Oral Platelet-Derived Growth Factor and Vascular Endothelial Growth Factor Inhibitor Sunitinib Prevents Chronic Allograft Injury in Experimental Kidney Transplantation Model.
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.
1 Transplantation Laboratory, University of Helsinki, Helsinki, Finland. 2 Department of surgery, Oulu University Central Hospital, Oulu, Finland. 3 Transplantation and Liver Surgery Unit, Helsinki University Central Hospital, Helsinki, Finland. 4 Division of Nephrology, Department of Medicine, Helsinki University Central Hospital, Helsinki, Finland.
Jukka M
JM
Rintala
Johanna
J
Savikko
Niina
N
Palin
Sini E
SE
Rintala
Petri K
PK
Koskinen
Eva
E
von Willebrand
D000284:Administration, Oral; D064591:Allografts; D000818:Animals; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D002908:Chronic Disease; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D006084:Graft Rejection / Q000201:enzymology / Q000276:immunology / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D007211:Indoles / Q000008:administration & dosage*; D007668:Kidney / Q000187:drug effects* / Q000201:enzymology / Q000276:immunology / Q000473:pathology / Q000503:physiopathology; D016030:Kidney Transplantation / Q000009:adverse effects*; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D058426:Neointima; D010982:Platelet-Derived Growth Factor / Q000037:antagonists & inhibitors* / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage*; D020574:Proto-Oncogene Proteins c-sis / Q000037:antagonists & inhibitors / Q000378:metabolism; D011758:Pyrroles / Q000008:administration & dosage*; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects; D000077210:Sunitinib; D013997:Time Factors; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors / Q000378:metabolism; D042561:Vascular Endothelial Growth Factor B / Q000037:antagonists & inhibitors / Q000378:metabolism; D042442:Vascular Endothelial Growth Factors / Q000037:antagonists & inhibitors* / Q000378:metabolism
D007211:Indoles; D010982:Platelet-Derived Growth Factor; D047428:Protein Kinase Inhibitors; D020574:Proto-Oncogene Proteins c-sis; D011758:Pyrroles; C581256:VEGFB protein, rat; D042461:Vascular Endothelial Growth Factor A; D042561:Vascular Endothelial Growth Factor B; D042442:Vascular Endothelial Growth Factors; C075278:platelet-derived growth factor A; C467498:vascular endothelial growth factor A, rat; D000077210:Sunitinib