MICA: Signalling pathways to proteinuria - part II. Establishment of b3 integrin and TRPC6 as tractable renal disease targets

终末期肾病（ESRD）是世界范围内发病率和死亡率的一个主要因素。英国目前约有4万名患者接受肾脏替代治疗，每百万人口中有650多人接受肾脏替代治疗，每年的费用超过7亿英镑，导致NHS预算的2%花在了不到0.1%的人口身上。至少10%的ESRD是由类固醇抵抗性肾病综合征（SRNS）引起的。这种毁灭性的疾病通常与水肿、蛋白尿、高血压、显微镜下血尿和肾功能不全有关，尽管长期使用毒性免疫抑制，但通常会导致终末期肾衰竭。SRNS的一个困难和有趣的方面是，在许多情况下，它会在肾移植后复发。SRNS的发病率在儿童中尤为常见，最近显著增加，最新的流行病学研究显示，SRNS在原发性肾小球病中的比例从1992年的17%急剧增加到2002年的59%。尽管SRNS的病因尚不清楚，但高达60%的首次接受肾移植治疗SRNS的患者会复发，这一事实表明，SRNS的病因不仅仅是肾脏疾病的结果。移植患者的疾病复发（通常在移植物灌注后的几分钟或几小时内）以及免疫抑制药物治疗和血浆置换已被证明对治疗SRNS复发有用的事实导致了该疾病发病机制的“循环毒性因子假说”。肾滤过屏障由两种细胞组成：肾小球内皮细胞和足细胞。我们和其他人已经证明，足细胞在SRNS中受到特异性损伤，并提供了强有力的证据，证明有毒的SRNS因子属于一类被称为蛋白酶的蛋白质。蛋白酶与细胞表面的特定受体（PARs）结合，导致细胞生物学的变化，本应用的目的是确定介导这些作用的细胞信号通路，并确定我们是否可以阻断特异性参与该通路的蛋白质，作为毒性最小的新药靶点，来治疗这种毁灭性疾病。鉴于其临床重要性，确定SRNS发展的细胞机制是必不可少的，也是设计和开发靶向治疗方法来解决这一问题的关键一步。

A major factor in morbidity and mortality worldwide is end stage renal disease (ESRD). The UK currently has around 40,000 patients on renal replacement therapy, over 650 per million population, at a cost of over £700 million per year resulting in 2% of the NHS budget being spent on less that 0.1 % of the population. At least 10% of ESRD is caused by steroid resistant nephrotic syndrome (SRNS). This devastating disease is typically associated with oedema, proteinuria, hypertension, microscopic haematuria, and renal insufficiency and usually leads to end stage renal failure despite the use of prolonged and toxic immunosuppression. A difficult and intriguing aspect of SRNS is that in many cases, it will recur following kidney transplantation. The incidence of SRNS, which is particularly common in children, has increased markedly recently with the latest epidemiological study showing a dramatic increase in SRNS as a proportion of primary glomerulopathy from 17 to 59% between 1992 and 2002. Although the cause of SRNS is still unknown, the fact that up to 60% of patients who receive a first kidney transplant to treat their SRNS, experience recurrence of the condition suggests that the cause is not just a result of intrinsic kidney disease. The recurrence of the disease in transplanted patients (often within minutes or hours of the graft being perfused) and the fact that immunosuppressive drug therapy and plasma exchange have proven to be useful in treating the recurrence of SRNS led to the 'circulating toxic factor hypothesis' in the pathogenesis of the disease. The kidney filtration barrier is made up of two cell types: glomerular endothelial cells and podocytes. We have and others have shown that the podocyte is specifically damaged in SRNS and also provided robust evidence that the toxic SRNS factor belongs to a class of proteins known as proteases. Proteases bind to specific receptors (PARs) on the surface of cells leading to changes in cell biology and the purpose of this application is to identify the cellular signalling pathways that mediate these effects and determine if we can block proteins specifically involved in that pathway, as new drug targets with minimal toxicity, to treat this devastating disease.Identifying the cellular mechanisms underlying the development of SRNS is essential given its clinical importance and is a critical step in designing and developing targeted therapeutic approaches to deal with this problem.