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Abstract: TH-PO070

Soluble Form of VCAM-1 Ameliorates Podocyte Phenotypic Change by Plasma Membrane PTEN Recruitment

Session Information

Category: Glomerular

  • 1002 Glomerular: Basic/Experimental Pathology

Authors

  • Manabe, Shun, University of Tsukuba, Tsukuba, Ibaraki, Japan
  • Sakamoto, Kazuo, University of Tsukuba, Tsukuba, Ibaraki, Japan
  • Ito, Naoko, University of Tsukuba, Tsukuba, Ibaraki, Japan
  • Saga, Nobuyuki, University of Tsukuba, Tsukuba, Ibaraki, Japan
  • Nitta, Kosaku, Tokyo Women's Medical University, Shinjuku-ku, ToKyo, Japan
  • Nagata, Michio, University of Tsukuba, Tsukuba, Ibaraki, Japan
Background

Podocyte stresses are the hallmark of glomerular diseases. The stresses cause podocyte phenotypic change and detachment. Podocyte has self-defense mechanism to resist and adapt against stresses by expressing several stress induced proteins. Vascular cell adhesion molecule-1 (VCAM-1) is a well-known stress induced protein that principally expressed in vascular endothelial cells. The VCAM-1 exerts physiological effects in membrane-bound form and soluble form. The membrane-bound form of VCAM-1 works as a pro-inflammatory molecule, whereas the soluble form of VCAM-1, that is generated by the cleavage of membrane-bound VCAM-1, antagonize the pro-inflammatory effect. However, the links between stress induced VCAM-1 and stress adaptation in podocyte remain largely unknown. Here, we aimed to investigate the role of VCAM-1 in podocyte stress adaptation.

Methods

We induced podocyte stress using NEP25 transgenic mice that develop podocyte specific injury by LMB2 toxin injection. We assessed glomerular VCAM-1 and protease expression eight days after the LMB2 injection. Immortalized podocyte with or without TGF-β1 stimulation was used to study the role of soluble VCAM-1.

Results

The glomerular staining of NEP25 mice indicated aberrant podocyte VCAM-1 expression. VCAM-1 and ADAM-13 (VCAM-1 cleavage enzyme) was simultaneously up regulated in isolated glomeruli that suggest the generation of soluble VCAM-1. Immortalized podocyte constitutively expressed integrin alpha 9 and beta 1, that works as receptor of soluble VCAM-1. The soluble VCAM-1 suppressed TGF-β1 induced podocyte migration and podocyte mRNA expression of EMT markers. The soluble VCAM-1 suppressed podocyte phenotypic change. Western blot analysis of Akt phosphorylation indicate soluble VCAM-1 to suppress the TGF-β1 induced Akt phosphorylation. Next, the treatment with soluble VCAM-1 recruited PTEN to plasma membrane by cell staining and western blot analysis of plasma membrane fraction. The soluble VCAM-1 suppressed PI3K/Akt pathway by plasma membrane PTEN recruitment.

Conclusion

We demonstrated stress induced podocyte VCAM-1 expression. The soluble form of VCAM-1 ameliorates podocyte phenotypic change by suppression PI3K-Akt pathway via plasma membrane PTEN recruitment. Podocyte VCAM-1 expression is one of the intrinsic stress adaptation mechanisms.