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

CCL2 在肾结核和常染色体显性多囊肾病 (ADPKD) 中的作用

• 批准号: 361416317
• 负责人: Professor Dr. E. Wolfgang Kühn
• 金额: --
• 依托单位: Klinik für Innere Medizin IV - Nephrologie und Allgemeinmedizin
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2017
• 资助国家: 德国
• 起止时间: 2016-12-31 至 2020-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/361416317?language=en
• 关键词: role; CCL2; nephronophthisis; autosomal; dominant

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.

肾病和常染色体显性多囊肾病（ADPKD）是导致肾衰竭的最常见的遗传性肾脏疾病。肾脏病患者的肾脏衰竭通常发生在儿童期或青春期，而ADPKD患者的肾脏衰竭则发生在成年期。目前还没有有效的治疗方法。肾病时，代表肾脏内部的肾髓质收缩。这会导致肾小管的阻塞和膨胀，以及肾组织的疤痕。在ADPKD中，肾脏逐渐获得越来越多的充满液体的囊肿，导致肾脏生长到正常大小的几倍，并通过对周围组织的压力形成疤痕。肾脏过大会导致慢性疼痛和进食正常量食物的问题。ADPKD是一种常见的疾病，大约每1000人中就有1人患有这种疾病，而肾病则不太常见。在肾功能衰竭的情况下，患者需要每周进行几次血液透析，每天进行几次腹膜透析或进行肾移植。移植需要几十年来每天服用几次药物来抑制免疫系统并防止排斥反应。在早期的工作中，我们的研究小组发现，两种名为Lkb1和Ccl2的蛋白质可能在两种疾病中发生的瘢痕形成中起重要作用。这两种疾病的共同之处在于，在正常情况下，突变蛋白位于纤毛中。纤毛是一种从细胞表面突出的毛发状结构，它的作用是接收来自环境的信号并将其传递到细胞内。我们发现Lkb1定位于纤毛内，并与肾病中突变的蛋白相互作用以抑制Ccl2。我们还发现，在超过80%的ADPKD患者中突变的蛋白参与抑制Ccl2。我们认为，这种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中导致囊肿生长。目前的项目旨在查明情况是否确实如此，并希望检测哪些其他纤毛蛋白参与了这一机制的解除。从这个项目中获得的知识将有助于找到治疗这些疾病的新方法，并维持受影响的人的肾脏功能。