Molecular mechanisms of podocyte injury in FSGS

总结 慢性肾脏疾病影响着全球7亿多人，是一种常见的原因。 肾衰竭和死亡导致肾功能衰竭的一个关键事件是过滤器损坏， 足细胞丢失。这是一种称为局灶性节段性肾病的原因 肾小球硬化（FSGS）。尽管肾脏疾病的患病率不断上升， 目前没有FDA批准的治疗方法来防止足细胞的损失。这项资助的目的是 应用是为了深入了解足细胞参与的分子机制， 与BRAF信号通路相关的损伤，因此它可以被靶向用于治疗益处。 我们从一种罕见的遗传性肾脏疾病开始，这种疾病是由一种叫做PDSS 2的酶突变引起的。 有趣的是，我们发现这种酶的功能丧失会导致足细胞死亡， 在FSGS。我们随后发现，防止足细胞死亡的关键分子是BRAF， 一种激活BRAF的小分子，称为GDC-0879，可以保护足细胞免于细胞死亡。 事实上，GDC-0879能够保护足细胞免受几种损伤，包括毒性脂质和 其他引起压力的分子最令人兴奋的是，我们现在有证据表明GDC-0879可以保护 小鼠足细胞损伤和由此产生的肾过滤器损伤（称为蛋白尿）。在这里，我们将 探索BRAF相关足细胞损伤的确切分子机制， GDC-0879有可能成为FSGS的治疗药物。 这项工作的成功完成可能会为FSGS提供一种新的，急需的治疗方法， 慢性肾脏疾病，并且可以容易地带到诊所，因为GDC-0879是 已经是FDA批准用于其他适应症的药物。

SUMMARY Chronic kidney diseases affect more than 700 million people worldwide, and are a frequent cause of kidney failure and death. A key event leading to kidney failure is filter damage, caused by the loss of podocytes. This is a cause of a kidney disease known as Focal segmental Glomerulosclerosis (FSGS). Despite the growing prevalence of kidney diseases, there are currently no FDA approved therapies to prevent the loss of podocytes. The goal of this grant application is to gain a deep understanding of the molecular mechanisms involved in podocyte injury related to the BRAF signaling pathway, so that it may be targeted for therapeutic benefit. We started with a rare genetic kidney disease caused by mutations in an enzyme called PDSS2. Interestingly, we found that the loss of function of this enzyme causes podocytes to die, resulting in FSGS. We subsequently found that a key molecule in preventing podocyte death is BRAF and a small molecule that activates BRAF, called GDC-0879, can protect podocytes from cell death. In fact, GDC-0879 was able to protect podocytes from several injuries including toxic lipids and other stress-causing molecules. Most excitingly, we now have evidence that GDC-0879 protects mice from podocyte injury and the resulting kidney filter damage (called proteinuria). Here, we will explore the precise molecular mechanisms involved in BRAF-related podocyte injury, and the potential for GDC-0879 to become a treatment for FSGS. Successful completion of this work may provide a new, much needed treatment for FSGS and chronic kidney diseases, and one that may be easily brought to the clinic, since GDC-0879 is already an FDA approved drug for other indications.