseases are not fully understood. The Rho family of small GTPases has been shown to be required in maintaining podocyte structure and function. Recent studies have indicated that podocyte-specific deletion of Cdc42 in vivo, but not of RhoA or Rac1, leads to congenital nephrotic syndrome and glomerulosclerosis. However, the underlying cellular events in podocyte controlled by Cdc42 remain unclear. Here, we assessed the cellular mechanisms by which Cdc42 regulates podocyte apoptosis. We found that the expression of Cdc42 and its activity were significantly decreased in high glucose-, lipopolysaccharide- or adriamycin-injured podocytes. Reduced Cdc42 expression in vitro and in vivo by small interfering RNA and selective Cdc42 inhibitor ML-141, respectively, caused podocyte apoptosis and proteinuria. Our results further demonstrated that insufficient Cdc42 or Nwasp, its downstream effector, could decrease the mRNA and protein expression of YAP, which had been regarded as an anti-apoptosis protein in podocyte. Moreover, our data indicated that the loss of stress fibers caused by Cdc42/Nwasp deficiency also decreased Yes-associated protein (YAP) mRNA and protein expression, and induced podocyte apoptosis. Podocyte apoptosis induced by Cdc42/Nwasp/stress fiber deficiency was significantly inhibited by overexpressing-active YAP. Thus, the Cdc42/Nwasp/stress fibers/YAP signal pathway may potentially play an important role in regulating podocyte apoptosis. Maintaining necessary Cdc42 would be one potent way to prevent proteinuria kidney diseases.
authors.affiliation: Southern Medical University, Guangzhou, Guangdong, China.|Department of Nephrology, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China.
authors.forename: Z
authors.initials: Z
authors.lastname: Huang
authors.affiliation: Department of Nephrology, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China.
authors.forename: L
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Nephrology, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Nephrology, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China.
authors.forename: H
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Department of Nephrology, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China.
authors.forename: Q
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: Department of Nephrology, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China.
authors.forename: R
authors.initials: R
authors.lastname: Li
authors.affiliation: Department of Nephrology, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China.
authors.forename: J
authors.initials: J
authors.lastname: Ma
authors.affiliation: Department of Nephrology, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China.
authors.forename: Z
authors.initials: Z
authors.lastname: Li
authors.affiliation: Department of Nephrology, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China.
authors.forename: C
authors.initials: C
authors.lastname: Yu
authors.affiliation: Department of Nephrology, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Lai
authors.affiliation: Department of Nephrology, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China.
authors.forename: T
authors.initials: T
authors.lastname: Lin
authors.affiliation: Department of Nephrology, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China.
authors.forename: X
authors.initials: X
authors.lastname: Zhao
authors.affiliation: Department of Nephrology, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China.
authors.forename: B
authors.initials: B
authors.lastname: Zhang
authors.affiliation: Department of Nephrology, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China.
authors.forename: Z
authors.initials: Z
authors.lastname: Ye
authors.affiliation: Department of Nephrology, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China.
authors.forename: S
authors.initials: S
authors.lastname: Liu
authors.affiliation: Department of Nephrology, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China.
authors.forename: W
authors.initials: W
authors.lastname: Wang
authors.affiliation: Department of Nephrology, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China.
authors.forename: X
authors.initials: X
authors.lastname: Liang
authors.affiliation: Department of Nephrology, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China.
authors.forename: R
authors.initials: R
authors.lastname: Liao
authors.forename: W
authors.initials: W
authors.lastname: Shi
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D017209:Apoptosis; D006801:Humans; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D050199:Podocytes / Q000378:metabolism* / Q000473:pathology; D011507:Proteinuria / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction; D022502:Stress Fibers / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D014157:Transcription Factors; D051317:Wiskott-Aldrich Syndrome Protein, Neuronal / Q000235:genetics / Q000378:metabolism*; D000091102:YAP-Signaling Proteins; D020764:cdc42 GTP-Binding Protein / Q000172:deficiency*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D010750:Phosphoproteins; D014157:Transcription Factors; C495771:WASL protein, human; D051317:Wiskott-Aldrich Syndrome Protein, Neuronal; D000091102:YAP-Signaling Proteins; C088374:YAP1 protein, human; D020764:cdc42 GTP-Binding Protein