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Translational characterization of hepatic miR-301a as a biomarker for acute rejection in experimental and clinical liver transplantation

ABSTRACT: Using a rat orthotopic liver transplantation (OLT) model and microarray, we compared the expression profiles of microRNAs in naïve and AR livers at day 7 after OLT obtained from the rats with short-term (<14 days, DA-LEW) or long-term (>60 days, DA-PVG) survival fate. AR-related microRNAs and pro-inflammatory cytokines were validated by using a quantitative real-time PCR. AR-related microRNA-mediated inflammatory responses were evaluated by overexpression of a target microRNA in rat primary hepatocytes. Human liver biopsies from recipients with AR or abnormal liver function were used for clinical verification. The microarray revealed that miR-301a was significantly upregulated in lethal AR livers of DA-LEW, while it was comparable to the naïve livers in DA-PVG, which spontaneously overcomes AR.

ORGANISM(S): Rattus norvegicus

PROVIDER: GSE64362 | GEO | 2014/12/20

SECONDARY ACCESSION(S): PRJNA270826

REPOSITORIES: GEO

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Project description:Objective: Apolipoprotein E (Apo E) is a multifunctional protein, originally described in the context of lipoprotein metabolism and cardiovascular disease. More recently, anti-inflammatory functions of ApoE have been documented. ApoE was studied in the context of several inflammatory disorders, but its role in the pathogenesis of acute organ rejection is unknown. In this study, we test the hypothesis that ApoE attenuates acute renal allograft rejection. Materials and methods: The Dark Agouti (DA) to Lewis (Lew) and the Brown Norway (BN) to Lew rat strain combinations were used to investigate fatal acute rejection. In addition, Fischer 344 (F344) kidneys were transplanted to Lew rats to study reversible acute rejection. Isograft recipients and untreated Lew rats were used as controls. ApoE mRNA expression was quantified in intravascular leukocytes accumulating in the blood vessels of renal grafts and in graft tissue. Apo E protein levels were assessed in blood plasma. To test the protective potential of ApoE, recipients of BN kidneys were treated with ApoE-mimetic peptide. Results: Intravascular graft leukocytes and renal tissue obtained from animals undergoing reversible acute rejection expressed increased levels of ApoE mRNA, whereas during fatal rejection, ApoE expression remained unchanged in the BN to Lew rat strain combination or was significantly reduced when DA rats were used as donors of the kidney. On the protein level, no changes in ApoE were seen in plasma. However, we do not know if local leukocytic ApoE expression results in increased ApoE concentrations inside graft blood vessels. Peptide treatment of allograft recipients reversed fatal rejection and significantly improved animal survival. Conclusions: ApoE plays a protective role in acute organ rejection. Further studies are needed to understand the exact mechanism how ApoE reverses acute rejection. dual-color balanced dye-swap design with 4 biological replicates, hybridized on 4 arrays

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Translational characterization of hepatic miR-301a as a biomarker for acute rejection in experimental and clinical liver transplantation

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