Cytotoxic effects of alteplase, a recombinant tissue plasminogen activator, on human retinal pigment epithelial cells

Shuhei Kimura, Yuki Morizane, Shinji Toshima, Yusuke Shiode, Shinichiro Doi, Kosuke Takahashi, Ryo Matoba, Yuki Kanzaki, Fumio Shiraga

Research output: Contribution to journalArticlepeer-review

Abstract

Purpose: To evaluate the cytotoxic effects of alteplase, a recombinant tissue plasminogen activator, and its additives on human retinal pigment epithelial (hRPE) cells. Study design: Laboratory study. Methods: We evaluated the cytotoxic effects of alteplase on human fetal RPE (hfRPE) cells, human induced pluripotent stem cell-derived RPE (hiPS-RPE), and ARPE-19 cells, as well as the cytotoxic effects of L-arginine and polysorbate 80, two additives of alteplase, on hfRPE cells. The effects of alteplase on the production of vascular endothelial growth factor (VEGF) and pigment epithelium-derived factor (PEDF) from hfRPE cells and the transepithelial resistance (TER) of hiPS-RPE cells were also assessed. The type of cell death induced by alteplase was investigated using ethidium homodimer III and FITC-Annexin V staining and terminal transferase deoxyuridine triphosphatase nick-end labeling. Results: Alteplase reduced the viability of hfRPE cells significantly in a dose- and time-dependent manner. The reaction of hiPS-RPE and ARPE19 cells to alteplase was similar to that of hfRPE cells. Out of L-arginine and polysorbate 80, only treatment with L-arginine significantly reduced the viability of hfRPE cells. Alteplase (83 μg/ml, 6 h) had no significant effect on the production of VEGF and PEDF from hfRPE cells. Alteplase decreased the TER of hiPS-RPE cells in a dose- and time-dependent manner and induced necrosis as the type of cell death. Conclusion: Alteplase can be cytotoxic to human RPE cells in a concentration- and time-dependent manner, with L-arginine being a possible causative factor.

Original languageEnglish
Pages (from-to)731-739
Number of pages9
JournalJapanese Journal of Ophthalmology
Volume65
Issue number5
DOIs
Publication statusPublished - Sep 2021

Keywords

  • Cytotoxicity
  • Human retinal pigment epithelial cell
  • L-arginine
  • Submacular hemorrhage
  • Tissue plasminogen activator

ASJC Scopus subject areas

  • Ophthalmology

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