MODIFICATION OF TUBULE CELL CYTOKINES REGULATING INTERSTITIAL INFLAMMATION IN CHRONIC PROTEINURIC RENAL DISEASE

目前对慢性肾病的治疗是无效的。因此，肾衰竭进展到患者需要透析或移植才能存活的阶段。每年有1500名澳大利亚人因此开始透析，更多的人死于肾衰竭或其并发症。肾衰竭进展的主要原因之一是肾细胞产生复杂的炎症介质（细胞因子）网络，其吸引炎症细胞进入肾的支持组织（肾小管）。最近，抑制这些细胞因子的药物已被用于慢性肾脏疾病的动物模型。这样的治疗方案至多仅部分有效，因为它们仅针对一种细胞因子，并且因为它们忽略了细胞因子谱随疾病阶段而变化的事实。该项目将使用人类慢性肾脏疾病的啮齿动物模型（阿霉素肾病）来定义使用抗细胞因子治疗预防间质性炎症的策略。我们的实验室已经确定了三种细胞因子，它们似乎在阿霉素肾病的间质炎症发展中起关键作用，并表明它们的产生随时间而变化。这些细胞因子之间的时间依赖性相互作用和调节的知识将用于定义针对所有三种细胞因子的治疗的最佳递送。由于抗细胞因子疗法已经在人类其他类型的（非肾脏）疾病中进行了试验，因此这种治疗方法在该动物模型中治疗进行性肾脏疾病的成功将对人类慢性肾脏疾病的治疗具有重要和直接的影响。

Current treatments for chronic kidney disease are ineffective. As a consequence, kidney failure progresses to the stage where patients require dialysis or transplantation to remain alive. Every year 1500 Australians commence dialysis for this reason, and many more die of kidney failure or its complications. One of the major reasons for progression of kidney failure is that kidney cells produce a complex network of inflammatory mediators (cytokines) which attract inflammatory cells into the supporting tissue of the kidney (the interstitium). Recently, drugs that inhibit these cytokines have been used in animal models of chronic kidney disease. Such treatment regimens have been at most only partially effective because they have been directed against only one cytokine, and because they have ignored the fact that the profile of cytokines varies with stage of disease. This project will use a rodent model (Adriamycin nephrosis) of human chronic kidney disease to define strategies for preventing interstitial inflammation using anti-cytokine therapy. Our laboratory has identified three cytokines which appear to play a pivotal role in the development of interstitial inflammation in Adriamycin nephrosis, and shown that their production varies with time. Knowledge of the time-dependent interactions among and regulation of these cytokines will be used to define optimal delivery of therapy directed against all three cytokines. As anti-cytokine therapy is already being trialled in other types of (non-kidney) disease in humans, the success of such a therapeutic approach to treating progressive kidney disease in this animal model will have important and immediate implications for the treatment of chronic kidney disease in humans.