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Reduced Complications after Arterial Reconnection in a Rat Model of Orthotopic Liver Transplantation
Published on: November 7, 2020
Involvement of the receptor for advanced glycation end products in liver transplantation
Teresa Navarra1, Paolo De Simone2, Serena Del Turco1
1Institute of Clinical Physiology, National Research Council, Pisa, Italy.
Background And Aim:
Receptor for advanced glycation end products (RAGE) blockade by a soluble form of RAGE (sRAGE) appears to be protective against hepatocellular death and necrosis after I/R injury. Little is known about the role of the hepatic RAGE, its ligands, and the plasma levels of sRAGE in liver transplantation (LT).
Material And Methods:
This was a prospective study on patients (n = 28) undergoing deceased donor LT. RAGE ligands [the N(epsilon)-carboxy-methyl-lysine (CML) adduct and the high-mobility group box 1 (HMGB1) protein] and sRAGE levels were measured in donors at the time of organ procurement, while in recipients they were tested before surgery (baseline), after graft reperfusion, and on day 1 and 7 posttransplantation. Donors and recipients liver biopsies were collected to assess the transcriptional expression of the full-length RAGE and of its truncated isoform, the endogenous secreted RAGE (esRAGE).
Results:
At baseline, CML levels were higher in LT recipients than in donors (p = 0.02), decreased immediately after graft reperfusion (p < 0.0001) and returned to baseline values on day 7. Baseline HMGB1 levels (3.8 ± 2.3 ng/mL) increased after graft reperfusion (39.9±18 ng/mL, p < 0.0001), and returned to baseline values within day 1, while circulating sRAGE decreased significantly on day 7 (p < 0.0001). The graft esRAGE mRNA expression was inversely associated with bilirubin on day 7 (β = -0.62, p = 0.005).
Conclusions:
Early on after LT, there is accumulation of CML and a rapid increase of HMGB1 concurrent with a remarkable decline in circulating sRAGE. The RAGE-ligand axis may also be involved in early graft dysfunction.
Insights
Soluble receptor for advanced glycation end products (sRAGE) levels decline after liver transplantation (LT). RAGE ligands accumulate, suggesting the RAGE-ligand axis may contribute to early graft dysfunction in LT recipients.
Area of Science:
- Immunology
- Transplantation Biology
- Hepatology
Background:
- Receptor for advanced glycation end products (RAGE) blockade shows promise in protecting against liver injury.
- The specific roles of hepatic RAGE, its ligands, and soluble RAGE (sRAGE) in liver transplantation (LT) remain largely uncharacterized.
Purpose of the Study:
- To investigate the role of the RAGE-ligand axis and sRAGE in the early phase of deceased donor liver transplantation (LT).
Main Methods:
- Prospective study of 28 LT recipients.
- Measured RAGE ligands (CML, HMGB1) and sRAGE in donors and recipients.
- Assessed RAGE and esRAGE mRNA expression in liver biopsies.
Main Results:
- Increased CML and HMGB1 levels were observed in recipients post-reperfusion.
- Circulating sRAGE levels significantly decreased by day 7 post-LT.
- Graft esRAGE mRNA expression correlated inversely with day 7 bilirubin levels.
Conclusions:
- Early LT involves CML accumulation and HMGB1 surge, alongside a marked sRAGE decline.
- The RAGE-ligand axis may play a role in early graft dysfunction following LT.
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