Early induction of platelet-derived growth factor ligands and receptors in acute rat renal allograft rejection.
BACKGROUND
Acute rejection is the single most important risk factor for the development of subsequent chronic rejection. Platelet-derived growth factor (PDGF) is a major mitogen that mediates mesenchymal cell proliferation in chronic rejection. Therefore, we investigated whether PDGF ligands and receptors are induced during acute renal allograft rejection in rat.


METHODS
Kidney transplantations were performed from Dark Agouti (DA) to Wistar-Furth (WF) rats, and syngenic controls were performed from DA to DA rats. Allografts were immunosuppressed with cyclosporine (CsA) 1.5 mg/kg/d subcutaneously or left untreated. Grafts were harvested at 1, 3, 5, and 7 days for histology and immunohistochemistry.


RESULTS
In syngenic grafts, no histological signs of acute rejection were seen and the expression of PDGF ligands and receptors remained almost nonexistent. In nontreated allografts, intense rejection resulted in graft necrosis in 7 days. Acute rejection was associated with the induction of all PDGF ligands and receptors (P<0.05 compared to syngenic controls). The expression of PDGF ligands and receptors was located mainly to graft-infiltrating macrophages but also to capillary endothelium and arteriolar smooth muscle cells. CsA significantly ameliorated acute rejection but failed to inhibit the induction of PDGF and its receptors in CsA-treated allografts.


CONCLUSIONS
Our results demonstrate that PDGF ligands and receptors are induced during acute rejection. PDGF may be induced directly as a reparative response to graft injury in acute rejection or indirectly by various inflammatory mediators released by graft-infiltrating inflammatory cells. This study indicates that PDGF ligands and receptors are already induced in acute rejection, which suggests a link between acute rejection and the subsequent development of chronic rejection.
Savikko
J
J
Transplantation Laboratory, and Helsinki University Central Hospital, P.O. Box 21 (Haartmaninkatu 3), University of Helsinki, FIN-00014 Helsinki, Finland.
Kallio
E A
EA
von Willebrand
E
E
D000208:Acute Disease; D000818:Animals; D000077214:Becaplermin; D006084:Graft Rejection / Q000378:metabolism*; D007150:Immunohistochemistry; D007668:Kidney / Q000378:metabolism / Q000473:pathology; D016030:Kidney Transplantation; D008024:Ligands; D008297:Male; D010982:Platelet-Derived Growth Factor / Q000378:metabolism*; D020574:Proto-Oncogene Proteins c-sis; D051381:Rats; D011919:Rats, Inbred Strains; D011920:Rats, Inbred WF; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000378:metabolism*; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000378:metabolism*; D014184:Transplantation, Homologous
D008024:Ligands; D010982:Platelet-Derived Growth Factor; D020574:Proto-Oncogene Proteins c-sis; C075278:platelet-derived growth factor A; D000077214:Becaplermin; D020796:Receptor, Platelet-Derived Growth Factor alpha; D020797:Receptor, Platelet-Derived Growth Factor beta