Protective effects of PG490-88 on chronic allograft rejection by changing intragraft gene expression profiles.
Our previous study showed that PG490-88 effectively ameliorated both functional and histological changes of chronic rejection in the rat. In this experiment, we investigated the intragraft gene expression profiles of PG490-88 under successful prevention of chronic rejection in rat kidney allografts. Kidneys of F344 rats were transplanted into bilaterally nephrectomized LEW recipients. Recipients with a brief course of low-dose FK506 (1 mg/kg per day for 10 days) were dosed with PG490-88 0.5 mg/kg per day, which was predetermined and defined as the effective dose of preventing chronic allograft rejection in this model, for 90 days after grafting. Kidney grafts were harvested on day 90 after transplantation and subjected to gene expression analysis by real-time RT-PCR. Overall, the expression levels of all genes tested were upregulated in the brief course of low-dose FK506 control. PG490-88 treatment exhibited significant inhibition of intragraft m RNA levels of iNOS, IL-6, and perforin and marginal downregulation of IL-2, IFNgamma, IRF-1, TNFalpha, and TGFbeta. There was no change in IL-10, granzyme B, and PDGFalpha, when compared to the brief course of low-dose FK506 control. These results suggested that downregulation of multiple intragraft gene expression by mainly suppression of iNOS, IL-6, and perforin might be responsible for successful prevention of chronic kidney allograft nephropathy by PG490-88 in rats.
Fisniku
O
O
Basic Research, Fujisawa Research Institute of America, Evanston, Illinois 60201, USA.
Pan
F
F
Wynn
C
C
Erickson
L M
LM
Crews
G
G
Jang
M S
MS
Sudo
Y
Y
Tamura
K
K
Kobayashi
M
M
Benediktsson
H
H
Jiang
H
H
D000818:Animals; D016207:Cytokines / Q000235:genetics*; D004224:Diterpenes / Q000494:pharmacology*; D020869:Gene Expression Profiling; D006084:Graft Rejection / Q000517:prevention & control*; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D016030:Kidney Transplantation / Q000276:immunology / Q000502:physiology*; D051381:Rats; D011916:Rats, Inbred F344; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016559:Tacrolimus / Q000494:pharmacology; D014184:Transplantation, Homologous / Q000276:immunology*
D016207:Cytokines; D004224:Diterpenes; D007166:Immunosuppressive Agents; C417603:omtriptolide; D016559:Tacrolimus