Relaxin Positively Influences Ischemia—Reperfusion Injury in Solid Organ Transplantation: A Comprehensive Review

Abstract

In recent decades, solid organ transplantation (SOT) has increased the survival and quality of life for patients with end-stage organ failure by providing a potentially long-term treatment option. Although the availability of organs for transplantation has increased throughout the years, the demand greatly outweighs the supply. One possible solution for this problem is to extend the potential donor pool by using extended criteria donors. However, organs from such donors are more prone to ischemia reperfusion injury (IRI) resulting in higher rates of delayed graft function, acute and chronic graft rejection and worse overall SOT outcomes. This can be overcome by further investigating donor preconditioning strategies, graft perfusion and storage and by finding novel therapeutic agents that could reduce IRI. relaxin (RLX) is a peptide hormone with antifibrotic, antioxidant, anti-inflammatory and cytoprotective properties. The main research until now focused on heart failure; however, several preclinical studies showed its potentials for reducing IRI in SOT. The aim of this comprehensive review is to overview currently available literature on the possible role of RLX in reducing IRI and its positive impact on SOT.

Human Relaxin-2 (Serelaxin) Attenuates Oxidative Stress in Cardiac Muscle Cells Exposed In Vitro to Hypoxia–Reoxygenation. Evidence for the Involvement of Reduced Glutathione Up-Regulation

“…An understanding of the key role of oxidative stress in the pathophysiology of IR is of pivotal importance in order to highlight the defensive mechanisms activated by cells and organs, as well as to identify effective therapeutic approaches [ 28 ]. Robust experimental evidence has been collected that RLX protects from IR-induced organ damage, not only because of indirect vasodilatory, anti-inflammatory and anti-fibrotic actions, but also via its direct cytoprotective effects, which increase the resistance of HR-exposed cells to oxygen deprivation and nitroxidative stress [ 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 ]. The current findings further strengthen and extend our previous reports that RLX blunts IR-induced injury and promotes the survival of H9c2 cardiac muscle cells subjected to HR [ 13 ].…”

“…In recent years, robust evidence has been accumulating that RLX can markedly reduce tissue and cell damage induced by ischemia and reperfusion (IR) [ 1 , 2 , 3 ]. Such a protective effect has been consistently observed in diverse experimental models, spanning from organ IR in whole animals (heart, gut, kidney) [ 4 , 5 , 6 , 7 , 8 ] and in isolated and perfused organs (heart, lung, liver) [ 9 , 10 , 11 , 12 ] to specific cell types (cardiomyocytes, trophoblast) subjected to in vitro hypoxia (associated or not with nutrient starvation) and reoxygenation [ 13 , 14 ]. The fact that RLX exerts similar protective effects on different organs and cells at relatively low concentrations (in the nanomolar range) suggests that this molecule specifically targets a common pathogenic mechanism of the IR-induced damage.…”

Combating Ischemia-Reperfusion Injury with Micronutrients and Natural Compounds during Solid Organ Transplantation: Data of Clinical Trials and Lessons of Preclinical Findings

“…In 2018, 36,529 SOTs have been performed in the USA according to the Organ Procurement and Transplantation Network data. Currently, there are 113,000 people registered on the waiting list, pointing out the discrepancy between donor organ demand and availability [ 1 ]. One attempt to enlarge the pool of possible organ donators is to include extended criteria donors (ECD) who exceed 60 years of age or are between 50 and 59 years of age suffering at least from two of the following conditions: history of hypertension, compromised renal function reflected by terminal serum creatinine > 1.5 mg/dL or cerebrovascular cause of death [ 2 ].…”

“…Although transplantation and organ preservation techniques are evolving and improving continuously, the IRI-associated initial graft reaction is still a success-limiting factor. This especially applies for organ transplantation of ECDs [ 1 , 20 ]. Recently, micronutrients and natural compounds have emerged increasing interest for supporting various clinical conditions.…”

“…In order not to overwhelm the reader, we restricted the manuscript to selected micronutrients and natural compounds. Additionally, we solely focused on the three most transplanted organs: heart, liver and kidney, accounting for 99% of all SOTs [ 1 ]. To illustrate the full potential of selected compounds, the current research gaps were filled with alternative settings of IRI.…”