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.
Highlights
Rho family small GTPases RhoA, Rac[1], and Cdc[42] are the three most extensively studied prototypes, and are known powerful regulators of actin cytoskeletal dynamics, cell adhesive interactions, motility, or cell polarity.[5]
Our results further demonstrated that insufficient Cdc[42] or neuronal Wiskott–Aldrich syndrome protein (Nwasp), its downstream effector, could decrease the mRNA and protein expression of Yes-associated protein (YAP), which had been regarded as an anti-apoptosis protein in podocyte
Consistent with the results above, the mRNA and protein expression of Bax, a well-recognized indicator of apoptosis were significantly increased in high glucose (HG), LPS and ADR-treated podocytes comparing to normal controls (Figures 1m–o)
Summary
Rho family small GTPases RhoA, Rac[1], and Cdc[42] are the three most extensively studied prototypes, and are known powerful regulators of actin cytoskeletal dynamics, cell adhesive interactions, motility, or cell polarity.[5]. YAP localizes in the nucleus and functions as a transcriptional co-activator that mainly through interacting with TEA domain family member family transcriptional factors to induce target gene expression.[15] YAP phosphorylation promotes its cytoplasmic sequestration and inactivation.[16,17] Recent studies have indicated that YAP is an anti-apoptotic molecule in podocyte, and podocyte-specific deletion of YAP leads to proteinuria kidney diseases.[18,19] loss of stress fiber. We demonstrate that the loss of Cdc[42] in vitro and in vivo by small interfering RNA (siRNA) and selective inhibitor ML-141, respectively, caused podocyte apoptosis and proteinuria, accompanied with increased pro-apoptotic Bax and decreased anti-apoptotic Bcl-2 gene and protein expression. Our data indicated that the loss of stress fibers caused by Cdc42/Nwasp deficiency decreased YAP mRNA and protein expression, and induced podocyte apoptosis. Maintaining necessary Cdc[42] would be one potent way to prevent proteinuria kidney diseases
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
