The role of CCL2 in nephronophthisis and autosomal dominant polycystic kidney disease (ADPKD)

肾单位病和常染色体显性遗传性多囊肾病(ADPKD)是导致肾功能衰竭的最常见的遗传性肾病。在肾炎患者中，肾功能衰竭通常发生在儿童或青春期，而在ADPKD患者中，这种情况发生在成年后。对于这些疾病，目前还没有有效的治疗方法。在肾性肾炎中，代表肾脏内部的肾髓质萎缩。这会导致肾小管阻塞和充气，并导致肾组织的疤痕形成。在ADPKD中，肾脏越来越多地获得越来越多充满液体的包囊，这会导致肾脏增大到正常大小的几倍，并通过对周围组织的压力形成疤痕。巨大的肾脏会导致慢性疼痛和正常摄取食物的问题。ADPKD是一种常见的疾病，大约每1000人中就有1人受到影响，另一方面，肾单位病则不太常见。如果发生肾功能衰竭，受影响的人需要每周做几次血液透析，每天进行几次腹膜透析，或者接受肾脏移植。几十年来，移植需要每天服用几次药物，以抑制免疫系统，防止排斥反应。在早期的工作中，我们的研究小组发现，两种名为Lkb1和CCL2的蛋白质可能在这两种疾病的瘢痕形成中发挥重要作用。这两种疾病的共同之处是，突变的蛋白质在正常情况下定位于纤毛。纤毛是一种毛发状结构，从细胞表面伸出，接收来自环境的信号，并将它们传递到细胞中。我们已经发现，Lkb1定位于纤毛内部，并与一种在肾炎中突变的蛋白质相互作用，以抑制CCL2。我们还发现，在超过80%的ADPKD患者中，该蛋白突变参与了CCL2的抑制。我们认为，这一调节机制的失活导致CCL2向肾脏招募免疫细胞，导致炎症、瘢痕形成，并在ADPKD中导致囊性生长。目前的项目旨在找出是否真的是这样，并希望检测哪些其他纤毛蛋白参与了这一机制的放松。从该项目中获得的知识将有助于找到治疗这些疾病的新方法，并维持受影响人群的肾脏功能。

Nephronophthisis and autosomal dominant polycystic kidney disease (ADPKD) are the most common forms of inherited kidney disease leading to kidney failure. In nephronophthisis the kidneys most often fail during childhood or adolescence, whereas in ADPKD this occurs in adulthood. No effective therapies for these conditions exist. In nephronophthisis, the renal medulla, which represents the inner part of the kidney, shrinks. This leads to obstruction and ballooning of the kidney tubules, and to scarring of kidney tissue. In ADPKD the kidneys increasingly acquire more and more fluid filled cysts which causes the kidneys to grow to several times the normal size, and to scarring through the pressure on the surrounding tissue. The large kidneys can lead to chronic pain and problems with eating normal quantities of food. ADPKD is a common disorder, affecting around 1 in 1000 persons, nephronophthisis on the other hand is less common. In the event of kidney failure affected persons need to do hemodialysis several times per week, administer peritoneal dialysis several times daily or undergo kidney transplantation. Transplantation requires that medications are taken several times daily for decades to suppress the immune system and prevent rejection. In earlier work our group has found that two proteins named Lkb1 and Ccl2 possibly play an important role in the scarring that occurs in both diseases. Both diseases have in common that the mutated proteins under normal circumstances localize in the cilium. The cilium is a hair-like structure that protrudes from the cell surface and acts to receive signals from the environment and to transduce them into the cell. We have found that Lkb1 localizes inside the cilium and interacts with a protein that is mutated in nephronophthisis to suppress Ccl2. We also find that the protein mutated in over 80% of patients with ADPKD takes part in suppressing Ccl2. We propose that inactivation of this regulation mechanism causes Ccl2 to recruit immune cells to the kidney leading to inflammation, scarring and in ADPKD to cyst growth. The current project aims to find out if this is indeed the case and wants to detect which other cilium proteins are involved in the deregulation of this mechanism. The knowledge derived from this project shall help to find new approaches to treat these diseases and maintain the function of the kidneys in affected persons.