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Physiology 19: 225-230, 2004; doi:10.1152/physiol.00003.2004
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Physiology, Vol. 19, No. 4, 225-230, August 2004
© 2004 Int. Union Physiol. Sci./Am. Physiol. Soc.

REVIEW

Cystic Kidney Diseases: All Roads Lead to the Cilium

Qihong Zhang, Patrick D. Taulman and Bradley K. Yoder

Department of Cell Biology, University of Alabama at Birmingham, Birmingham, Alabama 35294
byoder{at}uab.edu


   Abstract
 
Cystic kidney disorders are one of the leading causes of end-stage renal disease. Numerous experimental animal models have been used to understand the disease pathogenesis. Recent advancements in this field have provided a surprising finding: that many of the proteins associated with cystic kidney disease localize to a nearly forgotten organelle, the primary cilium.


   Introduction
Top
 Introduction
Cystic Kidney Disease-Associated...
 Cilium Structure and the...
 Physiological Role of Kidney...
 Conclusions
 References
 
The formation of kidney cysts is a pathological entity common to a number of inherited and acquired human diseases. Of these disorders, polycystic kidney disease (PKD) is one of the most prominent (reviewed in Ref. 31). The autosomal dominant form of human PKD (ADPKD) affects up to 1 in 500 individuals, with most patients reaching end-stage renal disease by the age of 60, requiring kidney dialysis or transplantation. ADPKD is caused by mutations in either PKD1 or PKD2, which encode the transmembrane proteins called polycystin-1 and polycystin-2, respectively (18, 44, 83). These proteins physically interact and function as a nonselective cation channel (26, 68). The subcellular localization of the polycystins remains the subject of considerable controversy. Polycystin-1 has been detected at the lateral and apical membranes, in the endoplasmic reticulum (ER), and at focal adhesion sites (23, 30, 59). Polycystin-2 has also been reported at the plasma membrane, but its predominant localization is in the ER (12, 22, 34, 70). In addition, both proteins have recently been detected in the cilia (62, 84), an organelle present on most of the epithelial cells lining the nephron (the exception being the intercalated cells).

Autosomal recessive PKD (ARPKD) is less common than ADPKD and affects up to 1 in 6,000 live births. Recently, the gene for ARPKD has been identified; it encodes a large transmembrane protein called fibrocystin or polyductin of unknown function that is also present in the primary cilium (6, 49, 77).

Pathological findings in ADPKD and ARPKD include the formation of epithelia-lined cysts throughout the nephron in ADPKD and predominantly in the collecting duct in ARPKD; changes in extracellular matrix composition; improper epithelial cell differentiation, proliferation, and apoptosis; and alterations in cell polarity (3, 13, 81). In addition to the renal lesions, abnormalities in ADPKD include hepatic and pancreatic cysts and intracranial aneurysms, whereas ARPKD patients display biliary ductal ectasia and dysgenesis along with periportal fibrosis in the liver (14, 40, 55).

Another form of human cystic kidney disorders is nephronophthisis (NPHP) (1, 72). The renal pathology in NPHP patients typically consists of tubular basement membrane disruption, tubular atrophy, cyst development, and interstitial infiltration along with fibrosis. Four loci (NPHP1–NPHP4) associated with NPHP have been identified, and, intriguingly, their corresponding proteins have recently been detected in the cilium.

Two other human diseases that develop cystic kidneys as part of their pathology are Bardet-Biedl Syndrome (BBS) and oral-facial-digital syndrome type 1 (OFD1). Although the corresponding proteins for OFD1 and BBS have not yet been reported in the cilium, they have been detected at the basal body from which the cilia emerges (2, 19, 21).


   Cystic Kidney Disease-Associated Proteins and Cilia Localization
Top
 Introduction
 Cystic Kidney Disease-Associated...
Cilium Structure and the...
 Physiological Role of Kidney...
 Conclusions
 References
 
The considerable morbidity and mortality caused by cystic kidney diseases has prompted intense investigative efforts to identify the molecular mechanism involved in cyst initiation and progression. As part of this effort, numerous animal models have been developed to study cystogenesis and to evaluate potential strategies for therapeutic intervention. These models arose through either spontaneous mutations (cpk, bpk, jck, kat, pcy, Han:SPRD-cy, kdkd, wpk, and pck), transgenic approaches (orpk and inv), chemical mutagenesis (jcpk), or gene-specific knockout events (pkd1, pkd2, and kif3A) [see TABLE 1Go; also, the reader is referred to a recent review (24) for more detailed information on the murine models of PKD]. The pathological features in several of these models closely resemble those seen in human cystic kidney diseases in terms of cyst localization, morphology, and progression, as well as the presence of extrarenal pathology in the liver and pancreas. These models also share similarities with the human diseases at the cellular level, which includes alterations in basement membrane and extracellular matrix components, abnormal cell proliferation and apoptosis, defects in epithelial polarity, and abnormal transepithelial fluid transport.


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  		TABLE 1. Animal models for cystic kidney diseases
 
Although in general each of these models is due to mutation in a unique gene, most have markedly similar renal pathologies, leading to the speculation that these mutations may affect a common pathway. Quite unexpectedly, the thread that now ties multiple models together is the localization of their corresponding proteins to the renal cilium or basal body at the base of cilia (FIGURE 1Go). This is evident with proteins whose function is known to be disrupted in human ADPKD (polycystin-1 and polycystin-2) (62, 84), ARPKD (fibrocystin/polyductin) (78), OFD1 (20, 21), BBS (2, 33), NPHP [nephrocystin-1 (NPHP1) (56), inversin (NPHP-2) (58, 79), nephrocystin-3 (NPHP3) (54), nephroretinin (NPHP4) (45, 57)], and in several mouse models (cystin, polaris, and KIF3A) (29, 37, 76, 84) for which associated human diseases have not yet been discovered (see TABLE 1Go). Together, these data suggest that defects in the primary cilia may be a universal abnormality underlying cystic kidney diseases. Therefore, one of the keys to further understanding the pathogenesis of cystic diseases and deriving potential therapeutic interventions will be to elucidate the physiological role of the primary renal cilium.



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  		FIGURE 1. Immunofluorescence staining of mouse kidney tissue section using antibodies against mouse polaris and ß-tubulin
Colocalization of the polaris (red) and ß-tubulin (green) proteins as revealed by immunofluorescence appears yellow. Both antibodies label a single cilium located on the apical surface of the epithelium. These cilia extend into the lumen of the tubule. The tubule is shown in cross section with the basolateral surface outlined in white. Nuclei of the epithelium are stained blue.

 

   Cilium Structure and the Mechanism of Cilia Assembly: Intraflagellar Transport
Top
 Introduction
 Cystic Kidney Disease-Associated...
 Cilium Structure and the...
Physiological Role of Kidney...
 Conclusions
 References
 
Cilia are small organelles that emanate from one of the basal bodies, a modified form of centriole (FIGURE 2Go). They are predominantly associated with epithelial cells. However, they are also present on endothelial cells, neurons, fibroblasts, chondrocytes, and many other cell types (80). The general structure of a cilium consists of a membrane-enclosed tube surrounding a central core of microtubules (axoneme). A cross section through a cilia axoneme reveals nine microtubule doublets (9+0) surrounding, in some cases, a central pair of microtubules (9+2) (75). Whereas 9+0 cilia, typical of those seen in the kidney, are normally immotile, 9+0 cilia found on the surface of the embryonic node are capable of rotational beating (53). The immotile forms of cilia (primary cilium) are thought to be sensory organelles involved in chemo-, photo-, and mechano-reception (11, 69). The 9+2 cilia, such as those found on epithelial cells lining the trachea, are motile where they are associated with either cell locomotion or fluid movement.



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  		FIGURE 2. The primary cilium
A: structural diagram. B: scanning electron micrograph of primary cilium located on the apical surface of the renal principal cell grown in culture.

 
Although relatively little is known about mammalian ciliogenesis, studies in Caenorhabditis elegans and Chlamydomonas have provided a great deal of insight into the process. From studies in these organisms, a model of ciliogenesis has been developed that is referred to as intraflagellar transport (IFT) (61). IFT describes the anterograde movement of large protein complexes (IFT particles, one of which is the Tg737 protein polaris) from the base of the cilia (basal body) to the cilia tip and retrograde movement from the tip back to the cilia base. Anterograde transport is mediated by the heterotrimeric kinesin II (KIF3A, KIF3B, and KAP3) complex, whereas retrograde movement back to the cilia base is performed by a cytoplasmic dynein. IFT is required for cilia formation, as evidenced by the phenotype of multiple mutations in IFT proteins in C. elegans and Chlamydomonas and by disruption of kif3A, kif3B, and Tg737 in mice (10, 16, 28, 48, 53, 60, 85).


   Physiological Role of Kidney Primary Cilia
Top
 Introduction
 Cystic Kidney Disease-Associated...
 Cilium Structure and the...
 Physiological Role of Kidney...
Conclusions
 References
 
Cilia are present on almost all cells lining the nephron, with the exception of intercalated cells. This includes cells in the parietal layer of Bowman’s capsule, proximal tubules, the loop of Henle, and the collecting duct (36). The function and importance of the renal cilia have been largely ignored until recently, when studies (60, 85) suggested that cilia defects are associated with cystic kidney disease.

In most cases, primary cilia have been assigned a sensory role. In the kidney, the primary cilium would be ideally positioned to act as a sensor extending from the cell surface into the tubule lumen. Thus a possible function of the renal cilium may be in chemosensation. Primary cilia found on olfactory cells have been shown to mediate chemosensation through receptors localized in the membrane of the cilia axoneme. Cilia in C. elegans neurons are essential for the worm to sense the chemical and osmotic cues in the environment, as evidenced by the phenotypes of worm cilia mutants (64). Furthermore, several G protein-coupled receptors, such as the somatostatin receptor-3 and one of the serotonin receptors (5-HT6), have been localized to the membrane of the primary cilia in neuronal cells in the mammalian brain (9, 27). By analogy, it seems likely that renal cilia may function in a similar capacity and sense concentration of specific ligands in the lumen of the nephron and then transmit this information to surrounding cells, which respond accordingly.

Another function that has been assigned to the renal cilia is the role of mechanosensor that detects fluid flow through the lumen of the tubule. In cell culture, deflection of the cilia axoneme initiates a transient increase in the level of intracellular Ca2+. This Ca2+ enters through a channel, possibly polycystin-1 and polycystin-2, located in the cilium (65, 66). This is supported by the fact that the Ca2+ influx generated by fluid flow is abolished in cell lines lacking polycystin-1 (50) and by the loss of fluid flow-mediated calcium signaling in the embryonic node of mice lacking polycystin-2 (41). How this elevated concentration of Ca2+ in renal epithelium affects cell function remains elusive. A localized increase in intracellular Ca2+ in other cell types can modulate a variety of processes such as targeted fusion of cytosolic vesicles with the plasma membrane, cell signaling by activating protein kinase cascades, gene expression, and protein targeting, which can eventually change the rate of cellular proliferation, apoptosis, and differentiation as well as alter fluid and ion transport (7, 42, 71, 73) (FIGURE 3Go). Thus the next challenges are to determine the downstream consequences of the increased calcium signaling and to evaluate whether the cilia perform a similar function in vivo as observed in cultured cells.



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  		FIGURE 3. Schematic diagram showing the cilium extending off the cell surface and the localization of proteins associated with cystic kidney disease
ER, endoplasmic reticulum; BBS, Bardet-Biedl syndrome; OFD1, oral-facial-digital syndrome.

 

   Conclusions
Top
 Introduction
 Cystic Kidney Disease-Associated...
 Cilium Structure and the...
 Physiological Role of Kidney...
 Conclusions
References
 
Recent data suggest that a common feature underlying cystic kidney diseases is a defect in primary cilia assembly or function. How cysts arise due to altered cilia function is still not clear. The challenge for researchers in this field is to elucidate the physiological role that the cilium plays on renal epithelium and to determine the consequences of cilia dysfunction on cell behavior. The answers to these questions will likely come from molecular genetics, cell biology, and biochemical approaches exploring model systems such as mice, zebrafish, C. elegans, and Chlamydomonas.


   Acknowledgments
 
We thank Dr. C. J. Haycraft for her critical reading of the manuscript.

We regret that space limitations prevented us from citing all of the literature relevant to this review.

This work was supported by grants from the National Institutes of Diabetes and Digestive and Kidney Diseases (DK-65655 and DK-62758).


   References
Top
 Introduction
 Cystic Kidney Disease-Associated...
 Cilium Structure and the...
 Physiological Role of Kidney...
 Conclusions
 References
 

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