Expression of A20 in the vessel wall of rat-kidney allografts correlates with protection from transplant arteriosclerosis.
BACKGROUND
Chronic rejection with development of transplant arteriosclerosis is the major culprit involved in loss of kidney allografts. The allografts' fate was thought to depend on the intensity of the host immune responses and the potency of immunosuppressive regimens. Recent data suggests that grafts contribute to their own survival by way of up-regulation of "cytoprotective" genes.


METHODS
We analyzed the expression of four cytoprotective genes, A20, Bcl-2, Bcl-x(L) and heme oxygenase (HO)-1, in three rat renal allograft models of chronic rejection: Fisher 344-Lewis (F344/Lew), Dark Agouti-Brown Norway (DA/BN), and DA-Wistar-Furth (WF). We chose these genes for their known anti-inflammatory and anti-apoptotic function in endothelial cells (EC) and the atheroprotective function of A20 in smooth muscle cells (SMC).


RESULTS
Twenty-eight and 9 weeks following transplantation, F344/Lew and DA/BN transplants had stable graft function. Histopathologic analysis showed moderate tissue damage, minimal cellular infiltrates, and preserved vascular integrity correlating with high expression of A20 in SMC. Conversely, impaired allograft function in the DA/WF combination with substantial transplant arteriosclerosis was noted in 60% of the grafts correlating with absent or decreased A20 expression in EC and SMC. In all combinations, expression of HO-1, Bcl-2, and Bcl-x(L) colocalized with infiltrating cells and was not informative on the graft status.


CONCLUSIONS
We demonstrate for the first time a strict correlation between A20 expression in the vessel and the absence of transplant arteriosclerosis in rat kidney-allograft models. This data is similar to data obtained in human kidney allografts and suggests that A20 may represent a novel therapeutic target for the prevention of chronic allograft rejection.
Kunter
Uta
U
Division of Nephrology, Department of Medicine, Universitätsklinikum der RWTH Aachen, Aachen, Germany.
Floege
Jürgen
J
von Jürgensonn
Almut S
AS
Stojanovic
Tomislav
T
Merkel
Saskia
S
Gröne
Hermann J
HJ
Ferran
Christiane
C
D000818:Animals; D001161:Arteriosclerosis / Q000517:prevention & control*; D019610:Cytoprotection; D019254:Genes, bcl-2; D007150:Immunohistochemistry; D007668:Kidney / Q000473:pathology; D016030:Kidney Transplantation / Q000009:adverse effects*; D009131:Muscle, Smooth, Vascular / Q000737:chemistry / Q000378:metabolism*; D011506:Proteins / Q000032:analysis / Q000235:genetics / Q000502:physiology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics; D051381:Rats; D011919:Rats, Inbred Strains; D012077:Renal Artery / Q000737:chemistry / Q000378:metabolism*; D014184:Transplantation, Homologous; D051020:bcl-X Protein
C494813:Bcl2l1 protein, rat; D011506:Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D051020:bcl-X Protein