Therapeutic targets in liver transplantation: angiotensin II in nonsteatotic grafts and angiotensin-(1-7) in steatotic grafts.
Numerous steatotic livers are discarded as unsuitable for transplantation because of their poor tolerance of ischemia-reperfusion(I/R). The injurious effects of angiotensin (Ang)-II and the benefits of Ang-(1-7) in various pathologies are well documented. We examined the generation of Ang II and Ang-(1-7) in steatotic and nonsteatotic liver grafts from Zucker rats following transplantation. We also studied in both liver grafts the effects of Ang-II receptors antagonists and Ang-(1-7) receptor antagonists on hepatic I/R damage associated with transplantation. Nonsteatotic grafts showed higher Ang II levels than steatotic grafts, whereas steatotic grafts showed higher Ang-(1-7) levels than nonsteatotic grafts. Ang II receptor antagonists protected only nonsteatotic grafts against damage, whereas Ang-(1-7) receptor antagonists were effective only in steatotic grafts. The protection conferred by Ang II receptor antagonists in nonsteatotic grafts was associated with ERK 1/2 overexpression, whereas the beneficial effects of Ang-(1-7) receptor antagonists in steatotic grafts may be mediated by NO inhibition. Our results show that Ang II receptor antagonists are effective only in nonsteatotic liver transplantation and point to a novel therapeutic target in liver transplantation based on Ang-(1-7), which is specific for steatotic liver grafts.
Alfany-Fernandez
I
I
Centro de Investigaciones Biomédicas Esther Koplowitz, CIBER-EHD, Instituto de Salud Carlos III, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain.
Casillas-Ramirez
A
A
Bintanel-Morcillo
M
M
Brosnihan
K B
KB
Ferrario
C M
CM
Serafin
A
A
Rimola
A
A
Rodés
J
J
Roselló-Catafau
J
J
Peralta
C
C
D000803:Angiotensin I / Q000235:genetics / Q000378:metabolism*; D000804:Angiotensin II / Q000235:genetics / Q000378:metabolism*; D000808:Angiotensinogen / Q000235:genetics / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D005234:Fatty Liver / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000601:surgery; D006085:Graft Survival; D006262:Health; D016031:Liver Transplantation; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D010446:Peptide Fragments / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D011945:Receptors, Angiotensin / Q000378:metabolism
D010446:Peptide Fragments; D011945:Receptors, Angiotensin; D000808:Angiotensinogen; D000804:Angiotensin II; D000803:Angiotensin I; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; C118790:angiotensin I (1-7)