TY - JOUR
T1 - Cytotoxic effects of alteplase, a recombinant tissue plasminogen activator, on human retinal pigment epithelial cells
AU - Kimura, Shuhei
AU - Morizane, Yuki
AU - Toshima, Shinji
AU - Shiode, Yusuke
AU - Doi, Shinichiro
AU - Takahashi, Kosuke
AU - Matoba, Ryo
AU - Kanzaki, Yuki
AU - Shiraga, Fumio
N1 - Funding Information:
We thank Nobue Mukai and Kumiko Kikuchi and Shiori Ikeda for their excellent technical assistance.
Publisher Copyright:
© 2021, Japanese Ophthalmological Society.
PY - 2021/9
Y1 - 2021/9
N2 - 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.
AB - 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.
KW - Cytotoxicity
KW - Human retinal pigment epithelial cell
KW - L-arginine
KW - Submacular hemorrhage
KW - Tissue plasminogen activator
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U2 - 10.1007/s10384-021-00848-2
DO - 10.1007/s10384-021-00848-2
M3 - Article
C2 - 34117982
AN - SCOPUS:85107769243
VL - 65
SP - 731
EP - 739
JO - Japanese Journal of Ophthalmology
JF - Japanese Journal of Ophthalmology
SN - 0021-5155
IS - 5
ER -