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

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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.