Ciliary Mechanisms of Cyst Formation in Polycystic Kidney Disease

Abstract

Autosomal-dominant polycystic kidney disease (ADPKD) is a disease of defective tissue homeostasis resulting in active remodeling of nephrons and bile ducts to form fluid-filled sacs called cysts. The causal genes PKD1 and PKD2 encode transmembrane proteins polycystin 1 (PC1) and polycystin 2 (PC2), respectively. Together, the polycystins localize to the solitary primary cilium that protrudes from the apical surface of most kidney tubule cells and is thought to function as a privileged compartment that the cell uses for signal integration of sensory inputs. It has been proposed that PC1 and PC2 form a receptor-channel complex that detects external stimuli and transmit a local calcium-mediated signal, which may control a multitude of cellular processes by an as-yet unknown mechanism. Genetic studies using mouse models of cilia and polycystin dysfunction have shown that polycystins regulate an unknown cilia-dependent signal that is normally part of the homeostatic maintenance of nephron structure. ADPKD ensues when this pathway is dysregulated by absence of polycystins from intact cilia, but disruption of cilia also disrupts this signaling mechanism and ameliorates ADPKD even in the absence of polycystins. Understanding the role of cilia and ciliary signaling in ADPKD is challenging, but success will provide saltatory advances in our understanding of how tubule structure is maintained in healthy kidneys and how disruption of polycystin or cilia function leads to the pathological tissue remodeling process underlying ADPKD.

Figure 1.

Schematic illustration of polycystin 1 (PC1)–polycystin 2 (PC2)–cilia-dependent cyst activation (CDCA) signaling. (A) The PC1–PC2 complex is expressed in cilia and maintains CDCA in a physiologically regulated quiescent state with epithelial cells retaining a columnar shape and the tubule with normal lumen diameter. Normal physiological input would adjust CDCA to physiological needs of cell shape, lumen morphology, cell transport, metabolic properties, etc. WT, Wild type. (B) Reduced PC1 dosage in heterozygous cells of autosomal-dominant polycystic kidney disease (ADPKD) patients may lead to weak constitutive activation of CDCA and a modest steady-state change in cell shape (less columnar) and lumen diameter (increased). (C) Loss of PC1 in the presence of intact cilia, the condition for cyst initiation in ADPKD, leads to inexorable activation of CDCA, profound changes in cells to a more squamoid shape, low-level proliferation, active remodeling of surrounding kidney parenchyma, and growth of cysts. Note that the images of cells and tubules (cysts) in panel C are at a much lower illustrative “magnification” than A, B, or D. (D) Loss of cilia in the absence of PC1 markedly reduces the activation of CDCA and maintains cell shape and tubule lumen diameter in a more normal range.

Figure 2.

Model of PC1 regulation after GPS cleavage. (A) Following G-protein-coupled receptor proteolytic site (GPS) cleavage, PC1–NTF and PC1–CTF remain associated with each other and traffic to cilia where the PC1–PC2 complex maintains cilia-dependent cyst activation (CDCA) in a regulated quiescent state. (B) In the presence of a stimulus, either ligand binding or mechanical input such as flow, PC1–NTF is displaced from PC1–CTF. This exposes the buried stalk region of PC1–CTF (red), which may serve as an autoligand that releases PC1–CTF inhibition of CDCA. Transient activation of CDCA leads to alterations in cell shape and lumen diameter (bottom panels). (C) Either reassociation of PC1–NTF with PC1–CTF or retrieval of unbound PC1–CTF from cilia and its replacement with PC1–NTF/CTF–PC2 complex returns CDCA to a reduced state of activity and the tubules to a baseline morphology.