Autosomal Dominant Polycystic Kidney Disease (ADPKD) is one of the most common genetic diseases affecting 12.5 million people worldwide and by far, the most common genetic disease of the kidney. It is caused by inactivating mutations in the PKD1 or PKD2 genes, encoding a receptor-channel complex (Polycystins or PKD1/PKD2). A hallmark of ADPKD is increased cell proliferation. However, how mutations in the Polycystin genes cause increased cell proliferation is not completely understood. A key organelle in disease development and progression is the primary cilium, an antenna-like organelle housing several mitogenic signaling pathways. Genetic and pharmacologic studies show that primary cilia ablation or acceleration of cilia disassembly reduces cell proliferation, suppresses cystic growth and improves kidney function, whereas deceleration of ciliary disassembly has the opposite effects in mouse models of ADPKD. While these observations are of paramount importance in understanding the pathophysiology of ADPKD and in developing therapeutic approaches to slow down disease progression, a unifying theory connecting cilia and cell proliferation in ADPKD is lacking. Ciliary assembly and disassembly or shedding are normal processes of actively proliferating cells. Cilia assemble in quiescent cells, while disassemble or shed when cells re-enter the cell cycle (G1/S). Our preliminary data show that deletion of Pkd1 increases the activity/levels of p53, which in turn, induces the expression of the substrate recognition receptor FBW7 of the SCFFBW7 Ubiquitin E3 ligase. FBW7 targets for proteasomal degradation a subset of disassembly factors delaying deciliation and stabilizing primary cilia. Continuous presence of cilia during the G1/S transition leads to sustained mitogenic signaling mediated by stabilized/remaining cilia resulting in more cells eventually entering the cell cycle. Finally, genetic modifications of this pathway, improve renal function of Pkd1-null mice. These results help explain the increased cell proliferation seen in ADPKD kidneys and the positive effect of cilia on disease progression. Using a vertical approach combining biochemical, cell biological, and genetic methods, we will determine the role of ciliary disassembly and shedding in cystic kidney disease progression. Successful completion of the proposed will have a significant impact on our understanding the biological role of ciliary disassembly/shedding in disease progression and on helping develop new therapeutic approaches for ADPKD.

R01DK126705

2021-03-15

2025-01-31