Ion-channel targeted therapy for progressive kidney diseases

项目总结 进行性蛋白尿肾病在全球范围内呈上升趋势，有500多种 数百万人受到影响，但目前还没有有效的治疗方法来阻止它们的进展 肾衰竭。高血压和糖尿病仍然是疾病进展的最大驱动力 世界各地的肾脏疾病。一大挑战是特定的分子和肾脏 参与肾脏疾病进展的细胞仍然知之甚少。 我们最近由这笔资金资助的工作揭示了两个这样的分子，rac1和TRPC5，作为 对称为足细胞的珍贵肾脏细胞的损伤和死亡负责。损失 足细胞导致蛋白尿，这是肾滤过屏障破裂的标志，最终 肾衰竭。在这笔资金的资助下，我们还发现了一种名为AC1903的TRPC5阻滞剂， 它可以防止rac1-TRPC5对足细胞的损伤。在两种大鼠肾脏模型中 一种名为FSGS(局灶性和节段性肾小球硬化)的疾病，我们发现AC1903 防止肾脏滤器受损和保护足细胞，使其成为一种极好的 是未来患者治疗方法发展的候选者。 然而，目前还不清楚AC1903或其他TRPC通道阻滞剂是否可以 有助于保护高血压或糖尿病肾病患者的肾脏 疾病。因此，修订后的竞争续订申请的目标是在 我们最新的发现，并在大鼠和小鼠模型上进行仔细和详细的研究 以进一步了解TRPC离子通道的作用 及其阻滞剂在治疗高血压相关肾脏疾病和 糖尿病。这项工作将为肾脏疾病患者的新疗法铺平道路， 是非常需要的。

PROJECT SUMMARY Progressive proteinuric kidney diseases are on the rise worldwide with more than 500 million people affected, and yet no effective therapies exist to halt their progression to kidney failure. High blood pressure and diabetes remain the biggest drivers of progressive kidney diseases worldwide. One big challenge is that the specific molecules and kidney cells involved in progression of kidney diseases remain poorly understood. Our recent work funded by this grant revealed two such molecules, Rac1 and TRPC5, as responsible for the injury and death of precious kidney cells called podocytes. Loss of podocytes resulted in proteinuria, the hallmark of a broken kidney filter barrier and ultimate kidney failure. Funded by this grant, we also discovered a TRPC5 blocker, called AC1903, which can prevent Rac1-TRPC5 from injuring podocytes. In two rat models of a kidney disease called FSGS (Focal and Segmental Glomerulosclerosis), we showed that AC1903 prevented kidney filter damage and protected podocytes, making this an excellent candidate for the development of a future therapy for patients. However, at this time, it is not clear if AC1903 or other TRPC channel blockers can be helpful in protecting the kidneys of patients with hypertension or diabetes-related kidney diseases. Therefore, the goal of this revised competitive renewal application is to build on our recent discoveries and perform careful and detailed studies in rat and mouse models of progressive kidney diseases to gain further insight into the role of TRPC ion channels and their blockers in the treatment of kidney diseases associated with hypertension and diabetes. This work will pave the way for new therapies for kidney disease patients, which are greatly needed.