Date Published: August 24, 2013
Publisher: Wiley Periodicals
Author(s): H Zhao, H R Watts, M Chong, H Huang, C Tralau-Stewart, P H Maxwell, M Maze, A J T George, D Ma.
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.
As a mainstream therapeutic method, kidney transplantation has drastically transformed the health quality of patients suffering from end-stage renal diseases. However, 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. Hypothermic preservation is routinely used to enable long-distance transport and to improve the histocompatibility match of the grafts; however, accumulating laboratory and clinical evidence highlights the importance of ischemia-reperfusion injury (IRI) as a contributing factor in the early delayed graft function (DGF) and the later graft loss 3–4. During prolonged cold ischemia, the absence of blood perfusion to the graft results in severe metabolic imbalance, which promotes tissue necrosis. Reinstitution of blood flow and concomitant reoxygenation is frequently associated with an exacerbation of tissue injury 5. The consequences of IRI are not only the initial ablation of functioning nephrons, but also 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-κB downstream signaling cascades and the induction of robust inflammatory cytokine production 7, consequently leading to an increased alloresponse and graft injury.
Our findings represent the first report on the renoprotective effects of xenon against cold ischemia associated delayed graft function in rodent transplant model. Xenon given either to graft donors (pretreatment) or to recipients (posttreatment) prolonged graft survival. The underlying mechanism is very likely to be due to sustained upregulation of HIF-1α and its down-stream products which led to protection from tubular cell injury induced by IRI and subsequently enhanced tubular cell survival. Ultimately, these effects in turn dampened the inflammatory response via inhibition of the HMGB1/TLR4 signaling pathways.