Abstract
Prolonged hypothermic storage causes ischemia-reperfusion injury (IRI) in the renal graft, which is considered to contribute to the occurrence of the delayed graft function (DGF) and chronic graft failure. Strategies are required to protect the graft and to prolong renal graft survival. We demonstrated that xenon exposure to human proximal tubular cells (HK-2) led to activation of range of protective proteins. Xenon treatment prior to or after hypothermia–hypoxia challenge stabilized the HK-2 cellular structure, diminished cytoplasmic translocation of high-mobility group box (HMGB) 1 and suppressed NF-κB activation. In the syngeneic Lewis-to-Lewis rat model of kidney transplantation, xenon exposure to donors before graft retrieval or to recipients after engraftment decreased caspase-3 expression, localized HMGB-1 within nuclei and prevented TLR-4/NF-κB activation in tubular cells; serum pro-inflammatory cytokines IL-1β, IL-6 and TNF-α were reduced and renal function was preserved. Xenon treatment of graft donors or of recipients prolonged renal graft survival following IRI in both Lewis-to-Lewis isografts and Fischer-to-Lewis allografts. Xenon induced cell survival or graft functional recovery was abolished by HIF-1α siRNA. Our data suggest that xenon treatment attenuates DGF and enhances graft survival. This approach could be translated into clinical practice leading to a considerable improvement in long-term graft survival.
Highlights
As a mainstream therapeutic method, kidney transplantation has drastically transformed the health quality of patients suffering from end-stage renal diseases
Xenon treatment enhanced the expression of HIF-1a, VEGF and Bcl-2 in Human kidney-2 (HK-2) cells Hypoxia inducible factor-1a (HIF-1a), vascular endothelial growth factor (VEGF) and Bcl-2 in human proximal tubular cell line (HK-2) were measured via immunofluorescent staining after exposure to 70% Xe and 5% CO2 balanced with O2 for 2 h (Figure 1)
We evaluated the effect of xenon treatment on graft function after severe ischemia-reperfusion
Summary
As a mainstream therapeutic method, kidney transplantation has drastically transformed the health quality of patients suffering from end-stage renal diseases. Improvement of renal graft life-span is far from satisfactory despite of advances in surgical techniques and more powerful immunosuppressants [1], with severe functional impairment occurring in the majority of recipients by 10 years posttransplantation [2]. The consequences of IRI are the initial ablation of functioning nephrons, and the activation of the immune response [4,6]. This immunity against the post-ischemic graft involves signaling events through damage associated molecular pattern molecules (DAMPs) such as HMGB-1, their binding to toll-like receptors (TLRs), subsequent initiation of NF-kB downstream signaling cascades and the induction of robust inflammatory cytokine production [7], leading to an increased alloresponse and graft injury
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