CD2-associated protein/phosphoinositide 3-kinase signaling has a preventive role in angiotensin II-induced podocyte apoptosis

Int J Biochem Cell Biol. 2016 Oct:79:370-381. doi: 10.1016/j.biocel.2016.08.042. Epub 2016 Aug 31.

Abstract

Angiotensin II (Ang II) works as a paracrine or autocrine cytokine agent to regulate renal functions and promotes podocytes dysfunction directly or indirectly, causing proteinuria. The glomerular slit diaphragm (SD) serves as a size-selective barrier and is linked to the actin-based cytoskeleton by adaptor proteins, including CD2-associated protein (CD2AP). Therefore, damages to CD2AP affect not only the function of the SD, but also directly disrupt the podocyte cytoskeleton, leading to proteinuria. In addition, CD2AP can facilitate the nephrin-induced phosphoinositide 3-kinase (PI3-K)/Akt signaling, which protects podocytes from apoptosis. Here we found that CD2AP staining was located diffusely but predominantly in the peripheral cytoplasm and CD2AP co-localized with nephrin in mouse podocytes; however, Ang II decreased CD2AP staining diffusely and induced a separation from concentrated nephrin. Ang II notably reduced CD2AP expression in time- and concentration-dependent manners, and this was significantly recovered by losartan. Ang II induced podocyte apoptosis in time- and concentration-dependent manners in TUNEL and FACS assays. LY294002, a PI3-K inhibitor, further reduced CD2AP expression and increased podocyte apoptosis, which was augmented by siRNA for CD2AP. Thus, Ang II induces the relocalization and reduction of CD2AP via AT1R, which would cause podocyte apoptosis by the suppression of CD2AP/PI3-K signaling.

Keywords: Angiotensin II; Apoptosis; CD2-associated protein; Phosphoinositide 3-kinase; Podocyte.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / deficiency
  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / metabolism*
  • Angiotensin II / pharmacology*
  • Animals
  • Apoptosis / drug effects*
  • Chromones / pharmacology
  • Cytoskeletal Proteins / deficiency
  • Cytoskeletal Proteins / genetics
  • Cytoskeletal Proteins / metabolism*
  • Dose-Response Relationship, Drug
  • Gene Expression Regulation / drug effects
  • Gene Knockdown Techniques
  • Mice
  • Morpholines / pharmacology
  • Phosphatidylinositol 3-Kinases / metabolism*
  • Podocytes / cytology*
  • Podocytes / drug effects*
  • Podocytes / metabolism
  • Protein Transport / drug effects
  • Receptor, Angiotensin, Type 1 / metabolism
  • Signal Transduction / drug effects

Substances

  • Adaptor Proteins, Signal Transducing
  • CD2-associated protein
  • Chromones
  • Cytoskeletal Proteins
  • Morpholines
  • Receptor, Angiotensin, Type 1
  • Angiotensin II
  • 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
  • Phosphatidylinositol 3-Kinases