Exendin-4 attenuates brain death-induced liver damage in the rat.
The majority of liver grafts destined for transplantation originate from brain dead donors. However, significantly better posttransplantation outcomes are achieved when organs from living donors are used, suggesting that brain death (BD) causes irreversible damage to the liver tissue. Recently, glucagon-like peptide-1 (GLP1) analogues were shown to possess interesting hepatic protection effects in different liver disease models. We hypothesized that donor treatment with the GLP1 analogue exendin-4 (Ex-4) could alleviate BD-induced liver damage. A rat model of BD was employed in order to estimate BD-induced liver damage and Ex-4's potential protective effects. Liver damage was assessed by biochemical determination of circulating hepatic markers. Apoptosis in the hepatic tissue was assessed by immunoblot and immunohistochemistry using an antibody that only recognizes the active form of caspase-3. Gene expression changes in inflammation and stress response genes were monitored by quantitative real-time polymerase chain reaction. Here, we show that Ex-4 administration to the brain dead liver donors significantly reduces levels of circulating aspartate aminotransferase and lactate dehydrogenase. This was accompanied by a remarkable reduction in hepatocyte apoptosis. In this model, BD caused up-regulation of tumor necrosis factor and stress-related genes, confirming previous findings in clinical and animal studies. In conclusion, treatment of brain dead rats with Ex-4 reduced BD-induced liver damage. Further investigation is needed to determine the molecular basis of the observed liver protection. After testing in a randomized clinical trial, the inclusion of GLP1 analogues in organ donor management might help to improve organ quality, maximize organ donation, and possibly increase liver transplantation success rates.
Laboratory of Human Pancreatic Islet Biology, Endocrine Division, Hospital de Clínicas de Porto Alegre, Porto Alegre, Rio Grande do Sul, Brazil.|Postgraduate Program in Medical Sciences, Endocrinology, Faculty of Medical Sciences, Universidade Federal do Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil.|School of Biomedical Sciences, Curtin Health Innovation Research Institute-Biosciences, Curtin University, Perth, Western Australia, Australia.
Rodrigo
R
Carlessi
Laboratory of Human Pancreatic Islet Biology, Endocrine Division, Hospital de Clínicas de Porto Alegre, Porto Alegre, Rio Grande do Sul, Brazil.|Postgraduate Program in Medical Sciences, Endocrinology, Faculty of Medical Sciences, Universidade Federal do Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil.
Natalia E
NE
Lemos
Laboratory of Human Pancreatic Islet Biology, Endocrine Division, Hospital de Clínicas de Porto Alegre, Porto Alegre, Rio Grande do Sul, Brazil.
Ana L
AL
Dias
Laboratory of Human Pancreatic Islet Biology, Endocrine Division, Hospital de Clínicas de Porto Alegre, Porto Alegre, Rio Grande do Sul, Brazil.|Postgraduate Program in Medical Sciences, Endocrinology, Faculty of Medical Sciences, Universidade Federal do Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil.
Leticia A
LA
Brondani
Biosciences Faculty, Pontificia Universidade Catolica do Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil.
Jarbas R
JR
Oliveira
Laboratory of Human Pancreatic Islet Biology, Endocrine Division, Hospital de Clínicas de Porto Alegre, Porto Alegre, Rio Grande do Sul, Brazil.
Andrea C
AC
Bauer
Laboratory of Human Pancreatic Islet Biology, Endocrine Division, Hospital de Clínicas de Porto Alegre, Porto Alegre, Rio Grande do Sul, Brazil.|Postgraduate Program in Medical Sciences, Endocrinology, Faculty of Medical Sciences, Universidade Federal do Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil.
Cristiane B
CB
Leitão
Laboratory of Human Pancreatic Islet Biology, Endocrine Division, Hospital de Clínicas de Porto Alegre, Porto Alegre, Rio Grande do Sul, Brazil.|Postgraduate Program in Medical Sciences, Endocrinology, Faculty of Medical Sciences, Universidade Federal do Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil.
Daisy
D
Crispim
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D001926:Brain Death / Q000378:metabolism; D053148:Caspase 3 / Q000096:biosynthesis / Q000235:genetics; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D000077270:Exenatide; D005786:Gene Expression Regulation; D052216:Glucagon-Like Peptide 1 / Q000031:analogs & derivatives; D007004:Hypoglycemic Agents / Q000008:administration & dosage; D015151:Immunoblotting; D007150:Immunohistochemistry; D008099:Liver / Q000187:drug effects / Q000473:pathology; D008107:Liver Diseases / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control*; D016031:Liver Transplantation; D008297:Male; D010455:Peptides / Q000008:administration & dosage*; D051381:Rats; D017208:Rats, Wistar; D060888:Real-Time Polymerase Chain Reaction; D014688:Venoms / Q000008:administration & dosage*
D016207:Cytokines; D007004:Hypoglycemic Agents; D010455:Peptides; D014688:Venoms; D052216:Glucagon-Like Peptide 1; D000077270:Exenatide; D053148:Caspase 3