The role of heat shock protein 90 inhibition as a novel means of modulating ischemia/reperfusion injury in the kidney

肾脏是腹部的一对器官，对生命至关重要。它们的功能是排泄废物，以及维持盐水平衡和血压。随着时间的推移，肾功能的进行性和不可逆的降低被称为慢性肾脏疾病（CKD）。虽然CKD的保守治疗在疾病的早期阶段是成功的，但一些患者会不幸发展到终末期（或已建立的）肾脏疾病（ESRD），这是CKD最严重的形式，被定义为肾功能不可逆转的下降，在没有透析或移植的情况下严重到足以致命。透析是一种代替肾脏过滤血液和清除废物的过程，而肾脏移植是一种将健康的肾脏从捐赠者转移到患有肾衰竭的接受者的手术过程。这两种疗法统称为肾替代疗法（RRT）。在英国，接受RRT治疗的患者数量正在迅速增加，在2000年至2006年期间增加了35%。到2009年，英国每百万人中有109人开始RRT。对于这些患者中的许多人来说，肾移植是一种治疗选择，因为它不仅可以避免每天或隔天透析，而且可以提高生存率和生活质量，并且卫生服务成本更低。然而，肾移植是其自身成功的受害者，目前等待肾移植的患者数量远远超过供体器官的可用性。由于移植的技术过程，10%的肾脏无法工作，40%的肾脏功能延迟，这一事实使问题更加复杂。这导致患者要么死亡，要么被迫重新进行透析，这对那些等待多年才接受移植的人来说是毁灭性的。即使对于移植肾功能延迟恢复的患者，也会对其移植肾的长期预后产生不利影响。我们的研究小组试图找出可以减少移植过程中器官损伤的药物。我们已经确定了一种很有希望的候选药物，可以在模拟移植过程中持续损伤的实验中减少肾细胞和小鼠肾脏的损伤。我们希望在人类移植患者身上研究这种药物，但在此之前，我们希望确定它是如何起作用的。方法本研究将在爱丁堡大学进行，由一名具有研究背景的医生进行，他正在接受移植外科医生的培训。他将由一位移植外科教授、一位肾脏医学教授和一位细胞生物学教授指导。工作将在小鼠模型中开始，在其中保护性药物治疗之前，将切断一个肾脏的血液供应并切除另一个肾脏，之后小鼠将恢复。这类似于移植过程中对器官造成的损伤。这些小鼠的肾脏和血液将通过各种调查技术进行分析，以确定药物保护肾脏的机制。然后，工作将扩展到实验室中的肾细胞。药物对白细胞、免疫细胞和肾细胞的细胞行为的影响以及这些细胞之间的相互作用将被检查。我们还将评估引起炎症的细胞途径，因为很可能这些途径中的一个或多个被这种药物阻断。细胞也将受到类似于移植器官的压力，并测量药物对炎症途径的影响。

BACKGROUND The kidneys are a pair of organs in the abdomen that are essential to life. They function to excrete waste products, as well as maintaining salt water balance and blood pressure. Progressive and irreversible reduction in kidney function over time is termed chronic kidney disease (CKD).While conservative management of CKD is successful in the early stages of the disease, some patients will unfortunately progress to end-stage (or established) renal disease (ESRD), which is the most severe form of CKD and is defined as an irreversible decline in kidney function that is severe enough to be fatal in the absence of either dialysis or transplantation. Dialysis is a process that substitutes for the kidneys in the tasks of filtering blood and removing waste products while kidney transplantation is an operative procedure to transfer a healthy kidney from a donor to a recipient who has kidney failure. Collectively these two treatments are known as renal replacement therapy (RRT).In the UK the number of patients on RRT is rising rapidly and between 2000 and 2006 increased by 35%. By 2009 the rate of persons commencing RRT in the UK was 109 per million of the population. For many of these patients kidney transplantation is the treatment of choice as it not only offers freedom from daily or alternate day dialysis, but leads to increased survival, quality of life and is cheaper for the health service. However, kidney transplantation is a victim of its own success and currently the number of patients awaiting a kidney transplant far outweighs the availability of donor organs. This problem is compounded by the fact that due to the technical process of transplantation 10% of kidneys never work and 40% have delayed function. This leads to patients either dying or being forced back onto dialysis, which is devastating for those who have waited many years to receive their transplant in the first place. Even for patients whose transplanted kidneys recover from a delay in graft function there is an adverse impact on the long term outcome of their transplanted kidney.Our research group seeks to identify drugs that may reduce organ injury caused by the transplantation procedure. We have identified a promising candidate drug that reduces damage in both kidney cells and mouse kidneys in experiments simulating the injury sustained during transplantation. We wish to study this drug in human transplant patients, but prior to this wish to establish exactly how it works.METHODSThe research will be conducted in the University of Edinburgh by a medical doctor with a research background who is training to be a Transplant Surgeon. He will be supervised by a Professor in Transplant Surgery, a Professor in Renal Medicine and a Professor of Cell Biology. Work will begin in a mouse model, where protective drug treatment will precede the clamping of the blood supply to one kidney and the removal of the other kidney, after which the mouse will recover. This is analogous to the injury caused to the organ during the transplantation procedure. The kidneys and blood from these mice will be analysed using various investigative techniques to determine the mechanism by which the drug protects the kidney. Work will then be extended to kidney cells in the laboratory. The effect of the drug on cellular behaviour of white blood cells, immune cells and kidney cells will be examined as well as the interaction between these cells. We will also evaluate cellular pathways causing inflammation as it is likely that one or more of these pathways is blocked by this drug. Cells will also be subjected to stresses similar to that of an organ being transplanted and the effects of the drug on inflammation pathways measured.