Treatment with a combined endothelin A/B-receptor antagonist does not prevent chronic renal allograft rejection in rats.
A markedly increased expression of endothelin (ET)-1 has been observed in renal allografts with chronic rejection, one of the most common causes of kidney graft loss. In this study we investigated the effect of treatment with a combined ET-A/B-receptor antagonist on the course of chronic renal allograft rejection. Experiments were performed in the Fisher-to-Lewis rat model of chronic rejection. Lewis-to-Lewis isografts and uninephrectomized Lewis rats served as controls. Animals were treated with either the oral combined ET-A/B-receptor antagonist LU224332 (20 mg/kg/day) or vehicle. Animal survival, blood pressure, creatinine clearance, proteinuria, and urinary ET excretion were investigated for 24 weeks. Kidneys were removed for light-microscopic evaluation and immunohistochemical assessment of cell-surface markers. Treatment with LU224332 did not improve survival after 24 weeks (0.47 vs. 0.38; p > 0.05 by log-rank test), nor did it have an influence on blood pressure, creatinine clearance, or proteinuria. Combined ET-A/B-receptor blockade was associated with a reduction of expression of cell-surface markers for macrophages (EDI), T-cells (R73), and major histocompatibility complex (MHC) II (F17-23-2), but did not lead to an improvement of histologic changes of chronic allograft rejection. Our data show that blocking both ET-A- and -B receptors, in opposition to a previously published beneficial effect of selective ET-A blockade, does not prevent the progression of chronic renal allograft rejection and does not prolong survival in this model. Functional integrity of the ET-B receptor therefore seems to play an important role in the nephroprotection provided by selective ET-A-receptor antagonists in chronic renal allograft nephropathy.
Braun
C
C
V. Department of Medicine (Nephrology/Endocrinology), University Hospital Mannheim, University of Heidelberg, Mannheim, Germany. cbraun@rumms.uni-mannheim.de
Conzelmann
T
T
Vetter
S
S
Schaub
M
M
Back
W E
WE
Kirchengast
M
M
Tullius
S G
SG
Schnülle
P
P
van der Woude
F J
FJ
Rohmeiss
P
P
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002908:Chronic Disease; D003404:Creatinine / Q000652:urine; D065128:Endothelin Receptor Antagonists; D016232:Endothelins / Q000652:urine; D005802:Genes, MHC Class II; D006084:Graft Rejection / Q000473:pathology / Q000517:prevention & control*; D006085:Graft Survival / Q000187:drug effects; D007150:Immunohistochemistry; D007668:Kidney / Q000473:pathology; D016030:Kidney Transplantation / Q000502:physiology*; D008297:Male; D011422:Propionates / Q000627:therapeutic use*; D011507:Proteinuria / Q000139:chemically induced; D011743:Pyrimidines / Q000627:therapeutic use*; D051381:Rats; D011916:Rats, Inbred F344; D011917:Rats, Inbred Lew; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B
D065128:Endothelin Receptor Antagonists; D016232:Endothelins; C113044:LU 224332; D011422:Propionates; D011743:Pyrimidines; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D003404:Creatinine