Am J Physiol Renal Physiol 305: F1085–F1098, 2013.
First published July 31, 2013; doi:10.1152/ajprenal.00399.2013.
Review
Primary cilia and kidney injury: current research status and future perspectives
Shixuan Wang1 and Zheng Dong1,2
1
Department of Cellular Biology and Anatomy, Medical College of Georgia, Georgia Regents University and Charlie
Norwood Veterans Affairs Medical Center, Augusta, Georgia; and 2Department of Nephrology, The Second Xiangya Hospital,
Central South University, Hunan, China
Submitted 10 July 2013; accepted in final form 26 July 2013
primary cilia; kidney injury; IFT; planar cell polarity; ciliopathy
CILIA OR FLAGELLA (here used interchangeably) contain nine sets
of microtubule doublets arranged in a circular pattern with
(9⫹2) or without (9⫹0) a central pair of microtubule singlets.
They are largely membrane-enclosed organelles that project
from the apical surface of cells (133, 185, 187). The majority
of cells in the human body have either one or multiple cilia. A
single or monocilium in one cell is called the primary or
nonmotile cilium (9⫹0), since it is immotile (for cells with
primary cilia, see http://www.bowserlab.org/primarycilia/cilialist.html), apart from the exceptions such as motile nodal cilia
(9⫹0) and nonmotile olfactory sensory cilia (9⫹2) (108, 120,
136). However, epithelial cells in some organs, for instance the
respiratory tract and reproductive system, harbor multiple cilia
(9⫹2) on the apical side of cells, which can beat upon stimulation, and therefore are named motile cilia although a chemosensory function has been recently suggested (179). Inside the
cilium is the microtubule-based axoneme, in connection with
bidirectional microtubule motors and associated protein complexes. Outside the axoneme is the enclosed ciliary membrane,
which is generally believed to be specific and different from
the rest of the plasma membrane. The structure connected to
the cilium at the bottom is the basal body, and it is derived
Address for reprint requests and other correspondence: Z. Dong, Dept. of
Cellular Biology and Anatomy, Medical College of Georgia, Augusta, GA
30912 (e-mail: [email protected]).
http://www.ajprenal.org
from the mother centriole of the centrosome, which provides a
docking site for the cilium and transforms into a centriole
during mitosis (Fig. 1). The basal body is structurally different
from the daughter centriole, owing to its additional distal and
subdistal appendages (79).
It has been known that cilia play pivotal roles in embryo
development, cell and tissue homeostasis, and human diseases.
Although specialized cilia in the retina and kinocilia in the
inner ear have been recognized for their specific roles in
photoreception and cell polarization, the functions of primary
cilia in humans have been obscure for more than a century. It
was not until the observation of expression of the polycystin-1
(PC1) homolog Lov-1 in sensory neurons of Caenorhabditis
elegans and the generation of Tg737°rpk mice that researchers
began to realize the importance of primary cilia, since Lov-1 is
required for C. elegans mating and Tg737°rpk mice unexpectedly die of polycystic kidney disease (PKD) shortly after birth.
Importantly, primary cilia in the kidney of mice with the Tg737
mutation are stunted (13, 219). These discoveries, for the first
time, link the primary cilia to PKD. Later, Nauli et al. (132,
208) found that dysfunctional primary cilia are responsible for
cystogenesis in human autosomal dominant (AD) and recessive
(AR) PKD. These studies disclosed that primary cilia in the
kidney epithelial cells are potentially the mechanosensors to
fluid flow (132, 158, 208). During recent years, studies of
primary cilia have been expanded to a spectrum of human
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Wang S, Dong Z. Primary cilia and kidney injury: current research status and
future perspectives. Am J Physiol Renal Physiol 305: F1085–F1098, 2013. First
published July 31, 2013; doi:10.1152/ajprenal.00399.2013.—Cilia, membraneenclosed organelles protruding from the apical side of cells, can be divided into two
classes: motile and primary cilia. During the past decades, motile cilia have been
intensively studied. However, it was not until the 1990s that people began to realize
the importance of primary cilia as cellular-specific sensors, particularly in kidney
tubular epithelial cells. Furthermore, accumulating evidence indicates that primary
cilia may be involved in the regulation of cell proliferation, differentiation,
apoptosis, and planar cell polarity. Many signaling pathways, such as Wnt, Notch,
Hedgehog, and mammalian target of rapamycin, have been located to the primary
cilia. Thus primary cilia have been regarded as a hub that integrates signals from
the extracellular environment. More importantly, dysfunction of this organelle may
contribute to the pathogenesis of a large spectrum of human genetic diseases,
named ciliopathies. The significance of primary cilia in acquired human diseases
such as hypertension and diabetes has gradually drawn attention. Interestingly,
recent reports disclosed that cilia length varies during kidney injury, and shortening
of cilia enhances the sensitivity of epithelial cells to injury cues. This review briefly
summarizes the current status of cilia research and explores the potential mechanisms of cilia-length changes during kidney injury as well as provides some
thoughts to allure more insightful ideas and promotes the further study of primary
cilia in the context of kidney injury.
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Fig. 1. Left: anti-acetylated tubulin-stained primary cilia of
human proximal tubular epithelial cells (HK-2). DAPI,
4’,6-diamidino-2-phenylindole. Right: basic structure of a
primary cilium.
primary cilia and focus on the potential roles of cilia in kidney
injury. A series of excellent reviews are available for more
information about cilia and flagella (7, 122, 130, 205).
Ciliogenesis and Intraflagellar Transport
Ciliogenesis generally occurs in differentiated cells and
involves a series of steps from cell cycle exit and mother
centriole transformation to basal body to axoneme growth and
extension. After cells exit the cell cycle, the mother centriole
moves to the apical surface of the cell and acquires a series of
components necessary for ciliary budding. A microtubulebased axoneme extends from the microtubule of the mature
Table 1. Cilia-associated human diseases and genes
Human Diseases
Genes
Alstrom syndrome
Asphyxiating thoracic dystrophy
Bardet-Biedl syndrome
Joubert syndrome
ALMS1
IFT80, DYNC2H1, TTC21B, WDR19
BBS1-15
TMEM67, 138, 216, 231, 237; CC2D2A, ARL13B, NPHP1, NPHP6/CEP290, INPP5E, AHI1, RPGRIP1L,
CXORF5, TTC21B, KIF7, TCTN1, CEP41
DNAI1, DNAH11, DNAH5
TMEM67, 216; CEP290, RPGRIP1L, CC2D2A, NPHP3, TCTN2, B9D1, 2; MKS1
NPHP1-13, NEK8, GLIS2
OFD1
PKD1, PKD2, PKHD1
DNAI1, 2; DNAH5, TXNDC3, DNAH11, KTU, RSPH4A, 9, LRRC50, CCDC39, 40, 103; DNAAF3,
NPHP1, 4, 5, 6; SDCCAG8
IFT122, IFT43, WDR19, 35
NEK1, DYNC2H1, WDR35
TSC1, TSC2
VHL
Kartegener syndrome
Meckel-Gruber syndrome
Nephrononphthisis
Orofaciodigital syndrome 1
Polycystic kidney disease
Primary ciliary dyskinesis
Senior-Loken syndrome
Sensenbrenner syndrome
Short-rib polydactyly syndrome
Tuberous sclerosis
von Hippel-Lindau disease
Diabetes
Hypertension
Kidney injury
Obesity
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genetic diseases, collectively termed the ciliopathies (61, 83),
as well as to a few nongenetic disorders such as kidney injury,
obesity, hypertension, and diabetes (125, 172) (Table 1). In
addition, cilia have been proposed to function in exocytosis
(11) in the ciliary pocket of the flagella and kinetoplastid
protozoa (66, 126).
Cilia or flagella have been studied using different model
systems. In addition to zebrafish, C. elegans, Xenopus laevis,
and Tetrahymena, the most popular model systems are Chlamydomonas (http://labs.umassmed.edu/chlamyfp/index.php) and
mammals (http://v3.ciliaproteome.org/cgi-bin/index.php). Indeed,
a large body of knowledge was obtained studying Chlamydomonas. In this review, we will discuss the current status of studies of
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CILIA IN KIDNEY INJURY
and methylated during flagellar resorption, implying that these
two posttranslational modifications are likely involved in ciliogenesis (74, 176). In addition to the effect of microtubules on
ciliogenesis, microtubule tip-associated proteins such as EB1
and EB3 also regulate ciliogenesis, because depletion of these
genes leads to a significant decrement of cilia number in
different mammalian cells (177).
In addition to the regulation of ciliogenesis by the cell cycle
and microtubules, actin dynamics is associated with ciliogenesis. Cytochalasin D and jasplakinolide are two reagents that
disrupt polymerization of actin filaments, both of which facilitate the lengthening of the primary cilia in different types of
cultured cells (20, 180). Bershteyn et al. (20) showed that MIM
(Missing-in-Metastasis), an actin-regulatory protein, is required for ciliogenesis at the basal body of mesenchymal cells,
and they proposed that MIM promotes ciliogenesis by antagonizing phosphorylation of cortactin. It has been known that
cortactin is a monomeric protein and plays an important role in
promoting polymerization and rearrangement of the actin cytoskeleton (46). ACTR3, an interaction protein of cortactin
identified by functional screening, has been shown to increase
the length of primary cilia (89). Filamin A, an actin-binding
protein, has been reported to be crucial in ciliogenesis and
positioning of the basal body (3), and meckelin, an interaction
protein of filamin A, regulates ciliogenesis possibly by affecting the distribution of cytoplasmic stress fibers (47).
IFT has been proven to be an indispensable process for
ciliogenesis and is well conserved evolutionally from C. elegans to Chlamydomonas, and to mammals. Kozminski et al.
(97) first described IFT as the bidirectional movement of
particles along the axoneme of flagella. Later, the same group
found that the IFT process is dependent on a protein called
FLA10 (96). Kinesin-II, the homolog of FLA10 in mammals,
was identified to be important for both motile and primary cilia
(110, 127). IFT is a two-parallel process of anterograde transport toward the tip of the axoneme and retrograde transport
toward the base of the cilia. Anterograde transport is performed
by the heterotrimeric kinesin-II motor protein complex (Kif3a,
Kif3b, Kap), and retrograde transport is facilitated by the motor
protein cytoplasmic dynein. Thus far, it has been known that
IFT particles contain at least 20 polypeptides which are divided
into complex A (IFT43, 121/122b, 122/122a, 139, 140, 144)
and B (IFT20, 22, 25, 27, 46, 52, 54, 57/55, 70, 74/72, 80, 81,
88, 172) (40, 62, 81, 145). Proteins in complex A and B are
distinct in functions because mutations of complex A proteins
generally do not affect cilia assembly while mutations of
complex B proteins do (162). The typical example for complex
B proteins is IFT88 mutation mice, which demonstrate shortened cilia (153). Compared with complex B proteins, mutation
of the complex A protein IFT140 causes PKD but does not
completely prevent cilia assembly (84).
Cilia Maintenance
Once cilia are established, the next step is to maintain them.
This process is also performed by IFT because no protein
synthesis machinery is found in the cilia. Thus almost all
ciliary components are synthesized in the cell body (167). Two
models for cilium/flagellum length control have been described
(7, 99, 117). The first one is the limiting-precursor model based
on the hypothesis that the quantity of precursors or building
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centriole/basal body, and new microtubule units are added to
the distal tip by a process called intraflagellar transport (IFT) to
lengthen the axoneme (68). When a certain point in its length
is reached, an axoneme stops growing and starts maintaining.
In most cases, the exit of the cell cycle is correlated with
ciliogenesis; however, in hTERT-RPE1 cells, cell spatial confinement seems to be a major regulator of ciliogenesis (157).
Convincing experiments showed that the cell cycle per se
regulates cilium length (80). During cell proliferation, cilium
length fluctuates in parallel with the four phases of the cell
cycle (G1, S, G2, and M). In the M phase, cilia are resorbed to
facilitate cell division while in the G1, S, and early G2 phases
cilia can still be observed (22). The molecular mechanisms
underlying ciliogenesis during the cell cycle have begun to
emerge. Cdc14b phosphatase, an antagonist of Cdk1, is required for both motile and primary ciliogenesis in zebrafish in
a manner independent of fibroblast growth factor (FGF) (38).
Aurora A, a mitotic kinase, induces ciliary disassembly in
hTERT-RPE cells (161). Cilia-associated proteins, vice versa,
have been found to regulate the cell cycle. A typical example
is polycystin-2 (PC2), a transmembrane protein responsible for
15% of cases of patients with ADPKD (189). PC2 has been
localized to the primary cilia and is known to regulate the cell
cycle (154, 198). Polaris, another protein responsible for ciliary
assembly, leads to misorientation of the spindle body during
mitosis and hyperproliferative kidney cysts if the normal function is disrupted (49).
Exiting the cell cycle is just the initial step for ciliogenesis.
Microtubule formation and posttranslational modifications are
all essential. In Chlamydomonas, tubulin levels are significantly upregulated after deflagellation (211). Sharma et al.
(180) further explored the role of tubulin in mammalian cells
and found that soluble cytosolic tubulin regulates cilium
length. Ciliary microtubules, consisting of ␣- and ␤-tubulins,
can undergo a wide range of posttranslational modifications,
including acetylation, glutamylation, glycylation, ubiquitination, methylation, and phosphorylation (93). The former three
are unique to the tubulin in cilia and flagella (184). It has been
known that acetylation is one characteristic of ␣-tubulin in the
cilia but not in the cytoplasm. Therefore, acetylated ␣-tubulin
is regarded as the standard marker of cilia in cell staining. In
Chlamydomonas, acetylation of ␣-tubulin is associated with
flagellar growth and resorption (104, 105) but does not correlate with ciliary growth in the sea urchin (191). In Tetrahymena, mutated glutamylation of ␤-tubulin leads to abnormal
axonemes and lethality (218). CEP41, an evolutionarily conserved polyglutamylase enzyme, is localized to the basal body
and primary cilia, and CEP41 was very recently found to be
causative of Joubert syndrome, suggesting that tubulin glutamylation is important in the pathogenesis of human ciliary
diseases (102). It seems that mammalian cilia function is not
dependent on the polymeric state of tubulin glycylation although monomeric glycylation is likely essential (51). TTLL3,
a tubulin glycine ligase, appears important for cilia assembly,
and in vivo, glutamic acid and glycine ligase oppose each other
probably by competition of shared modification sites of tubulin, because in both Tetrahymena and zebrafish, deletion of
TTLL3 leads to shortened cilia (217). Ubiquitination and
methylation and phosphorylation of tubulin do occur in cilia
but also in the cytoplasm. In Chlamydomonas, tubulin, IC2,
and dynein have been found to be abnormally ubiquitinated
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receptors and channels are located on the ciliary membrane,
including PC1, PC2, and fibrocystin/polyductin (FPC), somatostatin receptor 3, serotonin receptor 5, platelet-derived
growth factor receptor-␣ (PDGFR␣), and components of Wnt
and Hedgehog and Notch signaling pathways (1, 70, 77, 124,
140, 210). One key question is how these receptors and
channels arrive at the ciliary membrane.
Three working models have been suggested for ciliary membrane protein trafficking (130). The simplest one is that membrane proteins are transported into the nearby area of the cilium
and then fused with the ciliary membrane as occurs with the
plasma membrane proteins because the ciliary and plasma
membranes are topologically continuous and the ciliary axoneme is connected to the cytoskeleton of the cell body. However, data from a number of experiments do not support this
model. For instance, expressed glycosylphosphatidylinositolfluorescent protein (GPI-FP) is transported to the apical side of
the plasma membrane but excluded from an area around the
base of the primary cilia in Madin-Darby canine kidney
(MDCK) cells, suggesting that there is a special structure at the
base of the cilium preventing certain proteins from entering the
cilium (206). This observation is further supported by ultrastructural analysis of the ciliary base (173). The second model
and probably the most recognized one, is that vesicles containing membrane proteins are transported to the base of the cilium
and then, together with the ciliary membrane docking proteins,
gradually move to the ciliary membrane (168). This model has
been supported by a number of experiments (146, 155). The
third model is that membrane proteins first fuse with the
plasma membrane and then the proteins move to the ciliary
membrane laterally. This model originates from an observation
in the Snell lab (78). Additional evidence supporting this
model is Smo trafficking to the ciliary membrane (121). Indeed, considering the complexity at the ciliogenesis stage, all
these three possibilities may be feasible. The route that the
transported protein takes to the ciliary membrane depends on
the property of the protein and the stage of ciliogenesis. For
instance, at the very early stage, some ciliary membrane
proteins may be transported to the preciliary membrane by the
first route before the cilium starts to protrude, but disappear
from the cilia of well-differentiated cells. At the late stage of
ciliogenesis, proteins are transported to the ciliary membrane
by the second and third models. Thus proteins on the preciliary
membrane may not necessarily be the same ones present after
full differentiation of the cell.
Cilia-Associated Signaling Pathways
In the past, many studies, particularly on ligand-receptor
signaling pathways, have not focused on the cilia. Currently,
cilia have been proven to be a hub involved in many signaling
pathways relevant to development and human diseases. Thus it
is necessary to reexamine these signaling molecules and determine whether and how they function in terms of cilia.
Calcium signaling. The association between cilia and calcium has been noticed for decades but has been mainly focused
on motile cilia. However, people did not know that calcium can
enter into the cell through the primary ciliary membrane of
renal tubular epithelial cells until PC2 was localized on this
organelle (132, 154). Nauli et al. (132) found that PC1 and PC2
codistribute on the primary cilia where they regulate calcium
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blocks in one cell is limited (99). Obviously, this model cannot
explain why after flagella are severed, the residues of the
flagella can still regenerate to about half of their normal length
(167). Although there might be reserved building blocks, the
question is where they are inside the cell. Marshall et al. (117)
proposed the balance point model in which it was postulated
that there is continuous tubulin unit assembly and disassembly
at the tip of the cilia, and which one (assembly or disassembly)
predominates depends upon a set point. This means when cilia
are shorter than the set point, assembly will exceed the disassembly, and when cilia are longer than the set point, disassembly will be more predominant. The intriguing question then is
what determines the balance point.
Many factors (physical, chemical, and biological) have been
found to modulate cilium length. The regulators of cilium
length can be divided into two classes: intrinsic and extrinsic.
Intrinsic factors refer to those initiated by any molecules inside
the cell, and extrinsic factors point to those from the extracellular environment, while extrinsic factors most likely regulate
cilium length by affecting the intrinsic ones. The intrinsic
factors can be subclassified as structural and signaling molecules. Kif3a and Pitchfork are two typical examples of the
former molecules. Kinzel et al. (90) found that Pitchfork
regulates primary cilium disassembly, probably through activating Aurora A. Haploinsufficiency of Pitchfork leads to
left-right asymmetry, heart failure, and more importantly, node
cilia duplication phenotype. Among the cilium-signaling molecules, calcium and cAMP are two key players in determining
cilium length. Besschetnova et al. (21) reported that forskolin
and gadolinium can increase cilium length almost twofold in 3
h by activating adenylyl cyclase and decreasing intracellular
calcium and subsequent PKA activation in mIMCD3, MEK,
and bone mesenchymal cells. Three kinase members of the
NIMA family (Nek1, 4, 8) have been known to regulate cilium
length. Interestingly, loss of Nek1 shortens cilia in mice
whereas loss of Nek8 results in excessively long cilia (39, 188,
195).
Researchers have used different approaches to treat cultured
cells or animals and then defined the effect on cilium length.
Deflection of the primary cilium by fluid shear stress can
shorten its length and consequently ameliorate mechanosensitivity, which coincides with the observations seen with mutated
ADPKD gene products, PC1 or PC2 (123, 132). Miyoshi et al.
(123) showed that lithium elongates primary cilia in the mouse
brain and in cultured NIH3T3 and neuronal cells. Simultaneously, Ou et al. (143) independently found that lithium can
elongate the primary cilium length in FLS cells, rat PC12 cells,
and human astrocytes and suggested that lithium elongates
cilium length partially by the inhibition of adenylyl cyclase III
(ACIII) and reduction of the cAMP level. Ouabain, the inhibitor of Na-K-ATPase, at a concentration of 10 nM, promotes
ciliogenesis in an ERK1/2-dependent manner (101). Based on
the observation that primary cilium length is increased in
osteoarthritis, Wann and Knight (209) tested the effect of
interleukin-1 (IL-1) on cilium length and found that fibroblasts
and chondrocytes exhibited a significant increment in cilium
length after incubation with IL-1. They further identified that
this elongation depended upon protein kinase A.
If axoneme structure maintenance is the physical basis for
cellular function, ciliary membrane proteins are essential for
many signaling pathways. It has been known that a number of
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CILIA IN KIDNEY INJURY
Fig. 2. Wnt signaling pathway in the primary cilia. Binding of Wnt to Frizzled3
stabilizes ␤-catenin, which translocates to the nucleus and activates target
genes with TCF/LEF by the canonical pathway. Instead of ␤-catenin, Dishevelled2 transmits signals to small GTPase or inositol 1,4,5-trisphosphate (IP3)
receptor by the noncanonical pathway, which regulates the cytoskeleton and
calcium respectively. ER, endoplasmic reticulum.
As early as 2003, the Hedgehog signaling pathway was
connected to the cilium. Huangfu et al. (76) performed genetic
screening and identified that Wimple, Polaris, and Kif3a are
required for Hedgehog signaling in mice, and the Wimple gene
was shown to be IFT172 (67). Subsequent experiments done
by many groups showed that key Hedgehog components
(Patched1, Smo, Gli, and Sufu) are all enriched in the cilia
and/or basal body (44, 72, 166) (Fig. 3). In the absence of
Hedgehog molecules, Gli proteins are inhibited by the cytoplasmic form of SuFu (Suppressor of Fused). With Hedgehog
stimulation, the Gli-SuFu protein complex is quickly recruited
to the cilia proximal to Smo and Gli proteins are released to
enter into the nucleus to activate certain genes (199). Furthermore, Sufu controls the protein levels of Gli by antagonizing
the activity of Spop, a conserved Gli-degrading factor. Interestingly, regulation of Gli by SuFu is cilium independent (36).
In mammalian cells, Smo translocation to the primary cilia is
necessary for Smo-dependent signaling. With knockdown of
Arrestin, it was found that Smo failed to traffic to the primary
cilia and Smo-dependent activation of Gli was prevented,
suggesting that Arrestin plays a significant role in Hedgehog
signaling (95). Very recently, IFT25 was also shown to be
essential for movement of Hedgehog components (88). Interestingly, the IFT80 trap mouse exhibits short rib polydactyly
syndrome and abnormality of Hedgehog signaling without
malformation of cilia (165).
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signaling through PC2 upon fluid flow. Furthermore, PC2 can
regulate calcium signaling through genetic or biochemical
interactions with other molecules such as FPC (208), the
inositol 1,4,5-trisphosphate receptor (107), CAML (131), and
CAMK-II (170). It has been known that PC2 can form a
channel protein complex with TRPC1/TRPV4 on the primary cilia (10). Because depletion of TRPV4 abolishes flowinduced calcium transients, TRPV4 was considered to be an
essential component of the renal ciliary mechanosensor (94).
Clearly, the presence of cilia is required for calcium signaling
in ARPKD collecting duct cells (183).
Wnt signaling. The Wnt signaling pathway is best known for
its significant roles in embryonic development and cancer (15).
Nineteen WNT and 10 Frizzled genes have been found in
humans, and the encoded Wnt proteins comprise a large group
of secreted proteins of ⬃40 kDa in size (31). Based upon the
effect pattern, the Wnt signaling pathway can be classified into
the canonical and noncanonical types. The canonical signaling
pathway exerts its roles via Wnt-Frizzled-Dishevelled-␤catenin-TCF/LEF, while the noncanonical signaling pathway
functions through either Wnt-Frizzled-Dishevelled-small GTPase-cytoskeleton or Wnt-Frizzled-Dishevelled-inositol 1,4,5trisphosphate (IP3)-calcium (15). In the canonical pathway,
binding of Wnt proteins to Frizzleds induces phosphorylation
of Dishevelled, which prevents ␤-catenin from phosphorylation by either GSK-3 and/or casein kinase 1. Consequently,
stabilized ␤-catenin triggers downstream effects by translocation to the nucleus and complexes with LEF/TCF (Fig. 2). In
the noncanonical pathway, instead of ␤-catenin, Dishevelled
transmits its signals to downstream protein targets and then
regulates small GTPases such as Rho, Rac, and Cdc42, or
IP3/calcium (Fig. 2).
Several lines of evidence have revealed that the Wnt signaling pathway is coupled to cilia. Probably the earliest report
about cilia and Wnt is from the study of Inversin, mutations of
which lead to both NPHP and situs inversus (142). It has been
identified that several Wnt signaling members [Frizzled3, Dishevelled2, adenomatous polyposis coli (APC), ␤-catenin,
GSK-3␤, Vangl2] are located to the cilia, suggesting that both
canonical and noncanonical Wnt signaling cascades can occur
in the ciliary area (113, 148, 169, 196). Mice with knockout of
a few ciliary proteins (Kif3a, Tg737, BBS1, 4, 6) showed
abnormal ␤-catenin level and the dysfunctional canonical Wnt
responses (45, 64, 110). The PCP effector proteins Inturned
and Fuzzy function importantly in cilia formation and orientation and apical actin assembly (147, 222). All these experiments point to the association of cilia and Wnt signaling.
However, it is unknown why the IFT88 mutation in zebrafish
displays no cilia but normal Wnt signaling (75).
Hedgehog signaling. Hedgehog signaling was originally
identified by Nusslein-Volhard and Wieschaus (137) and later
was proven to be essential in cell proliferation and embryo
development. Basically, Hedgehog proteins consist of three
kinds of secreted molecules, i.e., Sonic Hedgehog, Indian
Hedgehog, and Desert Hedgehog. The best studied is Sonic
Hedgehog signaling. Sonic Hedgehog binds to the Hedgehog
receptor Patched, which relieves the downstream inhibition of
Smo. This then activates the Gli transcription factor. Subsequently, activated Gli trafficking to the nucleus regulates the
transcription of Hedgehog target genes.
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Fig. 3. Hedgehog signaling pathway in the primary cilia. In the absence of
Hedgehog, Smo is suppressed by an unclear mechanism. After Hedgehog
binding to Patched1, Smo is activated and subsequently facilitates the formation of active form of Gli, which enters the nucleus to regulate target genes.
SuFu and Spop are all involved in Gli trafficking and stability.
Notch signaling. Notch signaling is best known for cell-cell
communications. In mammals, Notch refers to four different
kinds of receptors, from Notch1 to Notch4. The Notch receptor
is a single transmembrane protein containing a large extracellular portion associated with calcium, a single membrane pass,
and a short intracellular fragment. Notch protein can undergo a
series of cleavages upon binding to its ligands. One of the
cleaved forms enters into the nucleus to regulate gene expression. It has been reported that the Notch signaling pathway
regulates left-right asymmetry by cilium length control and
plays a key role in cilium length adjustment (98, 111). Lopes
et al. (111) found that in deltaD zebrafish mutants, the cilium
length in Kupffer’s vesicle is decreased but can be restored by
Foxj1a, while cilium length increases if Notch signaling is
overactivated. In Tg737 and Kif3a mutant embryos, there are
defects of Notch signaling and cell differentiation that can be
rescued by activated Notch. Furthermore, Notch receptors are
located in cilia. All these findings suggest the roles of primary
cilia in the nexus of signaling, proliferation, and differentiation
(53). Apart from the primary cilia, Notch signaling regulates
multiple cilia formation and controls the balance of ciliated and
secretory cell fates in developing airways (116, 197).
Mammalian target of rapamycin signaling. The mammalian
target of rapamycin (mTOR) was identified in 1994 by Sabatini
et al. (171). mTOR is a serine/threonine protein kinase that is
responsible for a number of cellular functions such as cell
growth, proliferation, and survival. By binding to different
protein partners, mTOR forms rapamycin-sensitive (mTORC1)
and -insensitive (mTORC2) complexes. mTORC1 regulates
Role of Cilia in Cell Polarity and Planar Cell Polarity
Recent studies have shown that cilia play important roles in cell
and planar cell polarity (PCP) and left-right asymmetry (73). In
epithelial cells, there are three major cell polarity protein complexes, i.e., Polarity protein (Par), Crumbs, and Scribble (29).The
former two complexes define the apical polarity of the cell, and
the latter one functions at the basolateral surface. Pars have been
recognized as the fundamental players in animal cell polarity, in
coordination with atypical protein kinase C (PKC) and CDC42.
Fan et al. (55) reported that Par3, Par6, Crumbs3, atypical PKC␰,
and 14-3-3␩ are all localized in the primary cilia of MDCK and
IMCD3 cells by immunostaining and GFP-tagged target protein
expression. They also found that Crumbs3, atypical PKC␰, and
14-3-3␩ are all required for ciliogenesis. Furthermore, they
showed that Crumbs3 regulates ciliogenesis by an interaction with
Importin ␤ (54). These findings provided convincing evidence of
cellular polarity roles in ciliogenesis.
Unlike single-cell polarity, PCP involves a complex coordination of a group of cells. The best studied organism is
Drosophila, from which many signaling pathways, such as
Wnt, Hedgehog, Notch, and small GTPases, were elucidated
and found to regulate PCP (41, 57, 58, 87). Recent work
regarding cilia and PCP in cystic kidney diseases has drawn
much attention (60, 113, 150). By using Pck rats and HNF1␤deficient mice, Fischer et al. (60) found a distorted mitotic
orientation before the onset of cystogenesis in the kidney and
suggested that PCP is responsible for PKD. This discovery was
further confirmed by two other groups (113, 150). In one study,
Patel et al. (150) examined tubular regeneration in Kif3a
mutant mice by inducing acute kidney injury and found that the
loss of cilia does not promote cell proliferation but causes
aberrant PCP in the precystic tubules. They concluded that
primary cilia are essential for the maintenance of PCP, and
cystic kidney disease is exacerbated by acute kidney injury.
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transcription and protein synthesis through downstream S6
kinase and 4EBP1, and mTORC2 exerts its roles by Akt, Rac1,
protein kinase C, and cytoskeleton (114). The detailed subcellular localization of mTOR family members is largely unclear
except that Hamartin (TSC1) was localized to the basal body of
the primary cilia (71). It was reported that primary cilia
regulate mTORC1 activity by Lkb1 (25). Indeed, the most
intensive studies about primary cilia and mTOR in the kidney
field lie in the PKD-associated proteins (212). It was found that
the loss of primary cilia is involved in cystogenesis and kidney
hypertrophy signaling (17), and PC1 suppresses mTOR activity through regulation of Tuberin localization (50). Furthermore, mTOR inhibitors are effective for the treatment of PKD
in animal models (109). Very recently, CCDC28B, a BardetBiedl syndrome-related protein, was reported to interact with
SIN1 and modulate mTORC2 function (32).
Others. The evidence from the zebrafish study raised the
possibility that FGF signaling regulates cilium length, since
knockdown of Fgfr1 causes short cilia in Kupffer’s vesicles
(134). Christensen et al. (37) summarized the relationship of
primary cilia and receptor tyrosine kinases. PDGFR␣ has
previously been located to the primary cilia, and in growtharrested fibroblasts primary cilia coordinate PDGFR␣-mediated cell migration (174). Furthermore, NHE1 is required for
cell migration stimulated with PDGFR␣ (175).
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CILIA IN KIDNEY INJURY
Cilia and Kidney Injury
The earliest report linking kidney injury and cilia is, to our
knowledge, the study by Verghese et al. (203). By studying the
relationship between kidney injury and cystogenesis in a mu-
rine Pkd1 model, Takakura et al. (192) found that inactivation
of Pkd1 in the adult kidney increased cellular susceptibility to
ischemic injury, which promoted cystogenesis although the
cilium length in Pkd1 mutant mice was unknown. The contribution of kidney injury to cystogenesis was also confirmed in
a Pkd1 haploinsufficiency model by Bastos et al. (14) and in
Pkd2 heterozygous kidneys, in which more neutrophils and
macrophages were detected, followed by interstitial inflammation and fibrosis (159). Zhou et al. (224) further explored the
mechanism of cystogenesis underlying kidney injury by use of
Cys1cpk/cpk mice. They found that induction of heme oxygenase (HO) ameliorated both kidney injury and cystogenesis
while inhibition of HO enhanced cystogenesis. Furthermore,
component 3 strongly correlated with cystogenesis. All these
findings confirmed that kidney injury does play a certain role in
cystogenesis, although insightful detailed mechanisms are not
fully clear.
Since cilium length regulation and kidney injury bear some
common characteristics in cell proliferation, differentiation,
and cell death, it would be intriguing to investigate the functional roles of cilia in injured kidneys. Verghese et al. (202,
203) have studied cilium length of kidney tubular epithelial
cells in both humans and mice. After ischemia-reperfusion
kidney injury in mice, the average length of renal cilia in the
proximal tubule decreased at days 1 and 2 (⬃3 ␮m) compared
with the control (⬃4 ␮m). During the kidney repair stage at
days 4 and 7, the average length of cilia increased in both
proximal (⬃6 ␮m day 7) and distal tubule/collecting duct
(⬃5.5 ␮m day 7). In a unilateral ureteral obstruction model, at
day 8 cilium length in the distal tubule/collecting duct was also
lengthened. Thus it was proposed that cilia may play important
Table 2. Cilia formation and maintenance-associated factors
Factors (References)
Intrinsic
ACIII (143)
AurA (161)
cAMP (2, 21)
Cdc42 (226)
Cep131 (214)
Collectrin (223)
Dlic1 (92)
DYX1C1 (34)
Filamin A (3)
HDAC6 (161)
IFT54/DYF-11/TRAF3IP1 (18)
IFT140 (84)
Iqub (100)
Klp-6 (128)
MAP4 (65)
Nek1 (195)
Nrk2p (216)
OFD1 (59)
Ptpdc1 (100)
RP1 (139)
Tctex-1 (144)
Torc1 (221)
TTLL3 (217)
Extrinsic
Cytochalasin D (180)
Interleukin-1 (209)
Ouabain (101)
Taxol (180)
ACTR3 (89)
BBS9 (201)
Cc2d2a (63)
Cep41 (102)
CEP135/BLD10 (33)
D2lic (26)
DR5 (2)
EB1 (177)
FOP (103)
HFH-4 (35)
IFT70 (56)
INPP5E (42)
KIF3A (118)
LF2p (6, 194)
mC21orf2 (100)
Nek4 (39)
Nrk17p (216)
PHLP2 (28)
Rab GTPase (220)
S6K1 (221)
Tctn1 (63)
Traf3ip (18)
VDAC (115)
Arl-3 (106)
Bromi (91)
CCDC28B (32)
Cep70 (214)
CLUAP1 (149)
Daf-19 (156)
Dyf-5 (30)
EB3 (177)
Fuzzy (147)
HSP90 (160)
IFT88 (153)
Inturned (147, 222)
KIF3B (136)
LF4p (6, 19)
Meckelin (47)
Nek8 (186, 188)
Nrk30p (216)
Pitchfork (90)
Rer1p (86)
Septin (65)
Tctn2 (63)
TSC1 (71, 221)
Arl-13 (106)
Ca⫹2 (21)
Cdc14b (38)
Cep89/Cep123 (181)
Cnk2p (27)
DCDC2 (119)
Dynein-2 (5, 164)
FGFR1 (134)
GSK3␤ (123, 215)
IFT46 (100)
VDAC
LmxMKK (213)
Kinesin-13 (24, 48)
MAK (139)
MIM (20)
Nphp-8 (151)
OCRL1 (43)
PKC (2)
RFX3 (4)
Ssa2 (100)
Tmem67 (63)
TSC2 (71)
Forskolin (180)
Jasplakinolide (180)
LY294002 (129, 178, 200, 225)
Potassium-bromated (163)
U0126 (2, 178, 207)
Gadolinium (21)
KCl (123)
Hypoxia (204)
Li2CO3, LiCl (123, 143)
Ochratoxin A (163)
Rapamycin (221)
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Another study by Luyten et al. (113) is in line with the
observation of aberrant regulation of PCP in PKD. It is wroth
noting that Nishio et al. (135) did not find that precystic tubular
cells in Pkd1 and Pkd2 knockout mice lost oriented division
but found that distorted orientation of cells in Pkhd1 mice
occurred, which did not develop into kidney cysts. We do not
know exactly what causes this difference, but different animal
models are one factor to be considered.
Inversin, a protein mutated in nephronophthisis type II, has
been regarded to play a molecular switch role between canonical
and noncanonical Wnt signaling (182). The researchers found that
inversin degrades cytoplasmic Dishevelled to inhibit the canonical
Wnt pathway and is necessary for convergent extension in X.
laevis embryos, which is regulated by noncanonical Wnt signaling. Furthermore, in Xenopus, inversin suppresses Dishevelledinduced axis duplication. Ross et al. (169) recently knocked out
BBS protein in mice and found disrupted cochlear stereociliary
bundles. They further provided evidence showing the genetic
interaction between the PCP gene Vangl2 and the BBS genes. All
these findings suggest that cilia are involved in PCP signaling. In
a special form of PCP, i.e., left-right asymmetry, nodal cilia have
been studied in detail (9, 69). Many proteins have been localized
to the nodal cilia, and mutant mice exhibit left-right patterning
defects (120). Interestingly, in mice with mutations of a few of the
PCP genes, such as Fz3/6, Vangl1, Vangl2, and Dvl1/2, ciliogenesis seems normal (85, 190).
Review
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CILIA IN KIDNEY INJURY
very recently found that Erk1/2 regulates cilia length in renal
tubular cells and endothelial cells. The relationship between
cilia and many more kidney injury-associated molecules needs
to be further elucidated.
Conclusions and Perspectives
Taken together, we conclude that the primary cilium is an
important organelle responsible for integrative signaling from
outside cues to normal physiological functions of cells. Mutations of ciliary proteins cause different kinds of human diseases
displaying a diversity of clinical features. Probably a larger
spectrum of human ciliopathic diseases is related to primary
cilia than expected originally.
However, a large number of questions remain to be answered. One basic question is why a majority of, but not all,
cells grow cilia. Although different approaches have been used
to study the composition of cilia or flagella in different model
organisms (8, 12, 23, 141, 152), we have just begun to know
the composition of primary cilia (82). With regard to cilia and
kidney injury, the key question is the role of primary cilia
during kidney injury and recovery stages. Once the detailed
mechanisms are determined, we can design different strategies
to interfere with the process of kidney injury recovery in
animal models by regulating cilia-associated signaling pathways. It is expected that studies on cilia and kidney injury will
shed light on identifying novel mechanisms that can be translated into clinical treatment.
GRANTS
This work was supported in part by the National Basic Research Program
of China 973, Program No. 2012CB517600 (No. 2012CB517606) and grants
from the National Institutes of Health and US Department of Veterans Affairs.
DISCLOSURES
No conflicts of interest, financial or otherwise, are declared by the authors.
AUTHOR CONTRIBUTIONS
Author contributions: S.W. and Z.D. provided conception and design of
research; S.W. prepared figures; S.W. and Z.D. drafted manuscript; S.W. and
Z.D. edited and revised manuscript; S.W. and Z.D. approved final version of
manuscript.
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