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Abstract: TH-PO425

ZNF185 Prevents Stress Fiber Formation Through the Inhibition of RhoA in Endothelial Cells

Session Information

Category: Glomerular Diseases

  • 1301 Glomerular Diseases: Fibrosis and Extracellular Matrix

Authors

  • Suzuki, Soichiro, Tokyo Ika Shika Daigaku, Bunkyo-ku, Tokyo, Japan
  • Ando, Fumiaki, Tokyo Ika Shika Daigaku, Bunkyo-ku, Tokyo, Japan
  • Hara, Yu, Tokyo Ika Shika Daigaku, Bunkyo-ku, Tokyo, Japan
  • Fujiki, Tamami, Tokyo Ika Shika Daigaku, Bunkyo-ku, Tokyo, Japan
  • Mandai, Shintaro, Tokyo Ika Shika Daigaku, Bunkyo-ku, Tokyo, Japan
  • Susa, Koichiro, Tokyo Ika Shika Daigaku, Bunkyo-ku, Tokyo, Japan
  • Mori, Takayasu, Tokyo Ika Shika Daigaku, Bunkyo-ku, Tokyo, Japan
  • Sohara, Eisei, Tokyo Ika Shika Daigaku, Bunkyo-ku, Tokyo, Japan
  • Rai, Tatemitsu, Tokyo Ika Shika Daigaku, Bunkyo-ku, Tokyo, Japan
  • Uchida, Shinichi, Tokyo Ika Shika Daigaku, Bunkyo-ku, Tokyo, Japan
Background

Cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA) signaling promotes endothelial barrier function to prevent plasma leakage induced by inflammatory mediators. Although PKA is a major effector of vascular permeability, the molecular mechanisms underlying PKA signaling pathway in endothelial cells remain to be determined. In this study, we used a cAMP inducer, forskolin, and a phospho-PKA substrate antibody to identify ZNF185 as a novel PKA substrate. ZNF185 has been described as a protein involved in the regulation of cell differentiation and proliferation of cancers. However, its physiological relevance in endothelial cells has not yet been established.

Methods

We investigated the function of ZNF185 in human umbilical endothelial cells (HUVECs).

Results

ZNF185 is an actin cytoskeleton-associated protein and colocalized with F-actin in endothelial cells. ZNF185 also interacted with PKA which autophosphorylated ZNF185 itself. Both phospho-ZNF185 and F-actin accumulated at plasma membrane region in response to forskolin to stabilize the cortical actin structure. By contrast, ZNF185 knockdown disrupted actin filaments and promoted stress fiber formation without inflammatory mediators. Constitutive activation of RhoA was induced by ZNF185 knockdown, which resulted in forskolin-resistant endothelial barrier dysfunction. ZNF185 was essential for cAMP/PKA/RhoA singling for the suppression of endothelial hyperpermeability.

Conclusion

ZNF185 is necessary for the maintenance of cytoskeletal actin structures in endothelial cells.