Tissue kallikrein inhibits retinal neovascularization via the cleavage of vascular endothelial growth factor-165.

Abstract

OBJECTIVE:

Tissue kallikrein, a widely used vasodilator for the treatment of hypertension and peripheral circulatory disorder, acts by releasing kinin, a potent vasodilator peptide. To identify the role of tissue kallikrein in retinal neovascularization, we investigated the antiangiogenic effect by using an in vitro and in vivo angiogenesis model.

METHODS AND RESULTS:

Tissue kallikrein in vitreous fluid was markedly elevated in proliferative diabetic retinopathy patients compared with that in control patients with macular hole and epiretinal membrane. Tissue kallikrein inhibited vascular endothelial growth factor-165 (VEGF165)-induced tube formation, proliferation, and migration in vitro angiogenesis model via suppression of the VEGF165-induced phosphorylation of VEGF receptor-2. Furthermore, tissue kallikrein cleavage of VEGF165 was on the C-terminal side, which was analyzed by Western blotting and mass spectrometry. When administered subcutaneously, tissue kallikrein reduced the pathological vascular changes in retinal neovascularization induced in neonatal mice by returning the retina to normoxia after exposure to hyperoxia.

CONCLUSIONS:

These findings indicate that tissue kallikrein is partly involved in pathogenesis of proliferative diabetic retinopathy and may be a promising therapeutic agent that could cleave VEGF165 itself when administered by a peripheral route.

• Authors: Shinsuke Nakamura, Nobutaka Morimoto, Kazuhiro Tsuruma, Hiroshi Izuta, Yoshika Yasuda, Noriaki Kato, Tsunehiko Ikeda, Masamitsu Shimazawa, Hideaki Hara
• Journal: Arteriosclerosis, thrombosis, and vascular biology (Arterioscler Thromb Vasc Biol) Vol. 31 Issue 5 Pg. 1041-8 (May 2011) ISSN: 1524-4636 [Electronic] United States
• PMID: 21293011 (Publication Type: Journal Article)

Chemical References

• Angiogenesis Inhibitors
• VEGFA protein, human
• Vascular Endothelial Growth Factor A
• vascular endothelial growth factor A, mouse
• Vascular Endothelial Growth Factor Receptor-2
• Extracellular Signal-Regulated MAP Kinases
• p38 Mitogen-Activated Protein Kinases
• Tissue Kallikreins

Topics

• Aged
• Amino Acid Sequence
• Angiogenesis Inhibitors (administration & dosage, metabolism)
• Animals
• Blotting, Western
• Case-Control Studies
• Cell Movement (drug effects)
• Cell Proliferation (drug effects)
• Cells, Cultured
• Coculture Techniques
• Diabetic Retinopathy (enzymology, pathology)
• Disease Models, Animal
• Endothelial Cells (drug effects, metabolism)
• Extracellular Signal-Regulated MAP Kinases (metabolism)
• Female
• Humans
• Injections, Subcutaneous
• Male
• Mass Spectrometry
• Mice
• Mice, Inbred C57BL
• Middle Aged
• Molecular Sequence Data
• Phosphorylation
• Protein Processing, Post-Translational
• Rats
• Retinal Neovascularization (enzymology, pathology, prevention & control)
• Retinal Vessels (drug effects, enzymology, pathology)
• Time Factors
• Tissue Kallikreins (administration & dosage, metabolism)
• Up-Regulation
• Vascular Endothelial Growth Factor A (metabolism)
• Vascular Endothelial Growth Factor Receptor-2 (metabolism)
• Vitreous Body (enzymology)
• p38 Mitogen-Activated Protein Kinases (metabolism)