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Abstract: TH-PO993

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

Session Information

Category: Pathology and Lab Medicine

  • 1501 Pathology and Lab Medicine: Basic

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, Tokyo, Japan
  • Nagata, Michio, University of Tsukuba, Tsukuba, Ibaraki, Japan
Background

Various types of stresses cause epithelial-mesenchymal transitions (EMTs) and detachments of podocyte that result in glomerular sclerosis. Podocyte has self-defense mechanisms to resist against the stresses by expressing aberrant proteins. Vascular cell adhesion molecule-1 (VCAM-1) is a well-known protein induced by stresses that serve functions in membrane-bound and soluble form (sVCAM-1). However, in podocyte, the link between VCAM-1 and stress resistance remains unknown.

Methods

NEP25 transgenic mouse that develop podocyte-specific injury by immunotoxin injection were used. We assessed podocyte VCAM-1 and its ligand expressions by immunostaining, PCR, and western blot (WB). In vivo functions of sVCAM-1 were assessed by inhibiting ADAM17, the shedding enzyme of VCAM-1, by BB94. Immortalized podocyte were used for in vitro studies. The podocyte treated with H2O2, TGF-β1, sVCAM-1, and bpV were analyzed by immunostaining, real-time PCR, WB, and migration assay.

Results

Podocyte-specific injury of NEP25 mouse induced aberrant podocyte VCAM-1 and ADAM17 expression, which suggests the generation of sVCAM-1. Human focal segmental glomerular sclerosis also expressed podocyte VCAM-1. In vivoand in vitropodocyte expressed α9β1 integrin, which is the ligand of sVCAM-1.In vitro, sVCAM-1 ameliorated TGF-β1 induced podocyte EMT; amelioration of enhanced motility, maintenance of podocyte specific proteins, and inhibition of Akt phosphorylation. Mechanistically, sVCAM-1 recruited PTEN against plasma membrane, which was shown by immunostaining and WB analysis of plasma membrane fraction protein. Blockage of PTEN by bpV diminished the efficacy of sVCAM-1 to ameliorate podocyte EMT. Finally, we treated immunotoxin-injected NEP25 mouse by BB94 to inhibit sVCAM-1 generation that resulted in exacerbation of renal disfunction, urinary protein and glomerular sclerosis.

Conclusion

Aberrant sVCAM-1 generation recruited PTEN against plasma membrane to ameliorate podocyte injury by inhibiting Akt phosphorylation. VCAM-1 expression might be one of the intrinsic self-defense mechanisms to resist against stresses in podocyte.