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Oral Platelet-Derived Growth Factor and Vascular Endothelial Growth Factor Inhibitor Sunitinib Prevents Chronic Allograft Injury in Experimental Kidney Transplantation Model.
- Source :
-
Transplantation [Transplantation] 2016 Jan; Vol. 100 (1), pp. 103-10. - Publication Year :
- 2016
-
Abstract
- Background: Expression of both platelet-derived growth factor (PDGF) and vascular endothelial growth factor (VEGF) is increased during the development of chronic rejection which remains the major reason for late allograft loss in clinical kidney transplantation. Sunitinib is a tyrosine kinase inhibitor which inhibits both VEGF and PDGF receptors. Here we investigated its effect on the development of chronic rejection.<br />Methods: Rat aortic denudation model was used to define sunitinib dose. In vitro studies were done to investigate the effect of sunitinib on smooth muscle cell proliferation and migration. Kidney transplantations were performed from dark agouti rat strain (DA) to Wistar furth rat strain rats and syngenic DA-DA grafts were used as controls. Allografts were immunosuppressed either with cyclosporine or with cyclosporine and sunitinib. Grafts were harvested at 5 and 90 days for histology and immunohistochemistry. Serum creatinine levels were measured weekly to monitor graft function.<br />Results: Sunitinib decreased neointimal formation and smooth muscle cell proliferation and migration in a dose-dependent manner. Sunitinib was well tolerated and almost completely prevented chronic rejection changes and preserved significantly better renal graft function after transplantation. Sunitinib also inhibited chronic PDGF-A and -B and VEGF-A and -B expressions.<br />Conclusions: These results demonstrate that combined inhibition of PGDF and VEGF with sunitinib prevents chronic rejection changes in experimental kidney transplantation which indicates that sunitinib could be a potential intervention also in clinical kidney transplantation.
- Subjects :
- Administration, Oral
Allografts
Animals
Cell Movement drug effects
Cell Proliferation drug effects
Cells, Cultured
Chronic Disease
Disease Models, Animal
Dose-Response Relationship, Drug
Graft Rejection enzymology
Graft Rejection immunology
Graft Rejection pathology
Graft Rejection physiopathology
Kidney enzymology
Kidney immunology
Kidney pathology
Kidney physiopathology
Male
Muscle, Smooth, Vascular drug effects
Muscle, Smooth, Vascular enzymology
Muscle, Smooth, Vascular pathology
Myocytes, Smooth Muscle drug effects
Myocytes, Smooth Muscle enzymology
Myocytes, Smooth Muscle pathology
Neointima
Platelet-Derived Growth Factor metabolism
Proto-Oncogene Proteins c-sis antagonists & inhibitors
Proto-Oncogene Proteins c-sis metabolism
Rats, Wistar
Signal Transduction drug effects
Sunitinib
Time Factors
Vascular Endothelial Growth Factor A antagonists & inhibitors
Vascular Endothelial Growth Factor A metabolism
Vascular Endothelial Growth Factor B antagonists & inhibitors
Vascular Endothelial Growth Factor B metabolism
Vascular Endothelial Growth Factors metabolism
Graft Rejection prevention & control
Indoles administration & dosage
Kidney drug effects
Kidney Transplantation adverse effects
Platelet-Derived Growth Factor antagonists & inhibitors
Protein Kinase Inhibitors administration & dosage
Pyrroles administration & dosage
Vascular Endothelial Growth Factors antagonists & inhibitors
Subjects
Details
- Language :
- English
- ISSN :
- 1534-6080
- Volume :
- 100
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Transplantation
- Publication Type :
- Academic Journal
- Accession number :
- 26262503
- Full Text :
- https://doi.org/10.1097/TP.0000000000000837