Hailin Zhao

Xenon Preconditioning Protects against Renal Ischemic-Reperfusion Injury via HIF-1 alpha Activation

The mortality rate from acute kidney injury after major cardiovascular operations can be as high as 60%, and no therapies have been proved to prevent acute kidney injury in this setting. Here, we show that preconditioning with the anesthetic gas xenon activates hypoxia-inducible factor 1alpha (HIF-1alpha) and its downstream effectors erythropoietin and vascular endothelial growth factor in a time-dependent manner in the kidneys of adult mice. Xenon increased the efficiency of HIF-1alpha translation via modulation of the mammalian target of rapamycin pathway. In a model of renal ischemia-reperfusion injury, xenon provided morphologic and functional renoprotection; hydrodynamic injection of HIF-1alpha small interfering RNA demonstrated that this protection is HIF-1alpha dependent. These results suggest that xenon preconditioning is a natural inducer of HIF-1alpha and that administration of xenon before renal ischemia can prevent acute renal failure. If these data are confirmed in the clinical setting, then preconditioning with xenon may be beneficial before procedures that temporarily interrupt renal perfusion.

Dexmedetomidine provides renoprotection against ischemia-reperfusion injury in mice

IntroductionAcute kidney injury following surgery incurs significant mortality with no proven preventative therapy. We investigated whether the α2 adrenoceptor agonist dexmedetomidine (Dex) provides protection against ischemia-reperfusion induced kidney injury in vitro and in vivo.MethodsIn vitro, a stabilised cell line of human kidney proximal tubular cells (HK2) was exposed to culture medium deprived of oxygen and glucose. Dex decreased HK2 cell death in a dose-dependent manner, an effect attenuated by the α2 adrenoceptor antagonist atipamezole, and likely transduced by phosphatidylinositol 3-kinase (PI3K-Akt) signaling. In vivo C57BL/6J mice received Dex (25 μg/kg, intraperitoneal (i.p.)) 30 minutes before or after either bilateral renal pedicle clamping for 25 minutes or right renal pedicle clamping for 40 minutes and left nephrectomy.ResultsPre- or post-treatment with Dex provided cytoprotection, improved tubular architecture and function following renal ischemia. Consistent with this cytoprotection, dexmedetomidine reduced plasma high-mobility group protein B1 (HMGB-1) elevation when given prior to or after kidney ischemia-reperfusion; pretreatment also decreased toll-like receptor 4 (TLR4) expression in tubular cells. Dex treatment provided long-term functional renoprotection, and even increased survival following nephrectomy.ConclusionsOur data suggest that Dex likely activates cell survival signal pAKT via α2 adrenoceptors to reduce cell death and HMGB1 release and subsequently inhibits TLR4 signaling to provide reno-protection.

Dexmedetomidine attenuates remote lung injury induced by renal ischemia-reperfusion in mice.

Renal ischemia–reperfusion (I/R) may cause acute lung injury (ALI). The mortality of combined acute kidney injury and ALI is extremely high. Dexmedetomidine, an α2 adrenergic agonist, exerts potent anti‐inflammatory and organoprotective effects in addition to its sedative and analgesic properties. We sought to elucidate whether dexmedetomidine can attenuate lung injury following renal I/R in a murine model of renal I/R.

The protective profile of argon, helium, and xenon in a model of neonatal asphyxia in rats.

Objective:Xenon provides neuroprotection in multiple animal models; however, little is known about the other noble gases. The aim of the current study was to compare xenon, argon, and helium neuroprotection in a neonatal asphyxia model in rats. Design:Randomized controlled trial. Setting:Laboratory. Subjects:Seven-day-old postnatal Sprague-Dawley rats. Interventions:Seventy percent argon, helium, xenon, or nitrogen balanced with oxygen after hypoxic–ischemic brain injury. Measurements and Main Results:Control animals undergoing moderate hypoxic–ischemia endured reduced neuronal survival at 7 days with impaired neurologic function at the juvenile age compared with naïve animals. Severe hypoxic–ischemic damage produced a large cerebral infarction in controls. After moderate hypoxic–ischemia, all three noble gases improved cell survival, brain structural integrity, and neurologic function on postnatal day 40 compared with nitrogen. Interestingly, argon improved cell survival to naïve levels, whereas xenon and helium did not. When tested against more severe hypoxic–ischemic injury only, argon and xenon reduced infarct volume. Furthermore, postinjury body weight in moderate insult was lower in the helium-treated group compared with the naïve, control, and other noble gas treatment groups, whereas in the severe injurious setting, it is lower in both control and helium-treated groups than other groups. In the nondirectly injured hemisphere, argon, helium, and xenon increased the expression of Bcl-2, whereas helium and xenon increased Bcl-xL. In addition, Bax expression was enhanced in the control and helium groups. Conclusions:These studies indicate that argon and xenon provide neuroprotection against both moderate and severe hypoxia–ischemic brain injury likely through prosurvival proteins synthesis.

Role of Toll-like receptor-4 in renal graft ischemia-reperfusion injury

Toll-like receptor-4 (TLR-4) has been increasingly recognized as playing a critical role in the pathogenesis of ischemia-reperfusion injury (IRI) of renal grafts. This review provides a detailed overview of the new understanding of the involvement of TLR-4 in ischemia-reperfusion injury of renal grafts and its clinical significance in renal transplantation. TLR-4 not only responds to exogenous microbial motifs but can also recognize molecules which are released by stressed and necrotic cells, as well as degraded products of endogenous macromolecules. Upregulation of TLR-4 is found in tubular epithelial cells, vascular endothelial cells, and infiltrating leukocytes during renal ischemia-reperfusion injury, which is induced by massive release of endogenous damage-associated molecular pattern molecules such as high-mobility group box chromosomal protein 1. Activation of TLR-4 promotes the release of proinflammatory mediators, facilitates leukocyte migration and infiltration, activates the innate and adaptive immune system, and potentiates renal fibrosis. TLR-4 inhibition serves as the target of pharmacological agents, which could attenuate ischemia-reperfusion injury and associated delayed graft function and allograft rejection. There is evidence in the literature showing that targeting TLR-4 could improve long-term transplantation outcomes. Given the pivotal role of TLR-4 in ischemia-reperfusion injury and associated delayed graft function and allograft rejection, inhibition of TLR-4 using pharmacological agents could be beneficial for long-term graft survival.

Necroptosis and parthanatos are involved in remote lung injury after receiving ischemic renal allografts in rats

Early renal graft injury could result in remote pulmonary injury due to kidney-lung cross talk. Here we studied the possible role of regulated necrosis in remote lung injury in a rat allogeneic transplantation model. In vitro, human lung epithelial cell A549 was challenged with TNF-α and conditioned medium from human kidney proximal tubular cells (HK-2) after hypothermia-hypoxia insults. In vivo, the Brown-Norway rat renal grafts were extracted and stored in 4 °C Soltran preserving solution for up to 24 h and transplanted into Lewis rat recipients, and the lungs were harvested on day 1 and day 4 after grafting for further analysis. Ischemia-reperfusion injury in the renal allograft caused pulmonary injury following engraftment. PARP-1 (marker for parthanatos) and receptor interacting protein kinase 1 (Rip1) and Rip3 (markers for necroptosis) expression was significantly enhanced in the lung. TUNEL assays showed increased cell death of lung cells. This was significantly reduced after treatment with necrostatin-1 (nec-1) or/and 3-aminobenzamide (3-AB). Acute immune rejection exacerbated the remote lung injury and 3-AB or/and Nec-1 combined with cyclosporine A conferred optimal lung protection. Thus, renal graft injury triggered remote lung injury, likely through regulated necrosis. This study could provide the molecular basis for combination therapy targeting both pathways of regulated necrosis to treat such complications after renal transplantation.

Role of necroptosis in the pathogenesis of solid organ injury

Necroptosis is a type of regulated cell death dependent on the activity of receptor-interacting serine/threonine-protein (RIP) kinases. However, unlike apoptosis, it is caspase independent. Increasing evidence has implicated necroptosis in the pathogenesis of disease, including ischemic injury, neurodegeneration, viral infection and many others. Key players of the necroptosis signalling pathway are now widely recognized as therapeutic targets. Necrostatins may be developed as potent inhibitors of necroptosis, targeting the activity of RIPK1. Necrostatin-1, the first generation of necrostatins, has been shown to confer potent protective effects in different animal models. This review will summarize novel insights into the involvement of necroptosis in specific injury of different organs, and the therapeutic platform that it provides for treatment.

The potential role of HIF on tumour progression and dissemination

Cancer is the second cause of mortality worldwide, primarily owing to failure to cure metastatic disease. The need to target the metastatic process to reduce mortality is clear and research over the past decade has shown hypoxia‐inducible factor‐1 (HIF‐1) to be one of the promising targets. In order for metastatic disease to be established, multiple steps need to be taken whereby the tumour cells escape into the bloodstream and survive, disseminate and then establish at a premetastatic niche. HIF‐1 mediates hypoxia‐induced proangiogenic factors such as vascular endothelial growth factor (VEGF) and platelet‐derived growth factor (PDGF), which promote extravasation and chemotaxis. The migration of tumour cells is mediated by loss of E‐cadherin, which results in a more invasive phenotype; dissemination of the tumour cells by increased vascular permeability and survival in the bloodstream through resistance to apoptosis as well as adhesion at the premetastatic niche are all controlled by factors under the influence of HIF‐1. The overexpression of HIF in many aggressive cancer types as well as its role in the establishment of metastatic disease and treatment resistance demonstrate its potential target in therapeutics. Taken together, the role of HIF‐1 in cancer and metastatic disease is clear and the need for better treatment targeting metastases is paramount; more aggressive phenotypes with less response to treatment are associated with HIF‐1 expression. Our research has shown promise but many questions still remain to be answered.

The Role of Interleukin 17 in Tumour Proliferation, Angiogenesis, and Metastasis

With 7.6 million deaths globally, cancer according to the World Health Organisation is still one of the leading causes of death worldwide. Interleukin 17 (IL-17) is a cytokine produced by Th17 cells, a T helper cell subset developed from an activated CD4+ T-cell. Whilst the importance of IL-17 in human autoimmune disease, inflammation, and pathogen defence reactions has already been established, its potential role in cancer progression still needs to be updated. Interestingly studies have demonstrated that IL-17 plays an intricate role in the pathophysiology of cancer, from tumorigenesis, proliferation, angiogenesis, and metastasis, to adapting the tumour in its ability to confer upon itself both immune, and chemotherapy resistance. This review will look into IL-17 and summarise the current information and data on its role in the pathophysiology of cancer as well as its potential application in the overall management of the disease.

Pre-treatment with isoflurane ameliorates renal ischemic–reperfusion injury in mice

AIMS Perioperative renal dysfunction is associated with a high mortality. The aim of this study was to investigate whether isoflurane preconditioning provides a protection against renal ischemic-reperfusion injury and whether hypoxia inducible factor 1 α (HIF-1 α) is responsible for the protection afforded by isoflurane in mice. MAIN METHODS Adult male C57BL/6 mice received vehicle (PBS), scrambled siRNA or HIF-1 α siRNA via hydrodynamic injection through tail vein. Twenty-four hours after injection, they were exposed to 1.5% isoflurane in oxygen enriched air for 2h while controls without injection were exposed to oxygen enriched air. Twenty-four hours after gas exposure, mice were sacrificed and their kidney were harvested for western blot while other cohorts underwent renal ischemia-reperfusion injury induced by bilateral renal pedicle clamping for 25 min for renal histological or functional analysis 24h after reperfusion or by unilateral clamping for 40 min for survival rate analysis. KEY FINDINGS Survival rate and the expression of HIF-1 α and erythropoietin were significantly increased while apoptosis, renal tubule score, blood plasma creatinine and urea were decreased by isoflurane preconditioning. HIF-1 α siRNA but not scrambled siRNA injection abrogated the protective effect of isoflurane preconditioning. SIGNIFICANCE Our data suggested that isoflurane preconditioning provided a protection against renal ischemic-reperfusion injury which is very likely due to hypoxia inducible factor-1 α upregulation.