Oral Platelet-Derived Growth Factor and Vascular Endothelial Growth Factor Inhibitor Sunitinib Prevents Chronic Allograft Injury in Experimental Kidney Transplantation Model
| Autor: | Jukka Rintala, Niina Palin, Sini E. Rintala, Eva von Willebrand, Petri Koskinen, Johanna Savikko |
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| Rok vydání: | 2015 |
| Předmět: |
Graft Rejection
Male Vascular Endothelial Growth Factor A Vascular Endothelial Growth Factor B Platelet-derived growth factor Indoles Time Factors Administration Oral 030230 surgery Pharmacology urologic and male genital diseases Kidney Tyrosine-kinase inhibitor Muscle Smooth Vascular chemistry.chemical_compound 0302 clinical medicine Cell Movement Sunitinib Cells Cultured Platelet-Derived Growth Factor biology Vascular Endothelial Growth Factors Proto-Oncogene Proteins c-sis Allografts female genital diseases and pregnancy complications Vascular endothelial growth factor Vascular endothelial growth factor B Vascular endothelial growth factor A 030220 oncology & carcinogenesis Platelet-derived growth factor receptor medicine.drug Signal Transduction medicine.medical_specialty medicine.drug_class Myocytes Smooth Muscle 03 medical and health sciences Internal medicine Neointima medicine Animals Pyrroles Rats Wistar Protein Kinase Inhibitors Cell Proliferation Transplantation Dose-Response Relationship Drug business.industry Kidney Transplantation Disease Models Animal Endocrinology chemistry Chronic Disease biology.protein business |
| Zdroj: | Transplantation. 100(1) |
| ISSN: | 1534-6080 |
| Popis: | 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. 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. 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. 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. |
| Databáze: | OpenAIRE |
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