Glucocorticoid Receptor – Relaxin Signaling in Liver Transplant Ischemia-Reperfusion Injury (IRI): From Bench-to-Bedside.
1The Dumont-UCLA Transplant Center, Department of Surgery, David Geffen School of Medicine at University of California, Los Angeles, CA
2Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at University of California, Los Angeles, CA
Meeting: 2017 American Transplant Congress
Abstract number: 550
Keywords: Apoptosis, Glucocortocoids, Liver transplantation, Survival
Session Information
Session Name: Concurrent Session: Pathways in Ischemia Reperfusion
Session Type: Concurrent Session
Date: Tuesday, May 2, 2017
Session Time: 4:30pm-6:00pm
Presentation Time: 5:42pm-5:54pm
Location: E351
Background: Glucocorticoid receptor (GR) serves as a receptor for relaxin (RLX), a pregnancy hormone, with novel vasoactive and tissue remodeling properties. A phase III clinical trial evaluating the efficacy, safety and tolerability of serelaxin, the recombinant form of human RLX, in acute heart failure patients is underway. Although serelaxin may exert anti-oxidative functions in murine models of cardiac, lung and renal IRI, its effects in liver transplant recipients remain unknown. Aim: To analyze as to whether and how GR – RLX signaling may affect IR-stressed orthotopic liver transplantation (OLT). Methods/Results: [Experimental arm] We evaluated hepatocellular function in mouse OLT subjected to 18h of cold storage; and in H2O2-stressed native hepatocyte cultures. Treatment with RLX increased GR expression in hepatocytes in vitro and reduced hepatocellular damage in IR-stressed OLT. These effects were GR-dependent (siRNA silencing). RLX-induced GR reduced hepatocyte HMGB1 release, accompanied by decreased TLR4/RAGE; downstream IL1β, MCP1, TNFα, CXCL10 program; and neutrophil/macrophage OLT sequestration. RLX treatment increased anti-apoptotic Bcl-2/Bcl-xL while decreasing caspase 3/caspase 8 expression. [Clinical arm] Twenty-one adult primary orthotopic liver transplant patients were recruited under IRB protocol. Liver graft biopsies (Bx; taken at 2h after reperfusion) were analyzed by Western blots, based on high (n=10) vs. low (n=11) GR levels. The high-GR Bx group showed increased Bcl-2 (p<0.05) and Bcl-xL (p<0.05), and decreased caspase 3 (p<0.05) levels as compared with low-GR group. The molecular IRI-OLT signature was correlated with the hepatocellular function (ALT, AST, total bilirubin) at POD1-POD7. Remarkably, high-GR liver transplant patient group experienced superior clinical outcomes and survival (100% vs. 63.6%, p=0.0392), with median follow-up period of 712 days (range, 27-1009 days). Conclusion: This is the first study to document that GR – relaxin signaling exerts potent cytoprotection in IRI-OLT. By antagonizing hepatocyte apoptosis and innate immune activation, serelaxin may serve as a novel treatment in liver transplant patients.
CITATION INFORMATION: Kageyama S, Nakamura K, Sossa R, Reed E, Datta N, Zarrinpar A, Busuttil R, Kupiec-Weglinski J. Glucocorticoid Receptor – Relaxin Signaling in Liver Transplant Ischemia-Reperfusion Injury (IRI): From Bench-to-Bedside. Am J Transplant. 2017;17 (suppl 3).
To cite this abstract in AMA style:
Kageyama S, Nakamura K, Sossa R, Reed E, Datta N, Zarrinpar A, Busuttil R, Kupiec-Weglinski J. Glucocorticoid Receptor – Relaxin Signaling in Liver Transplant Ischemia-Reperfusion Injury (IRI): From Bench-to-Bedside. [abstract]. Am J Transplant. 2017; 17 (suppl 3). https://atcmeetingabstracts.com/abstract/glucocorticoid-receptor-relaxin-signaling-in-liver-transplant-ischemia-reperfusion-injury-iri-from-bench-to-bedside/. Accessed May 11, 2025.« Back to 2017 American Transplant Congress