Polycystic kidney disease and the renal cilium (Review Article)

Monash Immunology and Stem Cell Laboratories (MISCL), Monash University, Melbourne Victoria, Australia
Nephrology (Impact Factor: 2.08). 11/2007; 12(6):559 - 564. DOI: 10.1111/j.1440-1797.2007.00869.x


Polycystic kidney disease (PKD) is a common genetic condition characterized by the formation of fluid-filled cysts in the kidney. Mutations affecting several genes are known to cause PKD and the protein products of most of these genes localize to an organelle called the renal cilium. Renal cilia are non-motile, microtubule-based projections located on the apical surface of the epithelial cells that form the tubules and ducts of the kidney. With the exception of intercalated cells, each epithelial cell bears a single non-motile cilium that projects into the luminal space where it is thought to act as a flow sensor. The detection of fluid flow through the kidney by the renal cilium is hypothesized to regulate a number of pathways responsible for the maintenance of normal epithelial phenotype. Defects of the renal cilium lead to cyst formation, caused primarily by the dedifferentiation and over-proliferation of epithelial cells. Here we discuss the role of renal cilia and the mechanisms by which defects of this organelle are thought to lead to PKD.

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Available from: James A Deane
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    • "The significance of primary cilia in the kidney of mammals was unclear for many years. However, they have been the subject of intense investigation following the discovery that defects of this organelle can cause PKD (reviewed in Deane and Ricardo, 2007). "
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    ABSTRACT: Primary cilia are microscopic sensory antennae that cells in many vertebrate tissues use to gather information about their environment. In the kidney, primary cilia sense urine flow and are essential for the maintenance of epithelial architecture. Defects of this organelle cause the cystic kidney disease characterized by epithelial abnormalities. These findings link primary cilia to the regulation of epithelial differentiation and proliferation, processes that must be precisely controlled during epithelial repair in the kidney. Here, we consider likely roles for primary cilium-based signaling during responses to renal injury and ensuing epithelial repair processes.
    Full-text · Article · Jan 2012 · International review of cell and molecular biology
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    • "The exact mechanism by which the carboxy-terminus of PC-1 protects TSC2 from inactivating phosphorylation by AKT will require further investigation. However, while recent studies have emphasized the importance of localization of PC-1 to the primary cilia [45], [46], our data using non-ciliated cells would suggest that the regulation of mTOR by CP1 is a cilia-independent function of this cystoprotein. "
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    ABSTRACT: Autosomal dominant polycystic kidney disease (ADPKD) is a commonly inherited renal disorder caused by defects in the PKD1 or PKD2 genes. ADPKD is associated with significant morbidity, and is a major underlying cause of end-stage renal failure (ESRF). Commonly, treatment options are limited to the management of hypertension, cardiovascular risk factors, dialysis, and transplantation when ESRF develops, although several new pharmacotherapies, including rapamycin, have shown early promise in animal and human studies. Evidence implicates polycystin-1 (PC-1), the gene product of the PKD1 gene, in regulation of the mTOR pathway. Here we demonstrate a mechanism by which the intracellular, carboxy-terminal tail of polycystin-1 (CP1) regulates mTOR signaling by altering the subcellular localization of the tuberous sclerosis complex 2 (TSC2) tumor suppressor, a gatekeeper for mTOR activity. Phosphorylation of TSC2 at S939 by AKT causes partitioning of TSC2 away from the membrane, its GAP target Rheb, and its activating partner TSC1 to the cytosol via 14-3-3 protein binding. We found that TSC2 and a C-terminal polycystin-1 peptide (CP1) directly interact and that a membrane-tethered CP1 protects TSC2 from AKT phosphorylation at S939, retaining TSC2 at the membrane to inhibit the mTOR pathway. CP1 decreased binding of 14-3-3 proteins to TSC2 and increased the interaction between TSC2 and its activating partner TSC1. Interestingly, while membrane tethering of CP1 was required to activate TSC2 and repress mTOR, the ability of CP1 to inhibit mTOR signaling did not require primary cilia and was independent of AMPK activation. These data identify a unique mechanism for modulation of TSC2 repression of mTOR signaling via membrane retention of this tumor suppressor, and identify PC-1 as a regulator of this downstream component of the PI3K signaling cascade.
    Full-text · Article · Feb 2010 · PLoS ONE
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    • "The loss of ciliation in tumor cells may indicate either that the deregulated cell cycle which is a hallmark of cancer cells requires loss of a cell cycle-restrictive signal mediated through cilia, or that the loss of tumor cells ability to readily enter quiescence causes defects in ciliogenesis. Besides tumor cells, it has also been found that the cystogenesis found in polycystic kidney disease (PKD) or due to other mutations is accompanied both by defects in cell cycle progression, and shortened or absent cilia (Deane and Ricardo, 2007; Veland et al., 2009). The increasingly close connections apparent between inappropriate ciliation and disease state make understanding of the mechanisms involved of potentially great therapeutic value. "
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    ABSTRACT: Cilia are microtubule-based structures that protrude from the cell surface and function as sensors for mechanical and chemical environmental cues that regulate cellular differentiation or division. In metazoans, ciliary signaling is important during organismal development and in the homeostasis controls of adult tissues, with receptors for the Hedgehog, platelet derived growth factor (PDGF), Wnt, and other signaling cascades arrayed and active along the ciliary membrane. In normal cells, cilia are dynamically regulated during cell cycle progression: present in G0 and G1 cells, and usually in S/G2 cells, but almost invariably resorbed before mitotic entry, to reappear post-cytokinesis. This periodic resorption and reassembly of cilia, specified by the intrinsic cell cycle the intrinsic cell cycle machinery, influences the susceptibility of cells to the influence of extrinsic signals with cilia-associated receptors. Pathogenic conditions of mammals associated with loss of or defects in ciliary integrity include a number of developmental disorders, cystic syndromes in adults, and some cancers. With the continuing expansion of the list of human diseases associated with ciliary abnormalities, the identification of the cellular mechanisms regulating ciliary growth and disassembly has become a topic of intense research interest. Although these mechanisms are far from being understood, a number of recent studies have begun to identify key regulatory factors that may begin to offer insight into disease pathogenesis and treatment. In this chapter we will discuss the current state of knowledge regarding cell cycle control of ciliary dynamics, and provide general methods that can be applied to investigate cell cycle-dependent ciliary growth and disassembly.
    Full-text · Article · Dec 2009 · Methods in cell biology
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